KR102266691B1 - 항원 전달 플랫폼 - Google Patents

항원 전달 플랫폼 Download PDF

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KR102266691B1
KR102266691B1 KR1020207027706A KR20207027706A KR102266691B1 KR 102266691 B1 KR102266691 B1 KR 102266691B1 KR 1020207027706 A KR1020207027706 A KR 1020207027706A KR 20207027706 A KR20207027706 A KR 20207027706A KR 102266691 B1 KR102266691 B1 KR 102266691B1
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안더스 릴리아
레베카 루미스
마이클 프란티
피터 메이슨
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Abstract

본 개시 내용은 세포에 헤르페스바이러스 단백질, 특히 생체 내에서 복합체를 형성하는 단백질의 전달에 대한 플랫폼을 제공한다. 일부 구체예에서, 그것들이 형성하는 이 단백질 및 복합체는 효능 있는 중화 항체를 유도한다. 따라서, 개시된 플랫폼을 사용하는 헤르페스바이러스 단백질의 제공은 백신 개발에 유용한 광범위하고 효능 있는 면역 반응의 발생을 허용한다.

Description

항원 전달 플랫폼{ANTIGEN DELIVERY PLATFORMS}
관련 출원
이 출원은 2010년 10월 11일 출원된, 미국 가특허 출원 번호 61/391, 960의 이익을 주장하며, 이것의 전체 교시 내용은 본원에 참고로 포함된다.
배경기술
헤르페스바이러스는 널리 퍼져있고 최악의 경우에, 주로 면역력이 약화된 개인 (예를 들어, 이식 수령체 및 HIV-감염된 개인)에서, 실질적인 발병률 및 사망률로 이어질 수 있는 사람에서 다양한 질환을 유발한다. 사람은 적어도 8 가지의 헤르페스바이러스에 의한 감염에 민감하다. 단순 헤르페스바이러스-1 (Herpes simplex virus-1; HSV-1, HHV-1), 단순 헤르페스바이러스-2 (Herpes simplex virus-2; HSV-2, HHV-2) 및 수두 대상 포진 바이러스 (Varicella zoster virus; VZV, HHV-3)는 알파-서브패밀리 바이러스이고, 시토메갈로바이러스 (cytomegalovirus; CMV, HHV-5) 및 로세올로바이러스 (Roseolovirus; HHV-6 및 HHV-7)는 베타-서브패밀리 바이러스이고, 엡스타인-바 바이러스 (Epstein-Barr virus; EBV, HHV-4) 및 카포시 육종-관련 헤르페스바이러스 (Kaposi's sarcoma-associated herpes virus; KSHV, HHV-8)는 사람을 감염시키는 감마-서브패밀리 바이러스이다.
CMV 감염은 면역력이 약화된 개인 (예를 들어, 이식 수령체 및 HIV-감염된 개인)에서 실질적인 발병률 및 사망률로 이어지고 선천적 감염은 신생아의 신경 발달에 치명적 결함을 발생시킬 수 있다. CMV 외피 당단백질 gB, gH, gL, gM 및 gN은 그것들이 바이러스 표면 상에 발현되고 보호 바이러스-중화 체액성 면역 반응을 유도할 수 있기 때문에 매력적인 백신 후보물질을 나타낸다. 일부 CMV 백신 전략은 주요 표면 당단백질 B (gB)를 표적화하였으며, 이것은 우성 항체 반응을 유발할 수 있다 (Go and Pollard, JID 197: 1631-1633 (2008)). CMV 당단백질 gB는 중화 항체 반응을 유발할 수 있고, CMV-양성 환자의 혈청에서 섬유아세포의 감염을 중화시키는 항체의 큰 분획은 gB로 향한다 (Britt 1990). 유사하게, gH 및 gM/gN은 자연 감염에 대한 면역 반응의 표적이다 (Urban et al (1996) J. Gen. Virol. 77 (Pt. 7): 1537-47; Mach et al (2000) J. Virol. 74(24): 11881-92).
CMV 단백질의 복합체는 또한 그것들이 바이러스의 생활 주기에서 중요한 과정에 수반되는 것으로 보이기 때문에 매력적인 백신 후보물질이다. 예를 들어, gH/gL/gO 복합체는 섬유아세포 및 상피/내피 세포 유입에 중요한 역할을 갖는 것으로 보인다. 일반적인 모델은 gH/gL/gO 복합체가 섬유아세포의 감염을 매개한다는 것을 제안한다. hCMV gO-눌 (null) 돌연변이는 섬유아세포 상에 작은 플라크 및 아주 낮은 역가의 바이러스를 생성하며, 유입시 역할을 나타낸다 (Dunn (2003), Proc. Natl. Acad. Sci. USA 100:14223-28; Hobom (2000) J. Virol. 74:7720-29). 최근 연구는 gO가 gH/gL을 갖는 비리온에 포합되지 않지만, 분자 샤페론 (chaperone)으로 작용할 수도 있으며, ER에서 골지체로의 gH/gL 유출 및 비리온에 포함을 증가시킨다는 것을 제안한다 (Ryckman (2009) J. Virol 82:60-70). 파동 추적 실험 (pulse-chase experiment)을 통해, 소량의 gO가 장기간 동안 gH/gL에 결합된 것을 유지하지만 그것이 세포 외 비리온에서 발견되지 않거나 세포 내로부터 분비되지 않기 때문에, 대부분의 gO는 gH/gL/gO 복합체와 분리되고 및/또는 이로부터 분해된다는 것으로 나타났다. gO가 CMV의 임상적 균주 (TR)로부터 삭제되었을 때 그들 바이러스 입자들은 비리온에 포함된 gH/gL의 양을 크게 감소시켰다. 추가적으로, TR 바이러스로부터 삭제된 gO는 또한 상피 및 내피 세포 내로의 유입을 억제하였으며, gH/gL이 또한 상피/내피 세포 유입에 필요하다는 것을 제안한다 (Wille (2010) J. Virol. 84(5):2585-96).
CMV gH/gL은 또한 UL128, UL130, 및 UL131A (여기에서 UL131로 나타남)와 연관될 수 있고 상피 세포, 내피 세포, 수지상세포를 포함하는, 다수의 세포 타입으로의 유입에 필요한 펜타머 복합체를 형성한다 (Hahn et al (2004) J. Virol. 78(18): 10023-33; Wang and Shenk (2005) Proc. Natl. Acad. Sci USA 102(50): 18153-8; Gerna et al (2005). J. Gen. Virol. 84(Pt 6): 1431-6; Ryckman et al (2008) J. Virol. 82:60-70). 반대로, 이 복합체는 섬유아세포의 감염에 필요하지 않다. 연구실 hCMV 분리체는 UL128-UL131 자리에 돌연변이를 갖고 있고, 돌연변이는 배양된 섬유아세포의 단지 몇 번의 계대 후 임상 분리체에서 발생한다 (Akter et al (2003) J. Gen. Virol. 84(Pt 5): 1117-22). 자연 감염 동안, 펜타머 복합체는 매우 높은 효능으로 상피 세포, 내피 세포 (및 펜타머 복합체가 바이러스의 유입을 매개하는 일부 다른 세포 타입)의 감염을 중화시키는 항체를 유도한다 (Macagno et al (2010) J. Virol. 84(2): 1005-13). 또한 이 복합체에 대한 항체는 사람 혈청의 상피 세포의 감염을 중화시키는 능력에 크게 기여하는 것으로 보인다 (Genini et al (2011) J. Clin. Virol. 52(2): 113-8).
US 5,767,250은 gH 및 gL을 함유하는 특정 CMV 단백질 복합체를 만드는 방법을 개시한다. 복합체는 gH 및 gL이 동시발현되도록 gH를 암호화하는 DNA 구조 및 gL을 암호화하는 DNA 구조물을 세포 내로 도입함으로써 생성된다.
WO 2004/076645는 CMV 단백질을 암호화하는 재조합 DNA 분자를 설명한다. 이 문서에 따라, 다른 CMV 단백질을 암호화하는 별개의 DNA 분자의 조합이 암호화된 CMV 단백질의 동시발현을 유발하도록 세포 내로 도입될 수 있다. gM 및 gN이 이 방법으로 동시발현되었을 때, 그것들은 이황화 결합 복합체를 형성하였다. gM/gN 복합체를 생산하는 DNA 구조물 또는 gB를 암호화하는 DNA 구조물로 면역화된 토끼는 등량의 중화 항체 반응을 생산하였다.
둘 이상의 헤르페스바이러스 단백질을 암호화하는 핵산에 대한, 같은 세포에서 둘 이상의 헤르페스바이러스 단백질을 발현하는 방법에 대한, 및 더 양호한 면역 반응을 생산하는 면역화 방법에 대한 필요가 존재한다.
본 발명은 세포에 둘 이상의 헤르페스 단백질, 특히 생체 내에서 복합체를 형성하는 단백질, 예를 들어, 시토메갈로바이러스 (CMV) 단백질의 동시전달을 위한 플랫폼과 관련된다. 한 양태에서, 본 발명은 첫 번째 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편을 암호화하는 첫 번째 서열, 및 두 번째 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편을 암호화하는 두 번째 서열을 함유하는 재조합 폴리시스트론성 핵산 분자이다.
예를 들어, 본 발명은 a) 헤르페스바이러스의 첫 번째 단백질 또는 이들의 단편을 암호화하는 첫 번째 뉴클레오티드 서열; 및 b) 헤르페스바이러스로부터 두 번째 단백질 또는 이들의 단편을 암호화하는 두 번째 뉴클레오티드 서열을 포함하는 폴리뉴클레오티드를 포함하는 자가 복제 RNA 분자를 제공한다. 첫 번째 뉴클레오티드 서열 및 두 번째 뉴클레오티드 서열은 자가 복제 RNA 분자가 적합한 세포 내로 도입될 때, 첫 번째 및 두 번째 헤르페스바이러스 단백질 또는 이들의 단편이 첫 번째 및 두 번째 단백질 또는 단편을 함유하는 세포에서 복합체의 형성에 충분한 양으로 생산되도록 하나 이상의 조절 요소와 작동 가능하게 연결된다. 바람직하게, 첫 번째 단백질 및 두 번째 단백질은 같은 단백질 또는 같은 단백질의 단편이 아니고, 첫 번째 단백질은 두 번째 단백질의 단편이 아니고 두 번째 단백질은 첫 번째 단백질의 단편이 아니다. 첫 번째 뉴클레오티드 서열은 첫 번째 조절 요소와 작동 가능하게 연결될 수 있고 두 번째 뉴클레오티드 서열은 두 번째 조절 요소와 작동 가능하게 연결될 수 있다.
자가 복제 RNA 분자는 상기 헤르페스바이러스의 세 번째 단백질 또는 이들의 단편을 암호화하는 세 번째 뉴클레오티드 서열, 임의로 상기 헤르페스바이러스의 네 번째 단백질 또는 이들의 단편을 암호화하는 네 번째 뉴클레오티드 서열; 및 임의로 상기 헤르페스바이러스의 다섯 번째 단백질 또는 이들의 단편을 암호화하는 다섯 번째 뉴클레오티드 서열을 추가로 포함할 수 있다. 헤르페스바이러스의 추가적 단백질 또는 단편을 암호화하는 서열 (즉, 세 번째, 네 번째 및 다섯 번째 뉴클레오티드 서열)이 존재할 때, 그것들은 하나 이상의 조절 요소와 작동 가능하게 연결된다. 펜타시스트론성 구조물의 한 예에서, 첫 번째 뉴클레오티드 서열은 첫 번째 조절 요소와 작동 가능하게 연결되고, 두 번째 뉴클레오티드 서열은 두 번째 조절 요소와 작동 가능하게 연결되고, 세 번째 뉴클레오티드 서열은 세 번째 조절 요소와 작동 가능하게 연결되고, 네 번째 뉴클레오티드 서열은 네 번째 조절 요소와 작동 가능하게 연결되고, 다섯 번째 뉴클레오티드 서열은 다섯 번째 조절 요소와 작동 가능하게 연결된다. 구조물에 존재하는 조절 요소 (예를 들어, 첫 번째, 두 번째, 세 번째, 네 번째 및 다섯 번째 조절 요소)는 서브게놈 프로모터, IRES, 및 바이러스 (예를 들어, FMDV) 2A 부위로 구성된 그룹으로부터 독립적으로 선택될 수 있다.
헤르페스바이러스는 HSV-1, 1, HSV-2, VZV, EBV 타입 1, EBV 타입 2, CMV, HHV-6 타입 A, HHV-6 타입 B, HHV-7 및 HHV-8일 수 있다. 일부 구체예에서, 재조합 폴리시스트론성 핵산 분자 (예를 들어, 자가 복제 RNA)는 이 헤르페스바이러스 중 어느 하나의 gH 또는 이들의 단편 및 gL 또는 이들의 단편을 암호화한다. 더 특정 구체예에서, 헤르페스바이러스는 CMV 또는 VZV이다.
재조합 폴리시스트론성 핵산 분자 (예를 들어, 자가 복제 RNA)가 둘 이상의 VZV 단백질을 암호화할 때, 단백질은 gB, gE, gH, gI, gL 및 이들의 단편 (예를 들어, 적어도 10개의 아미노산 중)으로 구성된 그룹으로부터 선택될 수 있다. 일부 구체예에서, 재조합 폴리시스트론성 핵산 분자 (예를 들어, 자가 복제 RNA)는 VZV gH 또는 이들의 단편 및 VZV gL 또는 이들의 단편을 암호화한다.
특정 예에서, 본 발명은 a) 첫 번째 시토메갈로바이러스 (CMV) 단백질 또는 이들의 단편을 암호화하는 첫 번째 서열; 및 b) 두 번째 CMV 단백질 또는 이들의 단편을 암호화하는 두 번째 서열을 포함하는 폴리뉴클레오티드를 포함하는 자가 복제 RNA 분자를 제공한다. 첫 번째 서열 및 두 번째 서열은 자가 복제 RNA 분자가 적합한 세포 내로 도입될 때, 첫 번째 및 두 번째 CMV 단백질이 첫 번째 및 두 번째 CMV 단백질 또는 단편을 함유하는 세포에서 복합체의 형성에 충분한 양으로 생산되도록 하나 이상의 조절 요소와 작동 가능하게 연결된다.
첫 번째 CMV 단백질 및 두 번째 CMV 단백질은 gB, gH, gL; gO; gM, gN; UL128, UL130, UL131, 및 전술된 것들 중 어느 하나의 단편으로 구성된 그룹으로부터 독립적으로 선택된다. 바람직하게는, 첫 번째 CMV 단백질 및 두 번째 CMV 단백질은 같은 단백질 또는 같은 단백질의 단편이 아니며, 첫 번째, CMV 단백질은 두 번째 CMV 단백질의 단편이 아니고, 두 번째 CMV 단백질은 첫 번째 CMV 단백질의 단편이 아니다. 원하는 경우, 자가 복제 RNA 분자는 세 번째 CMV 단백질을 암호화하는 세 번째 서열을 추가로 포함할 수 있으며, 세 번째 서열은 조절 요소와 작동 가능하게 연결된다. 유사하게, 추가적 CMV 단백질을 암호화하는 추가적 서열 (예를 들어, 네 번째 CMV 단백질을 암호화하는 네 번째 서열, 다섯 번째 CMV 단백질을 암호화하는 다섯 번째 서열)이 포함될 수 있다. 조절 요소는 서브게놈 프로모터, 및 IRES, 및 바이러스 2A 부위로 구성된 그룹으로부터 독립적으로 선택될 수 있다.
일부 구체예에서, 자가 복제 핵산 분자는 CMV 단백질 gH 및 gL을 암호화한다. 다른 구체예에서, 자가 복제 RNA 분자는 CMV 단백질 gH, gL, 및 gO를 암호화한다. 다른 구체예에서, 자가 복제 RNA 분자는 CMV 단백질 gH, gL, UL128, UL130 및 UL131을 암호화한다.
자가 복제 RNA 분자는 알파바이러스 레플리콘일 수 있다. 이러한 예에서, 알파바이러스 레플리콘은 알파바이러스 레플리콘 입자 (VRP)의 형태로 전달될 수 있다. 자가 복제 RNA 분자는 또한 "노출 (naked)" RNA 분자의 형태일 수 있다.
본 발명은 여기에 설명된 바와 같dl 자가 복제 RNA 분자를 암호화하는 재조합 DNA 분자와 관련된다. 일부 구체예에서, 재조합 DNA 분자는 플라스미드이다. 일부 구체예에서, 재조합 DNA 분자는 암호화된 자가 복제 RNA 분자의 전사를 구동하는 포유동물 프로모터를 포함한다.
본 발명은 또한 여기에 설명된 바와 같dl 자가 복제 RNA 분자 및 약학적으로 허용 가능한 비히클을 포함하는 조성물과 관련된다. 자가 복제 RNA 분자는 "노출"될 수 있다. 일부 구체예에서, 조성물은 CMV 단백질 gH 및 gL을 암호화하는 자가 복제 RNA 분자를 포함한다. 다른 구체예에서, 조성물은 CMV 단백질 gB를 암호화하는 자가 복제 RNA 분자를 더 포함한다. 조성물은 또한 리포솜, 폴리머 나노파티클, 수중유 양이온성 나노에멀젼 또는 이들의 조합과 같은 RNA 전달 시스템을 함유할 수 있다. 예를 들어, 자가 복제 RNA 분자는 리포솜에서 캡슐화될 수 있다.
특정 구체예에서, 조성물은 둘 이상의 CMV 단백질을 암호화하는 알파 바이러스 레플리콘을 함유하는 VRP를 포함한다. 일부 구체예에서, VRP는 CMV gH 및 gL을 암호화하는 레플리콘을 포함한다. 원하는 경우, 조성물은 CMV gB를 암호화하는 레플리콘을 함유하는 두 번째 VRP를 추가로 포함할 수 있다. 조성물은 또한 보조제를 포함할 수 있다.
본 발명은 또한 CMV 단백질 복합체를 형성하는 방법과 관련된다. 일부 구체예에서, 둘 이상의 단백질을 암호화하는 자가 복제 RNA가 세포에 전달되고, 세포는 CMV 단백질의 발현에 적합한 조건 하에 유지되며, CMV 단백질 복합체가 형성된다. 다른 구체예에서, 둘 이상의 CMV 단백질을 암호화하는 자가 복제 RNA를 함유하는 VRP가 세포에 전달되고, 세포는 CMV 단백질의 발현에 적합한 조건 하에 유지되며, CMV 단백질 복합체가 형성된다. 방법은 생체 내 세포에서 CMV 단백질 복합체를 형성하기 위해 이용될 수 있다.
본 발명은 또한 개인의 면역 반응을 유발하는 방법과 관련된다. 일부 구체예에서, 둘 이상의 CMV 단백질을 암호화하는 자가 복제 RNA가 개인에게 투여된다. 자가 복제 RNA 분자는 리포솜과 같이, RNA 전달 시스템을 함유하는 조성물로서 투여될 수 있다. 다른 구체예에서, 둘 이상의 CMV 단백질을 암호화하는 자가 복제 RNA를 함유하는 VRP가 개인에게 투여된다. 바람직한 구체예에서, 자가 복제 RNA 분자는 CMV 단백질 gH 및 gL을 암호화한다. 바람직하게, 유발된 면역 반응은 중화 항-CMV 항체의 생산을 포함한다. 더 바람직하게는, 중화 항체는 보체-독립적이다.
본 발명은 또한 세포를 gH 및 gL과 같은 둘 이상의 CMV 단백질을 암호화하는 자가 복제 RNA 분자와 접촉시키는 단계를 포함하는, 세포 내로 CMV 유입을 억제하는 방법과 관련된다. 세포는 상피 세포, 내피 세포, 섬유아세포 및 이들의 조합으로 구성된 그룹으로부터 선택될 수 있다. 일부 구체예에서, 세포는 둘 이상의 CMV 단백질을 암호화하는 자가 복제 RNA를 함유하는 VRP와 접촉된다.
본 발명은 또한 면역 반응을 유발하기 위해 또는 세포 내로 CMV 유입을 억제하기 위해, 세포의 CMV 단백질 복합체를 형성하는 둘 이상의 CMV 단백질을 암호화하는 자가 복제 RNA 분자 (예를 들어, VRP, 자가 복제 RNA 분자 및 리포솜을 포함하는 조성물)의 이용과 관련된다.
도 1은 표적 세포 내로의 CMV 유입에 수반되는 알려진 당단백질 복합체를 확인하는 CMV의 개략도이다. 외피 당단백질은 그것들이 바이러스 표면 상에 발현되고 보호 및 지속성 바이러스-중화 체액 면역 반응을 유발할 수 있기 때문에 매력적인 백신 후보물질을 대표한다. 이 과정을 매개하는 구조 당단백질은 두 개의 클래스로 분류될 수 있다; 헤르페스바이러스 패밀리를 통해 보존되는 것들 및 그렇지 않은 것들. 보존되는 것들 중에는 gB, gH, gL, gM 및 gN이 있다. 이 당단백질 중 대부분은 바이러스 표면에 국부화을 용이하게 하고 바이러스의 부착, 유입 및 세포 융합시 그것들의 기능을 수행하기 위해 서로 복합체를 형성한다 (gH/gL/±gO; gH/gL/UL128/UL130/UL131; gM/gN).
도 2a-2f는 CMV 구조의 개략도이다. 도 2a, 실시예 1에서 설명된 gB 구조 ("gB FL", 전체 길이 gB; 가용성 gB "gB sol 750" 및 "gB sol 692")의 개략도. 두 개의 다른 가용성 버전의 gB가 구성되었다; gB sol 750은 막통과 스패닝 (spanning) 도메인 및 세포질 도메인이 없고, gB sol 692는 또한 소수성 영역이 없고 Reap et al. (2007) Clin. Vacc. Immunol. 14:748-55에 설명된 gB sol과 유사하다. 도 2b, 바이러스 복제 입자 (VRP)를 생산하기 위해 이용된 gB 레플리콘 벡터의 개략도. 도 2c, 실시예 1에서 설명된 gH 구조 ("gH FL", 전체 길이 gH; 가용성 gH "gH sol")의 개략도. 단일 가용성 버전의 gH가 구성되었으며 이것은 막통과 스패닝 도메인이 없다. 도 2d, VRP를 생산하기 위해 이용된 gH 레플리콘 벡터의 개략도. 도 2e, 실시예 1에서 설명된 gL 구조의 개략도. 도 2f, VRP를 생산하기 위해 이용된 gL 레플리콘 벡터의 개략도. 도 2b, 2d 및 2f에서, "NSP1", "NSP2", "NSP3", 및 "NSP4"는 각각 바이러스의 복제에 필요한 알파바이러스 비구조 단백질 1-4이다.
도 3a 및 3b는 gB (FL, sol 750, sol 692) 또는 gH (FL, sol) VRP로 면역화된 마우스가 기니피그 보체의 존재시 중화시키는 항체 반응을 유발하였다는 것을 나타낸다. ARPE-19 상피 세포의 감염 전에 마우스 혈청 및 기니피그 보체와 함께 CMV 바이러스 균주 TB40UL32E-GFP (이것은 향상된 녹색 형광 단백질-GFP를 암호화한다, Sampaio et al (2005) J. Virol. 79(5):2754-67)를 사전 배양함으로써 중화 검정을 수행하였다. 감염 5일 후, GFP 양성 세포의 수를 결정하였다. 도 3a, 보체의 존재시 ARPE-19 세포에서 분석된 모든 혈청에 대한 혈청 희석 곡선. 도 3b, 혈청 샘플에 대한 50% 중화 역가. 사전 면역 혈청과 함께 배양된 바이러스는 낮은 희석배수에서 낮은 중화를 수득하였다 (1:40-1:80). gB (FL, sol 750, sol 692) 혈청은 1:1800-1:2100에서 50% 중화 역가로 아주 강한 중화 활성을 갖고 있었다. 모든 gB 면역화된 마우스는 유사한 중화 프로파일을 수득하였다. gH (FL, sol) 혈청은 약 1:160에서 50% 중화 역가로 중화 활성을 가졌다. 실시예 1 참조.
도 4a는 녹색 형광 단백질 (GFP) 또는 적색 형광 단백질 (mCherry)를 암호화하는 모노시스트론성 레플리콘 및 GFP 및 mCherry를 암호화하는 바이시스트론성 레플리콘의 개략도이다. "NSP1", "NSP2", "NSP3", 및 "NSP4"는 각각 알파바이러스 비구조 단백질 1-4이다. 폴리시스트론성 알파바이러스 레플리콘 시스템은 원하는 유전자를 구동하는 다수의 서브게놈 프로모터를 수용하도록 기존 알파바이러스 레플리콘 시스템을 수정함으로써 설계되었다.
도 4b는 모노-및 바이시스트론성 RNA를 함유하는 VRP로 감염된 BHKV 세포의 FACS 분석을 나타내는 형광 발광 플롯이다. 폴리시스트론성 알파바이러스 VRP는 GFP VRP + mCherry VRP (26.30%)의 동시감염보다, 거의 같은 양으로 원하는 유전자 둘 다를 발현하는 더 많은 (GFP 및 mCherry; 72.48%) 세포를 수득한다. 실시예 2 참조.
도 5a는 gH/gL 및 gH/gL/gO를 암호화하는 폴리시스트론성 알파바이러스 레플리콘 구조의 개략도이다.
도 5b는 gH/gL가 시험관 내에서 복합체를 형성한다는 것을 나타낸다. gH, gL, gO, gH/gL 또는 gH/gL/gO를 암호화하는 레플리콘을 함유하는 VRP가 BHKV 세포에서 생산되었다. 결과의 VRP는 시험관 내에서 복합체 형성을 입증하기 위해 ARPE-19 세포를 감염시키는데 이용되었다. 알파바이러스 감염된 ARPE-19 세포는 gH 및 gL이 존재하는 동안 수확되었고 분석되었다. gH/gL을 암호화하는 VRP로 감염된 ARPE-19 세포는 gH/gL의 이황화 결합된 복합체를 생산하였다 (DTT의 부재시, 열 참조). gO는 gH/gL 결합을 검출 가능하게 변화시키지 않았다. 왼쪽 블롯은 gH 단백질의 발현을 나타낸다. 오른쪽 블롯은 gL 단백질의 발현을 나타낸다. 분자량 마커는 블롯들 사이에 표시된다. ● = 모노머 gH, ●● = 모노머 gL, < = 헤테로다이머 (gH + gL), * = 헤테로다이머의 다이머
도 5c는 VRP로 감염된 BHKV 세포의 gH 및 gH/gL 복합체의 면역 침강을 나타낸다. 면역 침강은 대조군 (레인 2, 4, 7, 및 10)으로 마우스 IgG 항체 또는 gH를 면역 침강하기 위해서 (레인 3, 5, 8, 및 11) 마우스 항-gH 항체 (Genway)를 이용하여 수행되었다. 웨스턴 블롯은 풀 (pool) 토끼 항-gL 항체 및 토끼 항-gH 항체를 이용하여 수행되었다. 레인 1, 6, 및 9는 참고로 gH 단백질 (75 kDa 정도의 높은 밴드) 및 gL 단백질 (30 kDa 정도의 낮은 밴드)를 나타낸다. 레인 2 및 3은 gH-VRP로 감염된 용해물이다. 레인 2는 대조군 항체가 gH를 면역 침강하지 않았다는 것을 나타낸다. 레인 3은 항-gH 항체가 gH를 면역 침강했다는 것을 나타낸다. 레인 4 및 5는 gL-VRP만으로 감염된 용해물이다. gH 단백질은 면역 침강되지 않았다. 레인 7 및 8은 바이시스트론성 gH/gL-VRP로 감염된 용해물이다. 레인 8은 gL이 gH 항체를 이용하여 면역 침강 되었다는 것을 나타낸다. (별표 참조). 레인 10 및 11은 트리시스트론성 gH/gL/gO-VRP로 감염된 용해물이다. 레인 11은 gL이 gH 항체를 이용하여 면역 침강 되었다는 것을 나타낸다. (별표 참조). 분자량 마커가 또한 나타난다 (MW). 실시예 3 참조.
도 6은 시험관 내에서 gH/gL 복합체 형성에 영향을 미치는 VRP가 gB VRP에 대한 반응보다 질적으로 및 양적으로 우수한 CMV에 대한 효능 있는 면역 반응을 유발한다는 것을 나타낸다. 도 6a 및 도 6b는 보체의 존재시 (도 6a) 또는 부재시 (도 6b) ARPE-19 세포의 TB40-UL32-EGFP 감염의 중화시 gH, gL, gO, gH + gL, gH + gL + gO, gH/gL 및 gH/gL/gO VRP-면역화된 마우스에 대한 혈청 희석 곡석을 나타낸다. 기니피그 보체의 존재시 또는 부재시 다양한 희석의 혈청은 TB40UL32E-GFP와 함께 사전 배양되었고 ARPE-19 상피 세포에 추가되었다. 바이러스로 감염 5일 후, GFP-양성 세포를 계산하였다. 도 6c는 보체의 존재시 또는 부재시 얻은 50% 중화 역가를 나타내는 그래프이다. "3wp3", 세 번째 면역화 3주 후. 단일 CMV 단백질을 발현하는 VRP (gH, gL, gO VRP 또는 동시투여된 gH, gL 및 gO VRP)는 gH 단독의 그것 너머로 중화 활성을 향상시키지 않았다. 반대로, 바이시스트론성 gH/gL 또는 트리시스트론성 gH/gL/gO VRP로 면역화된 마우스의 혈청은 효능 있는 중화 반응을 입증하였다. 게다가, 효능 있는 중화 반응은 기니피그 보체의 존재시 및 부재시 유사하였고, 폴리시스트론성 VRP는 성공적으로 보체-독립적인 면역 반응을 유발하였다는 것을 나타낸다. 실시예 4 참조.
도 7은 시험관 내에서 gH/gL 복합체 형성에 영향을 미치는 VRP가 MRC-5 섬유아세포의 감염을 효능있게 중화시키는 항체를 유발하였다는 것을 나타낸다. 도 7a는 보체의 부재시 MRC-5 세포의 gH, gL, gO, gH + gL, gH + gL + gO, gH/gL 및 gH/gL/gO VRP-면역화된 마우스에 대한 혈청 희석 곡선을 나타낸다. 다양한 희석의 혈청은 기니피그 보체의 존재시 또는 부재시 TB40GFP로 사전 배양되었고 MRC-5 섬유아세포에 추가되었다. 바이러스로 감염 5일 후, GFP-양성 세포를 계산하였다. 도 7b는 보체의 부재시 MRC-5 섬유아세포 모델에서 얻은 50% 중화 역가를 나타내는 그래프이다. "3wp3", 세 번째 면역화 3주 후. 단일 CMV 단백질을 발현하는 VRP (gH, gL, gO VRP 또는 동시투여된 gH, gL 및 gO VRP)는 gH 단독의 그것 이상으로 중화 활성을 향상시키지 않았다. 반대로 바이시스트론성 gH/gL 또는 트리시스트론성 gH/gL/gO VRP로 면역화된 마우스의 혈청은 매우 효능 있는 중화 반응을 입증하였다. 실시예 4 참조.
도 8a 및 8b는 폴리시스트론성 VRP의 전달에 의해 유발된 중화 항체가 항체를 교차-중화하였다는 것을 나타내는 그래프이다. gH/gL 및 gH/gL/gO VRP로 면역화된 마우스의 혈청은 IE-1 중화 검정시 기니피그 보체의 부재시 ARPE-19 상피 세포 (도 8a) 및 MRC-5 섬유아세포 (도 8b) 둘 다에서 CMV의 TB4OUL32E-GFP 및 VR1814 임상적 균주를 중화할 수 있었다.
도 9는 gH FL/gL에 대하여 유도된 중화 항체가 보체-독립적이고 역가에서 자연 면역력과 유사하다는 것을 나타내는 그래프이다. 마우스는 1 x 106 IU의 gB FL 또는 gH FL/gL VRP로, 최종 채혈 전 3주 간격으로 3번 면역화되었다. 혈청은 중화 검정에서 기니피그 보체의 존재시 및 부재시 ARPE-19 세포의 TB40UL32E-EGFP CMV 감염을 중화하는 능력에 대하여 분석되었다. gB에 의해 유도된 항체와 달리, gH FL/gL에 의해 유도된 항체는 보체-독립적이다. 게다가, 이 백신 접종된 마우스에서 gH FL/gL 항체는 자연 감염된 사람 대상체에서 발견된 것들에 대한 역가와 비슷했다.
도 10은 pVCR 변형된 gH-SGPgL-SGPgO에 대한 플라스미드 지도를 나타낸다.
도 11은 pVCR 변형된 gH-SGPgL에 대한 플라스미드 지도를 나타낸다.
도 12는 pVCR 변형된 gH sol-SGPgL에 대한 플라스미드 지도를 나타낸다.
도 13은 pVCR 변형된 gH sol-SGPgL-SGPgO에 대한 플라스미드 지도를 나타낸다.
도 14a-14g는 CMV 표면 당단백질 H (gH) 및 CMV 표면 당단백질 L (gL)을 암호화하는 A160 자가 복제 RNA 분자를 암호화하는 플라스미드의 뉴클레오티드 서열 (SEQ ID NO:83)을 나타낸다. gH 및 gL을 암호화하는 뉴클레오티드 서열은 밑줄쳐져 있다.
도 15a-15h는 CMV 표면 당단백질 H (gHsol) 및 CMV 표면 당단백질 L (gL)의 가용성 형태를 암호화하는 A322 자가 복제 RNA 분자를 암호화하는 플라스미드의 뉴클레오티드 서열 (SEQ ID NO:84)을 나타낸다. gHsol 및 gL을 암호화하는 뉴클레오티드 서열은 밑줄쳐져 있다.
도 16a-16h는 CMV 표면 당단백질 B (gB)를 암호화하는 A323 자가 복제 RNA 분자를 암호화하는 플라스미드의 뉴클레오티드 서열 (SEQ ID NO:85)을 나타낸다. gB를 암호화하는 뉴클레오티드 서열은 밑줄쳐져 있다.
도 17a 및 도 17b는 VRP 또는 자가 복제 RNA로 면역화된 마우스의 혈청의 50% 중화 역가를 나타내는 막대그래프이다. 도 17a는 ARPE-19 세포에서 사람 CMV 균주 TB40UL32E-EGFP ("TB40)에 대하여 50% 중화 역가를 나타내고, 도 17b는 ARPE-19 세포에서 사람 CMV 균주 8819에 대하여 50% 중화 역가를 나타낸다.
도 18은 다섯 개의 CMV 단백질을 암호화하는, 페타시스트론성 RNA 레플리콘, A526(SEQ ID NO:56), A527(SEQ ID NO:57), A554(SEQ ID NO:65), A555(SEQ ID NO:66) 및 A556(SEQ ID NO:67)의 개략도이다. 서브게놈 프로모터는 화살표로 나타나고, 다른 대조군 요소가 표시된다.
도 19는 A527 RNA 레플리콘으로 트랜스펙션된 BHKV 세포가 gH/gL/UL128/UL130/UL131 펜타머 복합체를 발현한다는 것을 나타내는 형광 발광 막대 그래프이다. 펜타머 복합체 상에 존재하는 구조 에피토프와 결합하는 항체를 이용하여 세포 염색을 수행하였다 (Macagno (2010) J. Virol. 84(2): 1005-13).
도 20은 개략도 및 그래프이다. 개략도는 CMV gH 및 gL을 암호화하는, 바이시스트론성 RNA 레플리콘, A160 및 A531-A537을 나타낸다. 그래프는 레플리콘을 함유한 VRP로 면역화된 마우스의 면역 혈청의 중화 활성을 나타낸다.
도 21은 VZV 단백질을 암호화하는 모노시스트론성 RNA 레플리콘 또는 VZV gE 및 gI, 또는 gH 및 gL을 암호화하는 바이시스트론성 RNA 레플리콘으로 면역화된 마우스의 면역 혈청에서 항-VZV 단백질 항체 반응을 나타낸다. 마우스는 CNE로 조제된 7 μg RNA로 면역화되었다 (실시예 7 참조).
도 22는 VZV 단백질을 암호화하는 모노시스트론성 RNA 레플리콘 또는 VZV gE 및 gI, 또는 gH 및 gL을 암호화하는 바이시스트론성 RNA 레플리콘으로 면역화된 마우스의 면역 혈청에서 항-VZV 단백질 항체 반응을 나타낸다. 마우스는 CNE로 조제된 1 μg RNA로 면역화되었다 (실시예 7 참조).
본 발명은 세포에 시토메갈로 바이러스 (CMV) 단백질과 같이, 헤르페스바이러스 단백질, 특히 생체 내에서 복합체를 형성하는 단백질의 동시전달을 위한 플랫폼을 제공한다. 일부 구체예에서, 이 단백질 및 그것들이 형성하는 복합체는 효능 있는 중화 항체를 유도한다. 헤르페스바이러스 (예를 들어, CMV) 단백질, 특히 생체 내에서 복합체를 형성하는 것들 (예를 들어, gH/gL)의 동시전달에 의해 생산된 면역 반응은 다른 접근법을 이용하여 생산된 면역 반응보다 더 뛰어날 수 있다. 예를 들어, CMV의 gH 및 gL을 암호화하는 RNA 분자 (예를 들어, 레플리콘)는 gB를 암호화하는 RNA 분자, gH를 암호화하는 RNA 분자, gL을 암호화하는 RNA 분자 또는 개별적으로 gH 또는 gL을 암호화하는 RNA 분자의 혼합물과 비교하여 더 양호한 중화 역가 및/또는 보호 면역력을 유발할 수 있다. 게다가, gH/gL/UL128/UL130/UL131을 암호화하는 레플리콘은 gH/gL만을 암호화하는 것들보다 더 뛰어난 반응을 제공할 수 있다.
일반적인 양태에서, 본 발명은 세포에 둘 이상의 헤르페스바이러스 (예를 들어, CMV) 단백질의 전달을 위한 플랫폼과 관련된다. 플랫폼은 첫 번째 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편을 암호화하는 첫 번째 서열, 및 두 번째 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편을 암호화하는 두 번째 서열을 함유하는 재조합 폴리시스트론성 핵산 분자를 포함한다. 원하는 경우, 추가적 단백질, 예를 들어, 세 번째 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편, 네 번째 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편, 다섯 번째 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편 등을 암호화하는 하나 이상의 추가적인 서열은 재조합 폴리시스트론성 핵산 분자에 존재할 수 있다. 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 단편이 재조합 폴리시스트론성 핵산을 함유하는 세포에 의해 생산되도록 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편을 암호화하는 서열은 하나 이상의 적합한 대조군 요소와 작동 가능하게 연결되었다.
여기에 설명된 폴리시스트론성 핵산에서, 암호화된 첫 번째 및 두 번째 헤르페스바이러스 단백질 또는 단편, 및 암호화된 세 번째, 네 번째, 및 다섯 번째 헤르페스바이러스 단백질 또는 단편은, 존재하면, 일반적으로 및 바람직하게 같은 헤르페스바이러스의 것이다. 특정 예에서, 폴리시스트론성 벡터에 의해 암호화된 모든 헤르페스바이러스 단백질 또는 단편은 CMV 단백질 또는 VZV 단백질이다.
여기에 설명된 재조합 폴리시스트론성 핵산 분자는 세포에 둘 이상의 헤르페스바이러스 (예를 들어, CMV) 단백질을 암호화하는 서열의 전달, 및 생체 내에서 둘 이상의 헤르페스바이러스 (예를 들어, CMV) 단백질을 함유하는 단백질 복합체의 형성을 일으키기 위해 충분한 수준으로 헤르페스바이러스 (예를 들어, CMV) 단백질의 발현의 구동의 이점을 제공한다. 이 접근법을 이용하여, 둘 이상의 암호화된 헤르페스바이러스 (예를 들어, CMV) 단백질은 헤르페스바이러스 (예를 들어, CMV) 단백질 복합체 (예를 들어, gH/gL)의 형성에 충분한 세포 내 수준으로 발현될 수 있다. 예를 들어, 암호화된 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편은 실질적으로 같은 수준으로, 또는 원하는 경우, 적절한 발현 조절 서열 (예를 들어, 프로모터, IRES, 2A 부위 등)을 선택함으로써 다른 수준으로 발현될 수 있다. 이것은 비효율적이고 매우 가변적일 수 있는, 같은 세포에 다른 헤르페스바이러스 (예를 들어, CMV)를 암호화하는 둘 이상의 개개의 DNA 분자를 동시전달하는 것보다 생체 내에서 단백질 복합체를 생산하기 위해 훨씬 더 효율적인 방법이다. 예를 들어, WO 2004/076645 참조.
재조합 폴리시스트론성 핵산 분자는 DNA (예를 들어, 플라스미드 또는 바이러스 DNA) 또는 RNA와 같이 어떤 원하는 핵산에도 기초할 수 있다. 어떤 적합한 DNA 또는 RNA는 헤르페스바이러스 (예를 들어, CMV) 단백질 또는 이들의 단편을 암호화하는 오픈 리딩 프레임을 갖고 있는 핵산 벡터로서 이용될 수 있다. 적합한 핵산 벡터는 하나 이상의 단백질 유전자를 운반하고 이의 발현을 구동하는 능력을 갖는다. 이러한 핵산 벡터는 업계에 알려져 있고, 예를 들어, 플라스미드, 우두 바이러스 (vaccinia virus) 벡터 (예를 들어, NYVAC, 미국 5,494,807 참조), 수두 바이러스 (poxvirus) 벡터 (예를 들어, ALVAC 카나리폭스 벡터, Sanofi Pasteur)와 같이, DNA 바이러스로부터 얻어진 DNA, 및 알파바이러스와 같이 적합한 RNA 바이러스로부터 얻어진 RNA를 포함한다. 원하는 경우, 재조합 폴리시스트론성 핵산 분자는 변형될 수 있다, 예를 들어, 추가로 여기에 설명된 바와 같이 변형된 핵염기 및/또는 결합을 함유할 수 있다. 바람직하게는, 폴리시스트론성 핵산 분자는 RNA 분자이다.
일부 양태에서, 재조합 폴리시스트론성 핵산 분자는 플라스미드 DNA와 같은 DNA 분자이다. 이러한 DNA 분자는, 예를 들어, 폴리시스트론성 레플리콘을 암호화하고 레플리콘의 전사를 구동하는 포유동물 프로모터를 함유할 수 있다. 재조합 폴리시스트론성 핵산 분자 또는 이 타입은 포유동물에 투여될 수 있고 이후 헤르페스바이러스 단백질을 발현하는 폴리시스트론성 레플리콘을 생산하기 위해 제자리에서 전사될 수 있다.
일부 양태에서, 본 발명은 헤르페스바이러스 gH 또는 이들의 단편, 및 헤르페스바이러스 gL 또는 이들의 단편을 암호화하는 서열을 함유하는 폴리시스트론성 핵산 분자이다. gH 및 gL 단백질, 또는 이들의 단편은 어떤 원하는 헤르페스바이러스, 예를 들어, HSV-1, HSV-2, VZV, EBV 타입 1, EBV 타입 2, CMV, HHV-6 타입 A, HHV-6 타입 B, HHV-7, KSHV, 등의 것일 수도 있다. 바람직하게는, 헤르페스바이러스는 VZV, HSV-2, HSV-1, EBV (타입 1 또는 타입 2) 또는 CMV이다. 더 바람직하게는, 헤르페스바이러스는 VZV, HSV-2 또는 CMV이다. 더 바람직하게, 헤르페스바이러스는 CMV이다. gH 및 gL 단백질의 서열 및 이 바이러스로부터 단백질을 암호화하는 핵산의 서열은 업계에 잘 알려져 있다. 전형적인 서열은 표 1에서 확인된다. 폴리시스트론성 핵산 분자는 표 1에 개시된 gH 단백질을 암호화하는 첫 번째 서열, 또는 이들의 단편, 또는 그것과 적어도 약 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 또는 99% 동일한 서열을 함유할 수 있다. 폴리시스트론성 핵산 분자는 또한 표 1에 개시된 gL 단백질을 암호화하는 두 번째 서열, 또는 이들의 단편, 또는 그것과 적어도 약 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 또는 99% 동일한 서열을 함유할 수 있다.
Figure 112020102169690-pat00001
본 발명의 이 설명에서, 핵산의 뚜렷한 설명을 용이하게 하기 위해서, 특정 서열 성분은 "첫 번째 서열", "두 번째 서열" 등으로 나타난다. 첫 번째 및 두 번째 서열은 어떤 원하는 순서 또는 방향으로도 나타날 수 있고, 특정 순서 또는 방향은 단어 "첫 번째", "두 번째 등에 의해 의도되지 않는 것으로 이해될 것이다. 유사하게, 단백질 복합체는 복합체, 예를 들어, gH/gL에 존재하는 단백질을 나열함으로써 나타난다. 이것은 복합체에 존재하는 단백질에 의해 복합체를 설명하기 위한 것이고 단백질의 상대적인 양 또는 재조합 핵산에서 단백질을 암호화하는 서열의 순서 또는 방향을 나타내기 위한 것이 아니다.
알파바이러스 VRP 및 CMV 단백질을 암호화하는 서열을 함유하는 자가 복제 RNA와 같이, 특정 바람직한 구체예는 여기에 추가로 설명된다. 이러한 바람직한 구체예에서, CMV 단백질을 암호화하는 서열은 다른 헤르페스바이러스의 gH 및 gL과 같이, 단백질을 암호화할 수 있는 서열로 대체될 수 있는 것으로 생각된다.
알파바이러스 VRP 플랫폼
일부 구체예에서, CMV 단백질은 하기 설명된 바와 같이 폴리시스트론성 레플리콘 (또는 벡터)을 이용하는 알파바이러스 레플리콘 입자 (VRP)를 이용하여 세포에 전달된다. 여기에 이용된 바와 같이, "폴리시스트론성"은 바이시스트론성 벡터 뿐만 아니라 셋 이상의 시스트론을 포함하는 벡터를 포함한다. 폴리시스트론성 벡터의 시스트론은 같은 CMV 균주로부터 또는 다른 CMV 균주로부터 CMV 단백질을 암호화할 수 있다. 시스트론은 어떤 5'-3' 순서의 방향도 될 수 있다. CMV 단백질을 암호화하는 어떤 뉴클레오티드 서열은 단백질을 생산하기 위해 이용될 수 있다. 둘 이상의 CMV 단백질 또는 이들의 단편을 암호화하는 폴리시스트론성 핵산의 제조에 유용한 전형적인 서열이 여기에 설명된다.
여기에 이용된 바와 같이, 용어 "알파바이러스"는 업계에서 그것의 통상적인 의미를 갖고 다양한 종, 예를 들어, 베네수엘라 말 뇌염 바이러스 (Venezuelan equine encephalitis virus; VEE; 예를 들어, 트리니다드 당나귀, TC83CR, 등), 셈리키 포레스트 바이러스 (Semliki Forest virus; SFV), 신드비스 바이러스 (Sindbis virus), 로스 리버 바이러스 (Ross River virus), 웨스턴 말 뇌염 바이러스 (Western equine encephalitis virus), 이스턴 말 뇌염 바이러스 (Eastern equine encephalitis virus), 치쿤군야 바이러스 (Chikungunya virus), S.A. AR86 바이러스, 에버글레이드 바이러스 (Everglades virus), 무캄보 바이러스 (Mucambo virus), 바마 포레스트 바이러스 (Barmah Forest virus), 미델부르크 바이러스 (Middelburg virus), 픽수나 바이러스 (Pixuna virus), 오뇽뇽 바이러스 (O'nyong-nyong virus), 게타 바이러스 (Getah virus), 사기야마 바이러스 (Sagiyama virus), 베바루 바이러스 (Bebaru virus), 마야로 바이러스 (Mayaro virus), 우나 바이러스 (Una virus), 아우라 바이러스 (Aura virus), 화타로아 바이러스 (Whataroa virus), 반반키 바이러스 (Banbanki virus), 키질라가크 바이러스 (Kyzylagach virus), 하이랜드 제이 바이러스 (highlands J virus), 포트 모건 바이러스 (Fort Morgan virus), 은두무 바이러스 (Ndumu virus), 및 버기 크릭 바이러스 (Buggy Creek virus)를 포함한다. 용어 알파바이러스는 또한 하나 이상의 알파바이러스의 게놈 서열을 함유하는 키메라 알파바이러스 (예를 들어, Perri et al, (2003) J. Virol. 77(19): 10394-403에 의해 설명된 바와 같은)를 포함할 수도 있다.
"알파바이러스 레플리콘 입자" (VRP) 또는 "레플리콘 입자"는 알파바이러스 구조 단백질로 둘러싸인 알파바이러스 레플리콘이다.
"알파바이러스 레플리콘" (또는 "레플리콘")은 표적 세포의 생체 내에서 자체의 증폭을 지시할 수 있는 RNA 분자이다. 레플리콘은 RNA 증폭을 촉진하는 폴리머라제(들) (nsP1, nsP2, nsP3, nsP4)을 암호화하고 암호화된 폴리머라제에 의해 인식되고 이용되는, 복제에 필요한 씨스 RNA 서열을 함유한다. 알파바이러스 레플리콘은 전형적으로 다음 순서의 요소를 함유한다: 씨스에서 복제에 필요한 5' 바이러스 서열, 생물학적 활성 알파바이러스 비구조 단백질 (nsP1, nsP2, nsP3, nsP4)을 암호화하는 서열, 씨스에서 복제에 필요한 3' 바이러스 서열, 및 폴리아데닐레이트 구역. 알파바이러스 레플리콘은 또한 이종 기원 뉴클레오티드 서열의 발현을 지시하는, 하나 이상의 바이러스 서브게놈 "접합 영역" 프로모터를 함유할 수도 있으며, 특정 구체예에서, 이것은 발현되는 서브게놈 단편 및 이종 기원 서열(들)의 바이러스 전사를 증가시키거나 감소시키기 위해 변형될 수도 있다. 하기 설명된 바와 같이, 다른 조절 요소들이 이용될 수 있다.
CMV 단백질을 암호화시키는 알파바이러스 레플리콘은 VRP를 생산하기 위해 이용된다. 이러한 알파바이러스 레플리콘은 적어도 두 개의 CMV 단백질 또는 이들의 단편을 암호화하는 서열을 포함한다. 이 서열은 서브게놈 프로모터, IRES (예를 들어, EMCV, EV71), 및 바이러스 2A 부위와 같은, 하나 이상의 적합한 조절 요소와 작동 가능하게 연결되며, 이것은 같거나 다를 수 있다. 여기에 설명된 폴리시스트론성 벡터를 이용하여 이 복합체의 성분의 전달은 원하는 상대적인 양으로 둘 이상의 CMV 단백질을 암호화하는 핵산 서열을 제공하는 효율적인 방법이다; 반면에 다수의 알파바이러스 구조물이 복합체 형성을 위해 개개의 CMV 단백질을 전달하는데 이용되는 경우, VRP의 효율적인 동시전달이 필요할 것이다.
적합한 조절 요소의 어떤 조합은 어떤 순서로도 이용될 수 있다. 한 예에서, 단일 서브게놈 프로모터는 두 개의 다른 CMV 단백질을 암호화하는 두 개의 서열과 작동 가능하게 연결되고, IRES는 두 개의 암호화 서열 사이에 위치한다. 또 다른 예에서, 두 개의 다른 CMV 단백질을 암호화하는 두 개의 서열은 별도의 프로모터와 작동 가능하게 연결된다. 또 다른 예에서, 두 개의 다른 CMV 단백질을 암호화하는 두 개의 서열은 단일 프로모터와 작동 가능하게 연결된다. 두 개의 다른 CMV 단백질을 암호화하는 두 개의 서열은 바이러스 2A 부위를 암호화하는 뉴클레오티드 서열을 통해 서로 연결되고, 따라서 CMV 단백질 둘 다의 아미노산 서열을 함유하는 단일 아미노산 사슬을 암호화한다. 이 맥락에서 바이러스 2A 부위는 암호화된 다단백질로부터 두 개의 CMV 단백질을 발생시키는데 이용된다.
서브게놈 프로모터
접합 영역 프로모터로도 알려진 서브게놈 프로모터는 단백질 발현을 조절하는데 이용될 수 있다. 알파바이러스 서브게놈 프로모터는 알파바이러스 구조 단백질의 발현을 조절한다. Strauss and Strauss, "The alphaviruses: gene expression, replication, and evolution", Microbiol Rev. 1994 Sep;58(3):491-562 참조. 폴리시스트론성 폴리뉴클레오티드는 어떤 알파바이러스의 서브게놈 프로모터도 포함할 수 있다. 둘 이상의 서브게놈 프로모터는 폴리시스트론성 폴리뉴클레오티드에 존재하고, 프로모터는 같거나 다를 수 있다. 예를 들어, 서브게놈 프로모터는 서열 CTCTCTACGGCTAACCTGAATGGA (SEQ ID NO:1)을 갖는다. 특정 구체예에서, 서브게놈 프로모터는 단백질의 바이러스 전사를 증가시키거나 감소시키기 위해 변형될 수 있다. 미국 특허 번호 6,592,874 참조.
내부 리보솜 유입점 (Internal Ribosomal Entry Site; IRES)
일부 구체예에서, 하나 이상의 조절 요소는 내부 리보솜 유입점 (IRES)이다. 리보솜이 각각의 IRES에 결합하고 정상적으로 진핵세포의 단백질의 번역을 개시하는데 필요한 5'-캡의 부재시 다수의 단백질이 번역을 개시하기 때문에, IRES는 단일 mRNA 전사로부터 만들어지는 것을 허용한다. 예를 들어, IRES는 EV71 또는 EMCV일 수 있다.
바이러스 2A 부위
FMDV 2A 단백질은 비구조 단백질로부터 FMDV의 구조 단백질을 분리하기 위해 제공하는 짧은 펩티드이다 (FMDV 2B). 이 펩티드에 대한 초기 연구는 그것이 자가 촉매 프로테아제로서 작용하는 것을 제안하였지만, 다른 작업 (예를 들어, Donnelly et al, (2001), J.Gen.Virol. 82, 1013-1025)은 이 짧은 서열 및 FMDV 2B (Gly)의 다음 단일 아미노산이 번역 중단-시작으로서 작용하는 것을 제안한다. 정확한 작용의 방식에 관계없이, 서열은 두 개의 폴리펩티드 사이에 삽입될 수 있고, 단일 오픈 리딩 프레임으로부터 다수의 개개의 폴리펩티드의 생산에 영향을 미칠 수 있다. 본 발명의 맥락에서, FMDV 2A 서열은 적어도 두 개의 CMV 단백질을 암호화하는 서열들 사이에 삽입될 수 있고, 단일 오픈 리딩 프레임의 일부로서 그것들의 합성이 생각된다. 예를 들어, 오픈 리딩 프레임은 바이러스 2A 부위를 암호화하는 서열에 의해 분리된 gH 단백질 및 gL 단백질을 암호화할 수도 있다. 어떤 적합한 바이러스 2A 서열도 이용될 수 있다. 종종, 바이러스 2A 부위는 공통 서열 Asp-Val/Ile-Glu-X-Asn-Pro-Gly-Pro을 포함하며, 여기에서 X는 어떤 아미노산 (SEQ ID NO:2)일 수도 있다. 예를 들어, 구제역 (Foot and Mouth Disease) 바이러스 2A 펩티드 서열은 DVESNPGP (SEQ ID NO:3)이다. Trichas et al, "Use of the viral 2A peptide for bicistronic expression in transgenic mice", BMC Biol. 2008 Sep 15;6:40, 및 Halpin et al, "Self-processing 2A-polyproteins--a system for co-ordinate expression of multiple proteins in transgenic plants", Plant J. 1999 Feb;17(4):453-9 참조.
일부 구체예에서, 알파바이러스 레플리콘은 VEE-신드비스 키메라 레플리콘 (VCR) 또는 VEE 균주 TC83 레플리콘 (TC83R) 또는 TC83-신드비스 키메라 레플리콘 (TC83CR)과 같은, 키메라 레플리콘이다. 일부 구체예에서, VCR은 nsP3의 서열의 위치에서 및 VEE 레플리콘의 3' 말단에서 패키징 시그날 및 신드비스 레플리콘의 3' UTR을 함유한다; Perri et al, J. Virol. 77, 10394-403, 2003 참조. 일부 구체예에서, TC83CR은 패키징 시그날 및 nsP3의 서열의 위치에서 및 VEE 균주 TC83레플리콘의 3' 말단에서 신드비스 레플리콘의 3' UTR을 함유한다.
VRP 생산
VRP를 제조하는 방법은 업계에 잘 알려져 있다. 일부 구체예에서, 알파바이러스는 패키징 세포를 이용하여 VRP로 조립된다. "알파바이러스 패키징 세포" (또는 "패키징 세포")는 하나 이상의 알파바이러스 구조 단백질 발현 카세트를 함유하고 알파바이러스 레플리콘, 진핵세포층 벡터 개시 시스템 (예를 들어, 미국 특허 5,814,482), 또는 재조합 알파바이러스 입자의 도입 후 재조합 알파바이러스 입자를 생산하는 세포이다. 하나 이상의 다른 알파바이러스 구조 단백질 카세트는 알파바이러스 구조 단백질을 제공함으로써 "헬퍼"의 역할을 한다. "알파바이러스 구조 단백질 카세트"는 하나 이상의 알파바이러스 구조 단백질을 암호화하는 발현 카세트이고 알파바이러스 레플리카제 인식 서열의 적어도 하나 및 최대 다섯 개의 카피 (즉, 1, 2, 3, 4, 또는 5)를 포함한다. 구조 단백질 발현 카세트는 전형적으로, 5'에서 3'으로, 알파바이러스 RNA의 전사를 개시하는 5' 서열, 임의의 알파바이러스 서브게놈 영역 프로모터, 알파바이러스 구조 단백질을 암호화하는 뉴클레오티드 서열, 3' 번역되지 않은 영역 (이것은 또한 RNA 전사를 지시한다), 폴리A 구역을 포함한다. 예를 들어, WO 2010/019437 참조.
바람직한 구체예에서, 두 개의 다른 알파바이러스 구조 단백질 카세트 ("분할" 결핍 헬퍼)는 복제-성분 바이러스를 생산할 수 있는 재조합 이벤트를 최소화하기 위해 패키징 세포에서 이용된다. 일부 구체예에서, 알파바이러스 구조 단백질 카세트는 캡시드 단백질 (C)을 암호화하지만 당단백질 (E2 및 E1) 중 어느 것도 암호화하지 않는다. 일부 구체예에서, 알파바이러스 구조 단백질 카세트는 캡시드 단백질 및 E1 또는 E2 당단백질 (하지만 둘 다는 아님)을 암호화한다. 일부 구체예에서 알파바이러스 구조 단백질 카세트는 E2 및 E1 당단백질을 암호화하지만 캡시드 단백질은 아니다. 일부 구체예에서, 알파바이러스 구조 단백질 카세트는 E1 또는 E2 당단백질 (하지만 둘 다는 아님)을 암호화하지만 캡시드 단백질은 아니다.
일부 구체예에서, VRP는 레플리콘 및 헬퍼 RNA의 다양한 근원의 세포 내로 동시의 도입에 의해 생산된다. 예를 들어, 이 조건 하에 BHKV 세포 (1 x 107)는, 예를 들어, 220 볼트, 1000 μF, 10 μg 레플리콘 RNA:6 μg 결핍된 헬퍼 Cap RNA:10 μg 결핍된 헬퍼 Gly RNA로 2번 수동 펄스로 전기 천공되고, 알파바이러스를 함유하는 상층액은 약 24 시간 후 수거된다. 레플리콘 및/또는 헬퍼는 또한 트랜스펙션된 세포 내에 적합한 RNA를 론치 (launch)하는 DNA 형태로 도입될 수 있다.
패키징 세포는 포유동물 세포 또는 곤충 (예를 들어, SF9) 또는 조류 세포 (1차 병아리 또는 오리 섬유아세포 또는 섬유아세포 세포주)와 같은 비포유동물 세포일 수도 있다. 미국 특허 7,445,924 참조. 조류 근원의 세포는 EB66® (VIVALIS)와 같은 조류 배아 줄기 세포; EBx® 세포와 같은 닭 배아 줄기 세포를 포함하는 닭 세포, 닭 배아 섬유아세포 및 닭 배아 생식 세포; 예를 들어, Vaccine 27:4975-4982 (2009) 및 WO2005/042728에 설명된 AGE1.CR 및 AGE1.CR.pIX 세포주 (ProBioGen)과 같은 오리 세포; 및 거위 세포를 포함하지만, 이에 제한되지 않는다. 일부 구체예에서, 패키징 세포는 1차 오리 섬유아세포 또는 AGE.CR (PROBIOGEN)과 같은 오리 망막 세포주이다.
동시 핵산 도입에 대한 포유동물 근원의 세포 및/또는 패키징 세포는 WO 01/38362 및 WO 02/40665에 설명되는 PerC6 (PER.C6) 세포 (CRUCELL N.V.) 뿐만 아니라 ECACC 수탁 번호 96022940 하에 기탁된 것들; MRC-5 (ATCC CCL-171); WI-38 (ATCC CCL-75); 태아 붉은털원숭이 폐 세포 (ATCC CL-160); 사람 배아 신장 세포 (예를 들어, 293 cells, 전형적으로 전단된 아데노바이러스 타입 5 DNA로 트랜스펙션됨); 원숭이 신장의 VERO 세포; 말, 소, (예를 들어, MDBK 세포), 양, 개 (예를 들어, 개 신장의 MDCK 세포, ATCC CCL34 MDCK (NBL2) 또는 MDCK 33016, WO 97/37001에 설명된 바와 같은 수탁 번호 DSM ACC 2219)의 세포; 고양이, 쥐 (예를 들어, BHK21-F, 및 HKCC 세포와 같은 햄스터 세포, 또는 중국 햄스터 난소 (CHO) 세포)의 세포를 포함하는, 사람 또는 비-사람 영장류 세포를 포함하지만, 이에 제한되지 않고, 예를 들어, 성인, 신생아, 태아, 및 배아를 포함하는 다양한 발달 단계로부터 얻어질 수도 있다.
일부 구체예에서, 패키징 세포는 하나 이상의 구조 단백질 발현 카세트(들)로 안정하게 트랜스펙션된다. 구조 단백질 발현 카세트는 트랜스페린-다가 양이온-매개 DNA 전이, 노출된 또는 캡슐화된 핵산으로 트랜스펙션, 리포솜-매개 세포 융합, 바이러스 감염, 전기 천공, "유전자 총 (gene gun)" 방법, 및 DEAE-또는 인산 칼슘-매개 트랜스펙션을 포함하는, 표준 재조합 DNA 기술을 이용하여 세포 내로 도입될 수 있다. 구조 단백질 발현 카세트는 전형적으로 DNA 분자로서 숙주 세포 내로 도입되지만, 또한 시험관 내-전사된 RNA로서 도입될 수 있다. 각각의 발현 카세트는 별도로 또는 실질적으로 동시에 도입될 수 있다.
일부 구체예에서, 안정한 알파바이러스 패키징 세포주는 재조합 알파바이러스 입자를 생산하는데 이용된다. 이것들은 게놈에 안정하게 포함되는 결핍된 헬퍼 RNA를 발현하는 DNA 카세트를 포함하는 알파바이러스-허용 세포이다. Polo et al, Proc. Natl. Acad. Sci. USA 96, 4598-603, 1999 참조. 헬퍼 RNA는 본질적으로 발현되지만 알파바이러스 구조 단백질은 아닌데, 유전자가 알파바이러스 서브게놈 프로모터의 조절 하에 있기 때문이다 (Polo et al., 1999). 알파바이러스 레플리콘의 트랜스펙션 또는 VRP 감염에 의한 패키징 세포의 게놈 내 도입시, 레플리카제 효소가 생산되고 헬퍼 RNA에서 캡시드 및 당단백질 유전자의 발현을 유발하고 결과 VRP가 생산된다. 레플리콘의 도입은 알파바이러스 레플리콘 입자의 종자로 트랜스펙션 및 감염을 포함하는, 다양한 방법으로 달성될 수 있다. 패키징 세포는 배양 상층액에서 포장된 알파바이러스 레플리콘 입자를 생산하는데 충분한 조건 하에 및 시간 동안 배양된다.
따라서, 패키징 세포는 VRP가 자가-번식 바이러스로서 작용하게 한다. 이 기술은 VRP가 아데노바이러스 E1A 및 E1B 유전자를 발현하는 세포에서 성장한 복제-불가능 아데노바이러스 벡터와 같이, 살아있는 감쇠 백신 또는 이용 가능한 생산자 세포주를 갖는 다른 바이러스 벡터에 이용된 것들과 거의 같은 방식으로, 및 같은 장비를 이용하여 생산되게 한다.
일부 구체예에서, 2-단계 공정이 이용된다: 제 1단계는 패키징 세포를 레플리콘 RNA 또는 플라스미드 DNA-기반 레플리콘으로 트랜스펙션함으로써 알파바이러스 레플리콘 입자의 종자를 생산하는 단계를 포함한다. 이 감염은 MOI=0.00001, 0.00005, 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 3, 5, 10 또는 20을 포함하는, 다양한 감염 다중도 (multiplicities of infection; MOI)를 이용하여 수행될 수 있다. 일부 구체예에서, 감염은 낮은 MOI (예를 들어, 1 미만)로 수행된다. 시간이 지남에 따라, 레플리콘 입자는 종자로 감염된 패키징 세포 내로부터 수확될 수 있다. 일부 구체예에서, 레플리콘 입자는 반복되는 낮은 감염 다중도에 의해 나이브 (naive) 패키징 세포의 더 큰 배양으로 계대 배양될 수 있으며, 같은 높은 역가를 갖는 상업적 규모의 조제물을 발생시킨다.
자가 복제 RNA 플랫폼
둘 이상의 CMV 단백질은 대상체의 세포의 단백질을 암호화하는 재조합 핵산의 발현에 의해 생산될 수 있다. 바람직하게는, 재조합 핵산 분자는 둘 이상의 CMV 단백질을 암호화하는데, 예를 들어, 폴리시스트론성인 것들이다. 상기 정의된 바와 같이, "폴리시스트론성"은 바이시스트론성을 포함한다. CMV 단백질의 생산을 유발하기 위해 대상체에 투여될 수 있는 바람직한 핵산은 자가 복제 RNA 분자이다. 본 발명의 자가 복제 RNA 분자는 RNA 바이러스의 게놈 RNA에 기초하지만, 하나 이상의 구조 단백질을 암호화하는 유전자가 결핍된다. 자가 복제 RNA 분자는 RNA 바이러스의 비-구조 단백질 및 자가 복제 RNA에 의해 암호화된 CMV 단백질을 생산하기 위해 번역될 수 있다.
자가 복제 RNA는 일반적으로 바이러스 레플리카제, 바이러스 프로테아제, 바이러스 헬리카제 및 다른 비구조 바이러스 단백질로 구성된 그룹으로부터 선택되는 적어도 하나 이상의 유전자를 함유하고, 또한 5'-및 3'-말단 씨스-활성 복제 서열, 및 둘 이상의 원하는 CMV 단백질을 암호화하는 이종 기원 서열을 포함한다. 이종 기원 서열(들)의 발현을 지시하는 서브게놈 프로모터는 자가 복제 RNA에 포함될 수 있다. 원하는 경우, 이종 기원 서열은 자가 복제 RNA의 다른 암호화 지역에 대한 프레임에 융합될 수도 있고 및/또는 내부 리보솜 유입점 (IRES)의 조절하에 있을 수도 있다.
본 발명의 자가 복제 RNA 분자는 감염성 바이러스 입자의 생산을 유발할 수 없도록 설계될 수 있다. 이것은, 예를 들어, 자가 복제 RNA에서 바이러스 입자의 생산에 필요한 구조 단백질을 암호화하는 하나 이상의 바이러스 유전자를 생략함으로써 달성될 수 있다. 예를 들어, 자가 복제 RNA 분자가 신드비스 바이러스 (SIN), 셈리키 포레스트 바이러스 및 베네수엘라 말 뇌염 바이러스 (VEE)와 같은 알파바이러스에 기초할 때, 캡시드 및/또는 외피 당단백질과 같은 바이러스 구조 단백질을 암호화하는 하나 이상의 유전자는 생략될 수 있다. 원하는 경우, 본 발명의 자가 복제 RNA 분자는 약화되거나 악성인 감염성 바이러스 입자의 생산을 유발하도록, 또는 다음 단일 라운드의 감염이 가능한 바이러스 입자를 생산하도록 설계될 수 있다.
자가 복제 RNA 분자는, 어떤 단백질도 없이 척추동물 세포에 전달될 때, 자체의 (또는 자체의 안티센스 카피의) 전사에 의해 다수의 딸 RNA의 생산으로 이어질 수 있다. 자가 복제 RNA는 세포에 전달 후 바로 번역될 수 있고, 이 번역은 전달된 RNA의 전사물을 생산하는 RNA-의존 RNA 폴리머라제를 제공한다. 따라서 전달된 RNA는 다수의 딸 RNA의 생산으로 이어진다. 이 전사물들은 전달된 RNA에 관하여 안티센스이고 암호화된 CMV 단백질의 제자리 발현을 제공하기 위해 스스로 번역될 수도 있거나, 암호화된 CMV 단백질(들)의 제자리 발현을 제공하도록 번역된 전달된 RNA와 같은 센스를 갖는 전사물을 추가로 생산하기 위해 전사될 수도 있다.
자가 복제를 달성하기 위한 한 적합한 시스템은 알파바이러스-기반 RNA 레플리콘, 예를 들어, 여기에 설명된 바와 같이 알파바이러스 레플리콘을 이용하는 것이다. 이 + 나선 레플리콘은 레플리카제 (또는 레플리카제-트랜스크립타제)를 생산하기 위해 세포에 전달 후 번역된다. 레플리카제는 + 나선 전달된 RNA의 게놈-나선 카피를 생성하는 복제 복합체를 제공하기 위해 자동 분할되는 다단백질로서 번역된다. 이들-나선 전사물은 + 나선 모체 RNA의 추가의 카피를 제공하기 위해 및 또한 둘 이상의 CMV 단백질을 암호화하는 하나 이상의 서브게놈 전사물을 유발하기 위해 스스로 전사될 수 있다. 서브게놈 전사물의 번역은 감염된 세포에 의해 CMV 단백질(들)의 제자리 발현으로 이어진다. 적합한 알파바이러스 레플리콘은 신드비스 바이러스, 셈리키 포레스트 바이러스, 이스턴 말 뇌염 바이러스, 베네수엘라 말 뇌염 바이러스, 등의 레플리카제를 이용할 수 있다.
바람직한 자가 복제 RNA 분자는 (i) 자가 복제 RNA 분자로부터 RNA를 전사할 수 있는 RNA-의존 RNA 폴리머라제 및 (ii) 둘 이상의 CMV 단백질 또는 이들의 단편을 암호화한다. 폴리머라제는, 예를 들어, 알파바이러스 단백질 nsP4를 포함하는 알파바이러스 레플리카제일 수 있다. 단백질 nsP4는 레플리카제의 주요 촉매 성분이다.
자연 알파바이러스 게놈은 비구조 레플리카제 다단백질에 더하여 구조 비리온 단백질을 암호화하는 한편, 본 발명의 자가 복제 RNA 분자 기반 알파바이러스나 모든 알파바이러스 구조 단백질을 암호화하지 않는 것이 바람직하다. 따라서 자가 복제 RNA는 세포에서 자체의 게놈 RNA 카피의 생산으로 이어질 수 있지만, RNA-함유 알파바이러스 비리온의 생산은 아니다. 이 비리온을 생산할 수 없는 것은, 야생형 알파바이러스와 달리, 자가 복제 RNA 분자가 자체를 감염성 형태로 영구화할 수 없다는 것을 의미한다. 야생형 바이러스의 영구화에 필요한 알파바이러스 구조 단백질은 본 발명의 자가 복제 RNA에 없고 그것들의 위치는 원하는 유전자 생성물 (CMV 단백질 또는 이들의 단편)을 암호화하는 유전자(들)에 의해 취해지고, 서브게놈 전사물은 구조 알파바이러스 비리온 단백질 대신에 원하는 유전자 생성물을 암호화한다.
따라서 본 발명에 유용한 자가 복제 RNA 분자는 다른 CMV 단백질 또는 이들의 단편을 암호화하는 두 개의 서열을 갖는다. CMV 단백질 또는 단편을 암호화하는 서열은 어떤 원하는 방향일 수도 있고, 같은 또는 별도의 프로모터에 작동 가능하게 연결될 수 있다. 원하는 경우, CMV 단백질 또는 단편을 암호화하는 서열은 단일 오픈 리딩 프레임의 일부일 수 있다. 일부 구체예에서, RNA는 하나 이상의 추가적인 (다운스트림) 서열 또는, 예를 들어, 다른 추가적인 CMV 단백질 또는 이들의 단편을 암호화하는 오픈 리딩 프레임을 가질 수도 있다. 자가 복제 RNA 분자는 암호화된 레플리카제와 호환되는 5' 서열을 가질 수 있다.
한 양태에서, 자가 복제 RNA 분자는 여기에 정의된 바와 같이 알파바이러스 레플리콘과 같은, 알파바이러스로부터 유도되거나 이에 기초한다. 다른 양태에서, 자가 복제 RNA 분자는 알파바이러스 이외의 바이러스, 바람직하게는, 양성-가닥 RNA 바이러스, 및 더 바람직하게는 피코르나바이러스 (picornavirus), 플라비바이러스 (flavivirus), 루비바이러스 (rubivirus), 페스티바이러스 (pestivirus), 헤파시바이러스 (hepacivirus), 칼리시바이러스 (calicivirus), 또는 코로나바이러스 (coronavirus)로부터 유도되거나 이에 기초한다. 적합한 야생형 알파바이러스 서열은 잘 알려져 있고 American Type Culture Collection, Rockville, Md와 같은, 서열 수탁소로부터 이용 가능하다. 적합한 알파바이러스의 적합한 예는 아우라 (ATCC VR-368), 베바루 바이러스 (Bebaru virus; ATCC VR-600, ATCC VR-1240), 카바쏘우 (Cabassou; ATCC VR-922), 치쿤군야 바이러스 (ATCC VR-64, ATCC VR-1241), 이스턴 말 뇌염 바이러스 (ATCC VR-65, ATCC VR-1242), 포트 모건 (ATCC VR-924), 게타 바이러스 (ATCC VR-369, ATCC VR-1243), 키질라가크 (ATCC VR-927), 마야로 바이러스 (ATCC VR-66; ATCC VR-1277), 미들부르크 (ATCC VR-370), 무캄보 바이러스 (ATCC VR-580, ATCC VR-1244), 은두무 (ATCC VR-371), 픽수나 바이러스 (ATCC VR-372, ATCC VR-1245), 로스 리버 바이러스 (ATCC VR-373, ATCC VR-1246), 셈리키 포레스트 (ATCC VR-67, ATCC VR-1247), 신드비스 바이러스 (ATCC VR-68, ATCC VR-1248), 토나테 (Tonate; ATCC VR-925), 트리니티 (Triniti; ATCC VR-469), 우나 (ATCC VR-374), 베네수엘라 말 뇌염 (ATCC VR-69, ATCC VR-923, ATCC VR-1250 ATCC VR-1249, ATCC VR-532), 웨스턴 말 뇌염 (ATCC VR-70, ATCC VR-1251, ATCC VR-622, ATCC VR-1252), 화타로아 (ATCC VR-926), 및 Y-62-33 (ATCC VR-375)을 포함한다.
본 발명의 자가 복제 RNA 분자는 하나 이상의 변형된 뉴클레오티드를 함유할 수 있고 그러므로 개선된 안정성을 갖고 생체 내에서 분해 및 제거에 대하여 저항성이고, 다른 이점을 갖는다. 어떤 특정 이론에 결부되지 않고, 자가 복제 RNA가 세포 내로 전달될 때 변형된 뉴클레오티드를 함유하는 자가 복제 RNA 분자는 엔도솜 및 세포질 면역 수용체의 자극을 방지하거나 감소시키는 것으로 생각된다. 이것은 단백질의 자가 복제, 증폭 및 발현이 발생하는 것을 허용한다. 이것은 또한 변형된 뉴클레오티드를 함유하지 않는 자가 복제 RNA에 관하여 안전 의식을 감소시키는데, 변형된 뉴클레오티드를 함유하는 자가 복제 RNA가 선천적인 면역 시스템의 활성화 및 이후의 원하지 않는 결과 (예를 들어, 주사 부위의 염증, 주사 부위의 자극, 통증, 등)를 감소시키기 때문이다. 또한 자가 복제의 결과로서 생산된 RNA 분자는 세포질 면역 수용체에 의해 외부 핵산으로 인식되는 것으로 생각된다. 따라서, 변형된 뉴클레오티드를 함유하는 자가 복제 RNA 분자는 숙주 세포에서 RNA의 효율적인 증폭 및 CMV 단백질의 발현, 뿐만 아니라 보조 효과를 제공한다.
RNA 서열은, 예를 들어, 번역 효과 및 RNA의 반감기를 증가시키기 위해 그것의 코돈 이용에 대하여 변형될 수 있다. 폴리 A 꼬리 (예를 들어, 약 30개 이상의 아데노신 잔기의)는 그것의 반감기를 증가시키기 위해 RNA의 3' 말단에 부착될 수도 있다. RNA의 5' 말단은 구조 m7G (5') ppp (5') N (캡 0 구조) 또는 이들의 유도체를 갖는 변형된 리보뉴클레오티드로 캐핑 (capped)될 수도 있으며, 이것은 RNA 합성 중에 포함될 수 있거나 RNA 전사 후 효소로 설계될 수 있다 (예를 들어, 이것은 N7-모노메틸화된 캡 0 구조의 구성을 촉진하는, mRNA 트리포스파타제, 구아닐일-트랜스퍼라제 및 구아닌-7-메티트랜스퍼라제로 구성된 우두 바이러스 캐핑 효소 (VCE)를 이용하여). 캡 0 구조는 RNA 분자에 대한 안정성 및 번역 효과를 제공할 수 있다. RNA 분자의 5' 캡은 캡 1 구조 (m7Gppp [m2'-O]N)의 발생을 일으키는 2'-0-메틸트랜스퍼라제에 의해 추가로 변형될 수도 있으며, 이것은 번역 효과를 추가로 증가시킬 수도 있다. 캡 1 구조는 또한 생체 내 효능을 증가시킬 수도 있다.
여기에 이용된 바와 같이, "변형된 뉴클레오티드"는 뉴클레오시드 (예를 들어, 시토신 (C), 티민 (T) 또는 유라실 (U), 아데닌 (A) 또는 구아닌 (G))의 질소 염기에서 또는 위에 하나 이상의 화학적 변형 (예를 들어, 치환)을 함유하는 뉴클레오티드를 나타낸다. 원하는 경우, 자가 복제 RNA 분자는 뉴클레오시드의 당 모이어티 (예를 들어, 리보스, 데옥시리보스, 변형된 리보스, 변형된 데옥시리보스, 6-멤버의 당 유사체, 또는 오픈-사슬 당 유사체), 또는 포스페이트에서 또는 위에 화학적 변형을 함유할 수 있다.
자가 복제 RNA 분자는 적어도 하나의 변형된 뉴클레오티드를 함유할 수 있고, 이것은 바람직하게 5' 캡의 일부가 아니다 (예를 들어, 5'' 캡의 일부인 변형에 더하여). 따라서, 자가 복제 RNA 분자는 단일 위치에서 변형된 뉴클레오티드를 함유할 수 있고, 둘 이상의 위치에서 특정 변형된 뉴클레오티드 (예를 들어, 슈도유리딘, N6-메틸아데노신, 5-메틸시티딘, 5-메틸유리딘)을 함유할 수 있거나, 둘, 셋, 넷, 다섯, 여섯, 일곱, 여덟, 아홉, 열 개 이상의 변형된 뉴클레오티드 (예를 들어, 하나 이상의 위치에서 각각)를 함유할 수 있다. 바람직하게는, 자가 복제 RNA 분자는 질소 염기 상에 또는 질소 염기에 변형을 함유하는 변형된 뉴클레오티드를 포함하지만, 변형된 당 또는 포스페이트 모이어티를 함유하지 않는다.
일부 예에서, 자가 복제 RNA 분자의 뉴클레오티드 중 0.001% 내지 99%는 변형된 뉴클레오티드이다. 예를 들어, 자가 복제 RNA 분자의 뉴클레오티드중 0.001%-25%, 0.01%-25%, 0.1%-25%, 또는 1%-25%는 변형된 뉴클레오티드이다.
다른 예에서, 자가 복제 RNA 분자의 특정 변형되지 않은 뉴클레오티드 중 0.001% 내지 99% 또는 100%는 변형된 뉴클레오티드로 대체된다. 예를 들어, 유리딘을 함유하는 자가 복제 RNA 분자 중 약 1%는, 예를 들어, 유리딘의 슈도유리딘으로의 대체에 의해 변형될 수 있다. 다른 예에서, 자가 복제 RNA 분자에서 둘, 셋, 또는 네 개의 특정 뉴클레오티드 (유리딘, 시티딘, 구아노신, 또는 아데닌을 함유하는 뉴클레오티드)의 원하는 양 (퍼센트)은 변형된 뉴클레오티드이다. 예를 들어, 자가 복제 RNA 분자의 특정 뉴클레오티드 중 0.001%-25%, 0.01%-25%, 0.1%-25, 또는 1%-25%는 변형된 뉴클레오티드이다. 다른 예에서, 자가 복제 RNA 분자의 특정 뉴클레오티드 중 0.001%-20%, 0.001%-15%, 0.001%-10%, 0.01%-20%, 0.01%-15%, 0.1%-25, 0.01%-10%, 1%-20%, 1%-15%, 1%-10%, 또는 약 5%, 약 10%, 약 15%, 약 20%는 변형된 뉴클레오티드이다.
자가 복제 RNA 분자의 뉴클레오티드 중 100% 미만이 변형된 뉴클레오티드인 것이 바람직하다. 또한 자가 복제 RNA 분자 중 특정 뉴클레오티드의 100% 미만이 변형된 뉴클레오티드인 것이 바람직하다. 따라서, 바람직한 자가 복제 RNA 분자는 적어도 일부 변형되지 않은 뉴클레오티드를 포함한다.
포유동물 RNA에서 발견된 96개 이상의 자연 발생 뉴클레오시드 변형이 있다. 예를 들어, Limbach et al., Nucleic acids Research, 22(12):2183-2196 (1994) 참조. 예를 들어, 미국 특허 번호 4373071, 4458066, 4500707, 4668777, 4973679, 5047524, 5132418, 5153319, 5262530, 5700642의 뉴클레오티드 및 변형된 뉴클레오티드 및 뉴클레오시드의 제조는 업계에 잘 알려져 있으며, 이것들 모두는 전문이 본원에 참고로 포함되고, 많이 변형된 뉴클레오시드 및 변형된 뉴클레오티드는 상업적으로 이용 가능하다.
변형된 뉴클레오시드 및 뉴클레오티드에 포함될 수 있고 RNA 분자에 존재할 수 있는 변형된 핵염기는 m5C (5-메틸시티딘), m5U (5-메틸유리딘), m6A (N6-메틸아데노신), s2U (2-티오유리딘), Um (2'-0-메틸유리딘), m1A (1-메틸아데노신); m2A (2-메틸아데노신); Am (2-1-0-메틸아데노신); ms2m6A (2-메틸티오-N6-메틸아데노신); i6A (N6-이소펜테닐아데노신); ms2i6A (2-메틸티오-N6이소펜테닐아데노신); io6A (N6-(씨스-히드록시이소펜테닐)아데노신); ms2hn6A (2-메틸티오-N6-(씨스-히드록시이소펜테닐)아데노신); g6A (N6-글리시닐카르바모일아데노신); t6A (N6-트레오닐 카르바모일아데노신); ms2t6A (2-메틸티오-N6-트레오닐 카르바모일아데노신); m6t6A (N6-메틸-N6-트레오닐카르바모일아데노신); hn6A(N6-히드록시노르발일카르바모일 아데노신); ms2hn6A (2-메틸티오-N6-히드록시노르발일 카르바모일아데노신); Ar(p) (2'-0-리보실아데노신 (포스페이트)); I (이노신); m1I (1-메틸이노신); m'Im (1, 2'-0-디메틸이노신); m3C (3-메틸시티딘); Cm (2T-0-메틸시티딘); s2C (2-티오시티딘); ac4C (N4-아세틸시티딘); f5C (5-포닐시티딘); m5Cm (5, 2-O-디메틸시티딘); ac4Cm (N4아세틸2TO메틸시티딘); k2C (리시딘); m1G (1-메틸구아노신); m2G (N2-메틸구아노신); m7G (7-메틸구아노신); Gm (2'-0-메틸구아노신); m22G (N2, N2-디메틸구아노신); m2Gm (N2, 2'-0-디메틸구아노신); m22Gm (N2, N2, 2'-0-트리메틸구아노신); Gr(p) (2'-0-리보실구아노신 (포스페이트)); yW (위부토신); o2yW (퍼옥시위부토신); OHyW (히드록시위부토신); OHyW* (변형되지 않은 히드록시위부토신); imG (위오신); mimG (메틸구아노신); Q (퀘오신); oQ (에폭시퀘오신); galQ (갈탁토실-퀘오신); manQ (만노실-퀘오신); preQo (7-시아노-7-데아자구아노신); preQi (7-아미노메틸-7-데아자구아노신); G* (아케오신); D (디히드로유리딘); m5Um (5, 2'-0-디메틸유리딘); s4U (4-티오유리딘); m5s2U (5-메틸-2-티오유리딘); s2Um (2-티오-2'-0-메틸유리딘); acp3U (3-(3-아미노-3-카르복시프로필)유리딘); ho5U (5-히드록시유리딘); mo5U (5-메톡시유리딘); cmo5U (유리딘 5-옥시아세트산); mcmo5U (유리딘 5-옥시아세트산 메틸 에스테르); chm5U (5-(카르복시히드록시메틸)유리딘)); mchm5U (5-(카르복시히드록시메틸) 유리딘 메틸 에스테르); mcm5U (5-메톡시카르보닐 메틸유리딘); mcm5Um (S-메톡시카르보닐메틸-2-O-메틸유리딘); mcm5s2U (5-메톡시카르보닐메틸-2-티오유리딘); nm5s2U (5-아미노메틸-2-티오유리딘); mnm5U (5-메틸아미노메틸유리딘); mnm5s2U (5-메틸아미노메틸-2-티오유리딘); mnm5se2U (5-메틸아미노메틸-2-셀레노유리딘); ncm5U (5-카르바모일메틸 유리딘); ncm5Um (5-카르바모일메틸-2'-0-메틸유리딘); cmnm5U (5-카르복시메틸아미노메틸유리딘); cnmm5Um (5-카르복시메틸아미노메틸-2-L-O메틸유리딘); cmnm5s2U (5-카르복시메틸아미노메틸-2-티오유리딘); m62A (N6, N6-디메틸아데노신); Tm (2'-0-메틸이노신); m4C (N4-메틸시티딘); m4Cm (N4, 2-0-디메틸시티딘); hm5C (5-히드록시메틸시티딘); m3U (3-메틸유리딘); cm5U (5-카르복시메틸유리딘); m6Am (N6, T-0-디메틸아데노신); rn62Am (N6, N6, 0-2-트리메틸아데노신); m2'7G (N2, 7-디메틸구아노신); m2'2'7G (N2, N2, 7-트리메틸구아노신); m3Um (3, 2T-0-디메틸유리딘); m5D (5-메틸디히드로유리딘); f5Cm (5-포밀-2'-0-메틸시티딘); m1Gm (1, 2'-0-디메틸구아노신); m'Am (1, 2-O-디메틸 아데노신) 이리노메틸유리딘); tm5s2U (S-타우리노메틸-2-티오유리딘)); imG-14 (4-데메틸 구아노신); imG2 (이소구아노신); ac6A (N6-아세틸아데노신), 히폭산틴, 이노신, 8-옥소-아데닌, 7-치환된 이들의 유도체, 디히드로유라실, 슈도유라실, 2-티오유라실, 4-티오유라실, 5-아미노유라실, 5-(C1-C6)-알킬유라실, 5-메틸유라실, 5-(C2-C6)-알케닐유라실, 5-(C2-C6)-알키닐유라실, 5-(히드록시메틸)유라실, 5-클로로유라실, 5-플루오로유라실, 5-브로모유라실, 5-히드록시시토신, 5-(C1-C6)-알킬시토신, 5-메틸시토신, 5-(C2-C6)-알케닐시토신, 5-(C2-C6)-알키닐시토신, 5-클로로시토신, 5-플루오로시토신, 5-브로모시토신, N2-디메틸구아닌, 7-데아자구아닌, 8-아자구아닌, 7-데아자-7-치환된 구아닌, 7-데아자-7-(C2-C6)알키닐구아닌, 7-데아자-8-치환된 구아닌, 8-히드록시구아닌, 6-티오구아닌, 8-옥소구아닌, 2-아미노퓨린, 2-아미노-6 클로로퓨린, 2, 4-디아미노퓨린, 2, 6-디아미노퓨린, 8-아자퓨린, 치환된 7-데아자퓨린, 7-데아자-7-치환된 퓨린, 7-데아자-8-치환된 퓨린, 수소 (무염기 잔기), m5C, m5U, m6A, s2U, W, 또는 2'-0-메틸-U를 포함한다. 이 변형된 핵염기 중 어느 하나 또는 어느 조합도 본 발명의 자가 복제 RNA에 포함될 수 있다. 이 변형된 핵염기 및 그것들의 해당 리보뉴클레오시드의 대부분은 상업적 공급자로부터 이용 가능하다. 원하는 경우, 자가 복제 RNA 분자는 포스포르아미데이트, 포스포로티오에이트, 및/또는 메틸포스포네이트 연결을 함유할 수 있다.
적어도 하나의 변형된 뉴클레오티드를 포함하는 자가 복제 RNA 분자는 어떤 적합한 방법을 이용하여 제조될 수 있다. 변형된 뉴클레오티드를 함유하는 RNA 분자를 생산하는 다수의 적합한 방법은 업계에 알려져 있다. 예를 들어, 변형된 뉴클레오티드를 함유하는 RNA 분자는 적합한 DNA-의존 RNA 폴리머라제, 예를 들어, T7 파지 RNA 폴리머라제, SP6 파지 RNA 폴리머라제, T3 파지 RNA 폴리머라제, 등, 또는 변형된 뉴클레오티드의 RNA 분자에 효율적인 포함을 허용하는 이 폴리머라제의 돌연변이를 이용하여 자가 복제 RNA 분자를 암호화하는 DNA를 전사 (예를 들어, 시험관 내 전사)함으로써 제조될 수 있다. 전사 반응은 뉴클레오티드 및 변형된 뉴클레오티드, 및 적합한 완충액, 및 적합한 염과 같은, 선택된 폴리머라제의 활성을 지원하는 다른 요소를 함유할 것이다. 뉴클레오티드 유사체의 자가 복제 RNA에 포함은, 예를 들어, 이러한 RNA 분자의 안정성을 변화시키기 위해, RN아제에 대한 저항성을 증가시키기 위해, 적절한 숙주 세포 내로 도입 후 복제 (RNA의 "감염성")를 확립하기 위해, 및/또는 선천적 및 후천적 면역 반응을 유발하거나 감소시키기 위해, 설계될 수도 있다.
하나 이상의 변형된 뉴클레오티드를 함유하는 자가 복제 RNA 분자를 생산하기 위하여, 적합한 합성 방법은 단독으로, 또는 하나 이상의 다른 방법 (예를 들어, 재조합 DNA 및 RNA 기술)과 조합하여 이용될 수 있다. 데 노보 (de novo) 합성에 적합한 방법은 업계에 잘 알려져 있고 특정 용도로 적용될 수 있다. 전형적인 방법은, 예를 들어, CEM과 같은 적합한 보호기를 이용하는 화학적 합성 (Masuda et al., (2007) Nucleic Acids Symposium Series 57:3-4), β-시아노에틸 포스포르아미디트 방법 (Beaucage S L et al. (1981) Tetrahedron Lett 22: 1859); 뉴클레오시드 H-포스포네이트 방법 (Garegg P et al. (1986) Tetrahedron Lett 27:4051-4; Froehler B C et al. (1986) Nucl Acid Res 14:5399-407; Garegg P et al. (1986) Tetrahedron Lett 27:4055-8; Gaffney B L et al. (1988) Tetrahedron Lett 29:2619-22). 이 화학법들은 상업적으로 이용 가능한 자동화된 핵산 합성기를 이용하여 수행되거나 적용될 수 있다. 추가적인 적합한 합성 방법은 Uhlmann et al. (1990) Chem Rev 90:544-84, 및 Goodchild J (1990) Bioconjugate Chem 1: 165에 개시된다. 핵산 합성은 또한 폴리뉴클레오티드 및 이러한 폴리뉴클레오티드에 의해 암호화된 유전자 생성물의 클로닝, 가공, 및/또는 발현을 포함하는, 업계에 잘 알려져 있고 통상적인 적합한 재조합 방법을 이용하여 수행될 수 있다. 유전자 단편 및 합성 폴리뉴클레오티드의 무작위 단편화 및 PCR 재결합에 의한 DNA 셔플링은 폴리뉴클레오티드 서열을 디자인 및 설계하기 위해 이용될 수 있다.
부위-방향 돌연변이 발생은, 예를 들어, 새로운 제한 부위를 삽입하고, 글리코실화 패턴을 변화시키고, 코돈 선호도를 바꾸고, 스플라이스 변이체를 생산하고, 돌연변이를 도입하기 위해 핵산 및 암호화된 단백질을 변화시키기 위해 이용될 수 있다. 핵산 서열의 전사, 번역 및 발현을 위한 적합한 방법은 업계에 알려져 있고 통상적이다. (일반적으로, Current Protocols in Molecular Biology, Vol. 2, Ed. Ausubel, et al., Greene Publish. Assoc. & Wiley Interscience, Ch. 13, 1988; Glover, DNA Cloning, Vol. II, IRL Press, Wash., D.C., Ch. 3, 1986; Bitter, et al., in Methods in Enzymology 153:516-544 (1987); The Molecular Biology of the Yeast Saccharomyces, Eds. Strathern et al., Cold Spring Harbor Press, Vols. I and II, 1982; 및 Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, 1989. 참조)
자가 복제 RNA 분자에서 하나 이상의 변형된 뉴클레오티드의 존재 및/또는 양은 어떤 적합한 방법을 이용하여 결정될 수 있다. 예를 들어, 자가 복제 RNA는 모노포스페이트에 분해되고 (예를 들어, 뉴클레아제 PI) 탈인산화될 수 있고 (예를 들어, CIAP와 같은 적합한 포스파타제를 이용하여), 결과의 뉴클레오시드는 역상 (reversed phase) HPLC (예를 들어, YMC Pack ODS-AQ 컬럼 (5 미크론, 4.6 X 250 mm)을 이용하여) 및 구배, 0% B (0-5 분) 내지 100% B (5-13 분) 및 100 % B (13-40 분), 유속 (0.7 ml/ 분), UV 검출 (파장: 260 nm), 컬럼 온도 (30 ℃)를 이용하여 용출에 의해 분석된다. 완충액 A (20mM 아세트산-암모늄 아세테이트 pH 3.5), 완충액 B (20mM 아세트산-암모늄 아세테이트 pH 3.5/메탄올 [90/10])).
자가 복제 RNA는 전달 시스템과 연관될 수도 있다. 자가 복제 RNA는 보조제와 함께 또는 없이 투여될 수도 있다.
RNA 전달 시스템
여기에 설명된 자가 복제 RNA는 노출 RNA 전달과 같이, 다양한 양상으로 또는 지질, 폴리머 또는 세포 내로 유입을 용이하게 하는 다른 화합물과 조합하여 전달에 적합하다. 자가 복제 RNA 분자는 어떤 적합한 기술을 이용하여, 예를 들어, 직접적인 주사, 미크로주사, 전기 천공, 리포펙션, 생물 분해, 등에 의해 표적 세포 또는 대상체 내로 도입될 수 있다. 자가 복제 RNA 분자는 또한 수용체-매개 세포 이물 흡수의 방법에 의해 세포 내로 도입될 수도 있다. 예를 들어, 미국 특허 번호 6,090,619; Wu and Wu, J. Biol. Chem., 263: 14621 (1988); 및 Curiel et al, Proc. Natl. Acad. Sci. USA, 88:8850 (1991) 참조. 예를 들어, 미국 특허 번호 6, 083, 741는 핵산을 다가 양이온 모이어티 (예를 들어, 3-100개의 리신 잔기(SEQ ID NO:4)를 갖는 폴리-L-리신)에 연관시킴으로써 포유동물 세포 내로 외인성 핵산을 도입하는 것을 개시하며, 그것은 스스로 인테그린 수용체-결합 모이어티 (예를 들어, 서열 Arg-Gly-Asp (SEQ ID NO:5)를 갖는 고리형 펩티드)에 결합된다
자가 복제 RNA 분자는 양친매성 물질 (amphiphile)을 통해 세포 내로 전달될 수 있다. 예를 들어, 미국 특허 번호 6, 071, 890 참조. 전형적으로, 핵산 분자는 양이온성 양친매성 물질과 함께 복합체를 형성할 수도 있다. 복합체에 접촉된 포유동물 세포는 쉽게 그것을 수용할 수 있다.
자가 복제 RNA는 노출 RNA로서 (예를 들어, 단지 RNA의 수용액으로서) 전달될 수 있지만, 세포 내로 유입 및 또한 이후의 세포 내 효과를 향상시키기 위해, 자가 복제 RNA는 바람직하게 미립자 또는 에멀젼 전달 시스템과 같은, 전달 시스템과 조합하여 투여된다. 다수의 전달 시스템이 당업자에게 잘 알려져 있다. 이러한 전달 시스템은, 예를 들어, 리포솜-기반 전달 (DebsVRPZhu (1993) WO 93/24640; Mannino and Gould-Fogerite (1988) BioTechniques 6(7): 682-691; Rose 미국 특허 번호 5,279,833; Brigham (1991) WO 91/06309; 및 Feigner et al. (1987) Proc. Natl. Acad. Sci. USA 84: 7413-7414), 뿐만 아니라 바이러스 벡터 (예를 들어, 아데노바이러스 (재검토를 위해, 예를 들어, Berns et al. (1995) Ann. NY Acad. Sci. 772: 95-104; Ali et al. (1994) Gene Ther. 1: 367-384; 및 Haddada et al. (1995) Curr. Top. Microbiol. Immunol. 199 (Pt 3): 297-306 참조), 파필로마바이러스 (papillomavirus), 레트로바이러스 (예를 들어, 상기 Buchscher et al. (1992) J. Virol. 66(5) 2731-2739; Johann et al. (1992) J. Virol. 66 (5): 1635-1640 (1992); Sommerfelt et al, (1990) Virol. 176:58-59; Wilson et al. (1989) J. Virol. 63:2374-2378; Miller et al, J. Virol. 65:2220-2224 (1991); Wong-Staal et al, PCT/US94/05700, 및 Rosenburg and Fauci (1993) in Fundamental Immunology, Third Edition Paul (ed) Raven Press, Ltd., New York 및 그것들의 참고문헌, 및 Yu et al, Gene Therapy (1994) 참조), 및 아데노-연관된 바이러스 벡터 (West et al. (1987) Virology 160:38-47; Carter et al. (1989) 미국 특허 번호 4,797,368; Carter et al. WO 93/24641 (1993); Kotin (1994) Human Gene Therapy 5:793-801; Muzyczka (1994) J. Clin. Invst. 94: 1351 및 AAV 벡터의 개요를 위해 Samulski (상기); 또한, Lebkowski, 미국 특허 번호 5,173,414; Tratschin et al. (1985) Mol. Cell. Biol. 5(11):3251-3260; Tratschin, et al. (1984) Mol. Cell. Biol, 4:2072-2081; Hermonat and Muzyczka (1984) Proc. Natl. Acad. Sci. USA, 81:6466-6470; McLaughlin et al. (1988) 및 Samulski et al. (1989) J. Virol, 63:03822-3828 참조), 등의 이용을 포함한다.
세 개의 특히 유용한 전달 시스템은 (i) 리포솜, (ii) 비독성 및 생 분해성 폴리머 미세입자, 및 (iii) 양이온성 서브미크론 수중유 에멀젼이다.
리포솜
다양한 양친매성 지질은 리포솜과 같은 RNA-함유 수성 코어를 캡슐화하기 위하여 수성 환경에서 이중층을 형성할 수 있다. 이 지질들은 음이온성, 양이온성 또는 쌍성이온성 친수성 머리 그룹을 가질 수 있다. 음이온성 인지질로부터 리포솜의 형성은 1960년대 부터이고, 양이온성 리포솜-형성 지질은 1990년대 이후에 연구되었다. 일부 인지질은 음이온성인 한편, 다른 것들은 쌍성이온성이다. 적합한 인지질의 종류는 포스파티딜에탄올아민, 포스파티딜콜린, 포스파티딜세린, 및 포스파티딜글리세롤을 포함하지만, 이에 제한되지 않고, 일부 유용한 인지질은 표 2에 나열된다. 유용한 양이온성 지질은 디올레오일 트리메틸 암모늄 프로판 (DOTAP), 1, 2-디스테아릴옥시-N, N-디메틸-3-아미노프로판 (DSDMA), 1, 2-디올레일옥시-N, N디메틸-3-아미노프로판 (DODMA), 1, 2-디리놀레일옥시-N, N-디메틸-3-아미노프로판 (DLinDMA), 1, 2-디리놀레닐옥시-N, N-디메틸-3-아미노프로판 (DLenDMA)을 포함하지만, 이에 제한되지 않는다. 쌍성이온성 지질은 아실 쌍성이온성 지질 및 에테르 쌍성이온성 지질을 포함하지만, 이에 제한되지 않는다. 유용한 쌍성이온성 지질의 예는 DPPC, DOPC, 및 도데실포스포콜린이다. 지질은 포화되거나 불포화될 수 있다.
리포솜은 단일 지질로부터 또는 지질의 혼합물로부터 형성될 수 있다. 혼합물은 (i) 음이온성 지질의 혼합물, (ii) 양이온성 지질의 혼합물, (iii) 쌍성이온성 지질의 혼합물, (iv) 음이온성 지질 및 양이온성 지질의 혼합물, (v) 음이온성 지질 및 쌍성이온성 지질의 혼합물, (vi) 쌍성이온성 지질 및 양이온성 지질의 혼합물 또는 (vii) 음이온성 지질, 양이온성 지질 및 쌍성이온성 지질의 혼합물을 포함할 수도 있다. 유사하게, 혼합물은 포화된 및 불포화된 지질 둘 다를 포함할 수도 있다. 예를 들어, 혼합물은 DSPC (쌍성이온성, 포화), DlinDMA (양이온성, 불포화), 및/또는 DMPG (음이온성, 포화)를 포함할 수도 있다. 지질의 혼합물이 이용되는 경우, 혼합물의 성분 지질 모두가 양친매성 물질일 필요는 없다, 예를 들어, 하나 이상의 양친매성 지질이 콜레스테롤과 혼합될 수 있다.
지질의 친수성 부 분은 PEG와 반응될 수 있다 (즉, 폴리에틸렌 글리콜의 공유 부착에 의해 변형된다). 이 변형은 안정성을 증가시킬 수 있고 리포솜의 비-특이적 흡착을 방지한다. 예를 들어, 리피드는 Heyes et al. (2005) J Controlled Release 107:276-87에 개시된 것들과 같은 기술을 이용하여 PEG와 접합될 수 있다.
DSPC, DlinDMA, PEG-DMPG 및 콜레스테롤의 혼합물은 리포솜을 형성하기 위해 이용될 수 있다. 본 발명의 별도의 양태는 DSPC, DlinDMA, PEG-DMG 및 콜레스테롤을 포함하는 리포솜이다. 이 리포솜은 바람직하게는, 예를 들어, 면역원을 암호화하는 자가 복제 RNA와 같은 RNA를 캡슐화한다.
리포솜은 보통 세 그룹으로 분류된다: 중층 소낭 (MLV); 작은 단층 소낭 (SUV); 및 큰 단층 소낭 (LUV). MLV는 각각의 소낭에 다수의 이중층을 갖고, 여러 별도의 수성 구획을 형성한다. SUB 및 LUV는 수성 코어를 캡슐화하는 단일 이중층을 갖는다; SUV는 전형적으로 50 nm보다 작은 직경을 갖고, LUV는 50 nm보다 큰 직경을 갖는다. 본 발명에 유용한 리포솜은 이상적으로 50-220 nm의 범위의 직경을 갖는 LUV이다. 다른 직경을 갖는 LUV의 개체군을 포함하는 조성물에 대하여: (i) 숫자로 적어도 80%는 20-220 nm의 범위의 직경을 갖고, (ii) 개체군의 평균 직경 (Zav, 강도로)은 이상적으로 40-200 nm의 범위에 있고, 및/또는 (iii) 직경은 0.2보다 작은 다 분산 지수 (polydispersity index)를 가져야 한다.
적합한 리포솜을 제조하는 기술은 업계에 잘 알려져 있다, 예를 들어, Liposomes: Methods and Protocols, Volume 1: Pharmaceutical Nanocarriers: Methods and Protocols, (ed. Weissig). Humana Press, 2009. ISBN 160327359X; Liposome Technology, volumes I, II & III. (ed. Gregoriadis). Informa Healthcare, 2006; 및 Functional Polymer Colloids and Microparticles volume 4 (Microspheres, microcapsules & liposomes), (eds. Arshady & Guyot). Citus Books, 2002 참조. 한 유용한 방법은 (i) 지질의 에탄올성 용액, (ii) 핵산의 수용액 및 (iii) 완충액을 혼합한 후 이어서 혼합, 평형, 희석 및 정제하는 단계를 수반한다 (Heyes et al. (2005) J Controlled Release 107:276-87.).
RNA는 바람직하게는 리포솜 내에 캡슐화되고, 그래서 리포솜은 수성 RNA-함유 코어 주위에 외층을 형성한다. 이 캡슐화는 RN아제 분해로부터 RNA를 보호하는 것으로 발견되었다. 리포솜은 일부 외부 RNA를 포함할 수 있지만 (예를 들어, 리포솜의 표면 상에), 바람직하게는, 적어도 절반의 RNA (및 이상적으로는 그것의 실질적으로 모든 것)는 캡슐화된다.
폴리머 미세입자
다양한 폴리머는 RNA를 캡슐화하거나 흡착하기 위해 미세입자를 형성할 수 있다. 실질적으로 비-독성 폴리머의 이용은 수령체가 안전하게 입자를 받을 수 있다는 것을 의미하고, 생 분해성 폴리머의 이용은 입자가 장기간 지속을 방지하기 위해 전달 후 대사될 수 있다는 것을 의미한다. 유용한 폴리머는 또한 약학적 등급의 제형의 제조를 돕기 위해, 멸균 가능하다.
적합한 비-독성 및 생 분해성 폴리머는 폴리(α-히드록시산), 폴리히드록시 부티르산, 폴리락톤 (폴리카프로락톤을 포함), 폴리디옥사논, 폴리발레로락톤, 폴리오르토에스테르, 폴리무수물, 폴리시아노아크릴레이트, 티로신-유도된 폴리카르보네이트, 폴리비닐피롤리디논 또는 폴리에스테르-아미드, 및 이들의 조합을 포함하지만, 이에 제한되지 않는다.
일부 구체예에서, 미세입자는 폴리(락티드) ("PLA")와 같은 폴리(α-히드록시산), 폴리(D, L-락티드-코-글리콜리드) ("PLG")와 같은 락티드 및 글리콜리드의 코폴리머, 및 D, L-락티드 및 카프로락톤의 코폴리머로부터 형성된다. 유용한 PLG 폴리머는, 예를 들어, 20:80 내지 80:20, 예를 들어, 25:75, 40:60, 45:55, 55:45, 60:40, 75:25의 범위의 락티드/글리콜리드 분자비를 갖는 것들을 포함한다. 유용한 PLG 폴리머는, 예를 들어, 5, 000-200, 000 Da, 예를 들어, 10, 000-100, 000, 20, 000-70, 000, 40, 000-50, 000 Da의 분자량을 갖는 것들을 포함한다.
미세입자는 이상적으로 0.02 μm 내지 8 μm의 범위의 직경을 갖는다. 숫자로 적어도 80%에서 다른 직경을 갖는 미세입자의 개체군을 포함하는 조성물은 0.03 μm-7 μm의 범위의 직경을 갖는다.
적합한 미세입자를 제조하는 기술은 업계에 잘 알려져 있고, 예를 들어, Functional Polymer Colloids Microparticles volume 4 (Microspheres, microcapsules & liposomes), (eds. Arshady & Guyot). Citus Books, 2002; Polymers in Drug Delivery, (eds. Uchegbu & Schatzlein). CRC Press, 2006. (특히 7장에) 및 Microparticulate Systems for the Delivery of Proteins and Vaccines. (eds. Cohen & Bernstein). CRC Press, 1996 참조. RNA의 흡착을 용이하게 하기 위해서, 미세입자는, 예를 들어, O'Hagan et al. (2001) J Virology 75: 9037-9043; 및 Singh et al. (2003) Pharmaceutical Research 20: 247-251에 개시된 바와 같은, 양이온성 계면활성제 및/또는 지질을 포함할 수도 있다. 폴리머 미세입자를 만드는 대체 방법은, 예를 들어, WO2009/132206에 개시된 바와 같이 성형 및 경화에 의한 것이다.
본 발명의 미세입자는 40-100 mV의 제타 전위를 가질 수 있다.
RNA는 미세입자에 흡착될 수 있고, 흡착은 미세입자에 양이온성 물질 (예를 들어, 양이온성 지질)을 포함함으로써 촉진된다.
수중유 양이온성 에멀젼
수중유 에멀젼은 보조 인플루엔자 백신, 예를 들어, FLUAD™ 제품의 MF59™, 및 PREPANDRIX™ 제품의 AS03 보조제에 대하여 알려져 있다.RNA 전달은 수중유 에멀젼의 이용으로 달성될 수 있으며, 에멀젼이 하나 이상의 양이온성 분자를 함유한다는 것이 제공된다. 예를 들어, 양이온성 지질은 음전하를 띈 RNA가 부착할 수 있는 양전하를 띈 방울 표면을 제공하기 위해 에멀젼에 포함될 수 있다.
에멀젼은 하나 이상의 오일을 포함한다. 적합한 오일(들)은, 예를 들어, 동물 (물고기와 같은) 또는 식물성 근원의 것들을 포함한다. 오일은 이상적으로 생 분해성 (대사 가능) 및 생체적합성이다. 식물성 오일에 대한 근원은 견과류, 씨앗 및 곡물을 포함한다. 가장 일반적으로 이용 가능한, 땅콩 오일, 대두 오일, 코코넛 오일, 및 올리브 오일은 견과류 오일의 예이다. 예를 들어, 호호바 (jojoba) 콩에서 얻어진 호호바 오일이 이용될 수 있다. 씨앗 오일은 잇꽃 오일, 목화씨 오일, 해바라기 씨 오일, 참기름 등을 포함한다. 곡물 그룹에서, 옥수수 오일은 가장 쉽게 이용 가능하지만, 밀, 귀리, 호밀, 쌀, 테프 (teff), 라이밀 (triticale) 등과 같은 다른 곡물의 오일이 또한 이용될 수도 있다. 글리세롤 및 1, 2-프로판디올의 6-10개의 탄소 지방산 에스테르는 씨앗 오일에서 자연 발생하지 않는 반면, 견과류 및 씨앗 오일에서 적절한 물질의 가수 분해, 분리 및 에스테르화에 의해 제조될 수도 있다. 포유동물의 우유의 지방 및 오일은 대사 가능하고 그래서 이용될 수도 있다. 분리, 정제, 비누화에 대한 공정 및 동물 근원의 순수한 오일을 얻는데 필요한 다른 방법들은 업계에 잘 알려져 있다.
대부분의 물고기는 쉽게 회수될 수도 있는 대사 가능한 오일을 함유한다. 예를 들어, 대구 간 오일, 상어 간 오일, 및 경뇌유 (spermaceti)와 같은 고래 오일은 여기에 이용될 수도 있는 다양한 물고기 오일의 예이다. 다수의 분지형 사슬 오일이 생화학적으로 5-탄소 이소프렌 단위로 합성되고 일반적으로 테르페노이드로서 나타난다. 스쿠알렌, 스쿠알렌에 대한 포화 유사체가 또한 이용될 수 있다. 스쿠알렌 및 스쿠알란을 포함하는 물고기 오일은 상업적 근원으로부터 쉽게 이용 가능하거나 업계에 알려진 방법에 의해 얻어질 수도 있다.
다른 유용한 오일은, 특히 스쿠알렌과 조합된, 토코페롤이다. 에멀젼의 유상이 토코페롤을 포함하는 경우, α, β, γ, δ, ε 또는 ξ 토코페롤 중 어느 것도 이용될 수 있지만, α-토코페롤이 바람직하다. D-α-토코페롤 및 DL-α-토코페롤은 둘 다 이용될 수 있다. 바람직한 α-토코페롤은 DL-α-토코페롤이다. 스쿠알렌 및 토코페롤 (예를 들어, DL-α-토코페롤)을 포함하는 오일 조합이 이용될 수 있다.
바람직한 에멀젼은 분지형, 불포화 테르페노이드 (C30H50; [(CH3)2C[=CHCH2CH2C(CH3)]2=CHCH2-]2; 2, 6, 10, 15, 19, 23-헥사메틸-2, 6, 10, 14, 18, 22-테트라코사헥사엔; CAS R 7683-64-9)인, 스쿠알렌, 상어 간 오일을 포함한다.
에멀젼 중의 오일은 오일의 조합, 예를 들어, 스쿠알렌 및 적어도 하나의 추가 오일을 포함할 수도 있다.
에멀젼의 수성 성분은 담수 (예를 들어, w.f.i.)일 수 있거나 추가 성분, 예를 들어, 용질을 포함할 수 있다. 예를 들어, 그것은 완충액을 형성하기 위해 염, 예를 들어, 시트레이트 또는 포스페이트 염, 예를 들어, 나트륨 염을 포함할 수도 있다. 전형적인 완충액은 포스페이트 완충액; 트리스 완충액; 붕산염 완충액; 숙신산염 완충액; 히스티딘 완충액; 또는 시트레이트 완충액을 포함한다. 완충된 수상이 바람직하고, 완충액은 전형적으로 5-20 mM 범위에 포함될 것이다.
에멀젼은 또한 양이온성 지질을 포함한다. 바람직하게는 이 지질은 에멀젼의 형성 및 안정화를 용이하게 할 수 있는 계면활성제이다. 예를 들어, 3차 또는 4차 아민과 같이 유용한 양이온성 지질은 일반적으로 생리학적 조건하에 양전하를 띈 질소 원자를 함유한다. 이 질소는 양친매성 계면활성제의 친수성 머리 그룹에 있을 수 있다. 유용한 양이온성 지질은 1, 2-디올레오일옥시-3-(트리메틸암모니오)프로판 (DOTAP), 3'-[N-(N', N'-디메틸아미노에탄)-카르바모일]콜레스테롤 (DC 콜레스테롤), 디메틸디옥타데실암모늄 (DDA, 예를 들어, 브로마이드), 1, 2-디미리스토일-3-트리메틸-암모늄프로판 (DMTAP), 디팔미토일(C16:0)트리메틸 암모늄 프로판 (DPTAP), 디스테아로일트리메틸암모늄 프로판 (DSTAP)을 포함하지만, 이에 제한되지 않는다. 다른 유용한 양이온성 지질은 벤잘코늄 클로라이드 (BAK), 벤제토늄 클로라이드, 세트라미드 (이것은 테트라데실트리메틸암모늄 브로마이드 및 경우에 따라 소량의 데데실트리메틸암모늄 브로마이드 및 헥사데실트리메틸 암모늄 브로마이드를 포함한다), 세틸프리디늄 클로라이드 (CPC), 세틸 트리메틸암모늄 클로라이드 (CTAC), Ν, Ν', Ν'-폴리옥시에틸렌 (10)-N-수지-1, 3-디아미노프로판, 도데실트리메틸암모늄 브로마이드, 헥사데실트리메틸-암모늄 브로마이드, 혼합된 알킬-트리메틸-암모늄 브로마이드, 벤질디메틸도데실암모늄 클로라이드, 벤질디메틸헥사데실-암모늄 클로라이드, 벤질트리메틸암모늄 메톡시드, 세틸디메틸에틸암모늄 브로마이드, 디메틸디옥타데실 암모늄 브로마이드 (DDAB), 메틸벤제토늄 클로라이드, 데카메토늄 클로라이드, 메틸 혼합된 트리알킬 암모늄 클로라이드, 메틸 트리옥틸암모늄 클로라이드), N, N-디메틸-N-[2(2-메틸-4-(1, 1, 3, 3테트라메틸부틸)-페녹시]-에톡시)에틸]-벤젠메타-나미늄 클로라이드 (DEBDA), 디알킬디메틸암모늄 염, [1-(2, 3-디올레일옥시)-프로필]-N, N, N, 트리메틸암모늄 클로라이드, 1, 2-디아실-3-(트리메틸암모니오) 프로판 (아실기=디미리스토일, 디팔미토일, 디스테아로일, 디올레오일), 1, 2-디아실-3 (디메틸암모니오)프로판 (아실기=디미리스토일, 디팔미토일, 디스테아로일, 디올레오일), 1, 2-디올레오일-3-(4'-트리메틸-암모니오)부타노일-sn-글리세롤, 1, 2-디올레오일 3-숙시닐-sn-글리세롤 콜린 에스테르, 콜레스테릴 (4'-트리메틸암모니오) 부타노에이트), N-알킬 피리디늄 염 (예를 들어, 세틸프리디늄 브로마이드 및 세틸프리디늄 클로라이드), N-알킬피페리디늄 염, 이중양이온성 볼라폼 전해질 (C12Me6; C12BU6), 디알킬글리세틸포스포릴콜린, 리소레시틴, L-α디올레오일포스파티딜에탄올아민, 콜레스테롤 헤미숙시네이트 콜린 에스테르, 디옥타데실아미도글리실스페르민 (DOGS), 디팔미토일 포스파티딜에탄올-아미도스페르민 (DPPES), 리포폴리-L (또는 D)-리신 (LPLL, LPDL), N-글루타릴포스파티딜에탄올아민에 접합된 폴리 (L (또는 D)-리신을 포함하지만, 이에 제한되지 않는, 리포폴리아민, 펜던트 아미노기를 갖는 디도데실 글루타메이트 에스테르 (C^GluPhCnN), 펜던트 아미노기를 갖는 디테트라데실 글루타메이트 에스테르 (C14GIuCnN+), 콜레스테릴-3 β-옥시숙신아미도에틸렌트리메틸암모늄 염, 콜레스테릴-3 β-옥시숙신아미도에틸렌-디메틸아민, 콜레스테릴-3 β-카르복시아미도에틸렌트리메틸암모늄 염, 및 콜레스테릴-3 β-카르복시아미도에틸렌디메틸아민을 포함하지만, 이에 제한되지 않는, 콜레스테롤의 양이온성 유도체이다. 다른 유용한 양이온성 지질은 US 2008/0085870 및 US 2008/0057080에 설명되며, 이것은 본원에 참고로 포함된다. 양이온성 지질은 바람직하게는 생 분해성 (대사 가능) 및 생체적합성이다.
오일 및 양이온성 지질에 더하여, 에멀젼은 비이온성 계면활성제 및/또는 쌍성이온성 계면활성제를 포함한다. 이러한 계면활성제는 폴리옥시에틸렌 소르비탄 에스테르 계면활성제 (일반적으로 Tween으로 나타냄), 특히 폴리소르베이트 20 및 폴리소르베이트 80; DOWFAX™ 상표명 하에 판매되는 에틸렌 옥시드 (EO), 프로필렌 옥시드 (PO), 및/또는 부틸렌 옥시드 (BO)의 코폴리머, 예를 들어, 선형 EO/PO 블록 코폴리머; 옥톡시놀-9 (Triton X-100, 또는 t-옥틸페녹시폴리에톡시에탄올)가 특히 흥미있는, 반복되는 에톡시 (옥시-1, 2-에탄디일) 기의 수에 따라 달라질 수 있는 옥톡시놀; (옥틸페녹시)폴리에톡시에탄올 (IGEPAL CA-630/NP-40); 포스파티딜콜린 (레시틴)과 같은 포스포리피드; 라우릴, 세틸, 스테아릴 및 올레일 알콜로부터 유도된 폴리옥시에틸렌 지방 에테르 (Brij 계면활성제로서 알려짐), 예를 들어, 트리에틸렌글리콜 모노라우릴 에테르 (Brij 30); 폴리옥시에틸렌-9-라우릴 에테르; 및 소르비탄 에스테르 (일반적으로 Span으로 알려짐), 예를 들어, 소르비탄 트리올레에이트 (Span 85) 및 소르비탄 모노라우레이트를 포함하지만, 이에 제한되지 않는다. 에멀젼에 포함하기 위한 바람직한 계면활성제는 폴리소르베이트 80 (Tween 80; 폴리옥시에틸렌 소르비탄 모노올레에이트), Span 85 (소르비탄 트리올레에이트), 레시틴 및 Triton X-100이다.
이 계면활성제의 혼합물, 예를 들어, Tween 80/Span 85 혼합물, 또는 Tween 80/Triton-X100 혼합물은 에멀젼에 포함될 수 있다. 폴리옥시에틸렌 소르비탄 모노올레에이트 (Tween 80)와 같은 폴리옥시에틸렌 소르비탄 에스테르 및 t-옥틸페녹시-폴리에톡시에탄올 (Triton X-100)과 같은 옥톡시놀의 조합이 또한 적합하다. 또 다른 유용한 조합은 라우레쓰 9 플로스 폴리옥시에틸렌 소르비탄 에스테르 및/또는 옥톡시놀을 포함한다. 유용한 혼합물은 10-20의 범위의 HLB 값을 갖는 계면활성제 (예를 들어, 15.0의 HLB를 갖는 폴리소르베이트 80) 및 1-10의 범위의 HLB 값을 갖는 계면활성제 (예를 들어, 1.8의 HLB를 갖는 소르비탄 트리올레에이트)를 포함할 수 있다.
최종 에멀젼에서 바람직한 오일의 양 (부피%)은 2-20%, 예를 들어, 5-15%, 6-14%, 7-13%, 8-12%이다. 약 4-6% 또는 약 9-11%의 스쿠알렌 함량이 특히 유용하다.
최종 에멀젼에서 바람직한 계면활성제의 양 (중량%)은 0.001% 내지 8%이다. 예를 들어, 폴리옥시에틸렌 소르비탄 에스테르 (폴리소르베이트 80와 같은)는 0.2 내지 4%, 특히 0.4-0.6%, 0.45-0.55%, 약 0.5% 또는 1.5-2%, 1.8-2.2%, 1.9-2.1%, 약 2%, 또는 0.85-0.95%, 또는 약 1%; 또는 소르비탄 에스테르 (소르비탄 트리올레에이트와 같은)는 0.02 내지 2%, 특히 약 0.5% 또는 약 1%; 옥틸-또는 노닐페녹시 폴리옥시에탄올 (Triton X-100와 같은)은 0.001 내지 0.1%, 특히 0.005 내지 0.02%; 폴리옥시에틸렌 에테르 (라우레쓰 9)는 0.1 내지 8%, 바람직하게 0.1 내지 10% 및 특히 0.1 내지 1% 또는 약 0.5%이다.
오일 및 계면활성제의 절대적인 양, 및 그것들의 비율은 에멀젼을 형성하는 동안 넓은 한도 내에서 달라질 수 있다. 숙련자는 원하는 에멀젼을 얻기 위해서 성분의 상대적 비율을 쉽게 바꿀 수 있지만, 오일 및 계면활성제에 대하여 4:1 내지 5:1의 중량비가 전형적이다 (오일 과다).
특히 큰 동물에서, 에멀젼의 면역자극 활성을 보장하는 중요한 파라미터는 오일 방울 크기 (직경)이다. 가장 효율적인 에멀젼은 서브미크론 범위의 방울 크기를 갖는다. 적합하게 방울 크기는 범위 50-750 nm에 있을 것이다. 가장 유용하게는, 평균 방울 크기는 250 nm 미만, 예를 들어, 200 nm 미만, 150 nm 미만이다. 평균 방울 크기는 유용하게도 80-180 nm의 범위에 있다. 이상적으로, 에멀젼의 오일 방울 중 적어도 80% (숫자로)는 직경이 250 nm보다 작다, 예를 들어, 200 nm보다 작고, 150보다 작다. 평균 방울 크기는 유용하게도 80-180 nm의 범위에서 유용하다. 이상적으로, 에멀젼 오일 방울 중 적어도 80% (숫자로)는 직경이 250 nmq보다 작고, 바람직하게 적어도 90%도 그러하다. 에멀젼의 평균 방울 크기, 및 크기 분포를 결정하는 기구는 상업적으로 이용 가능하다. 이것들은 전형적으로 동적 광산란 (dynamic light scattering) 및/또는 단일-입자 광학 판독 (single-particle optical sensing)의 기술, 예를 들어, Particle Sizing Systems (Santa Barbara, USA)에서 이용 가능한 기기의 Accusizer™ 및 Nicomp™ 시리즈, 또는 Malvern Instruments (UK)에서 이용 가능한 Zetasizer™ 기기, 또는 Horiba (Kyoto, Japan)의 Particle Size Distribution Analyzer 기기를 이용한다.
이상적으로, 방울 크기 (숫자로)의 분포는 두 개의 최대값 대신에, 단 하나의 최대값을 갖는다, 즉, 평균 (방식) 주위에 분포된 방울의 단일 개체군이 있다. 바람직한 에멀젼은 0.4보다 작은, 예를 들어, 0.3, 0.2보다 작은 다 분산성을 갖는다.
서브미크론 방울 및 좁은 크기 분포을 갖는 적합한 에멀젼은 미세유동화의 이용에 의해 얻어질 수 있다. 이 기술은 높은 온도 및 높은 속도에서 기하학적으로 고정된 채널을 통해 투입 성분의 스트림을 추진함으로써 평균 오일 방울 크기를 감소시킨다. 이 스트림들은 채널 벽, 챔버 벽 및 서로와 접촉한다. 결과 전단, 영향 및 캐비테이션 (cavitation) 힘은 방울 크기의 감소를 유발한다. 반복된 미세유동화 단계는 원하는 방울 크기 평균 및 분포를 갖는 에멀젼이 달성될 때까지 수행될 수 있다.
미세유동화에 대한 대안으로서, 열법 (thermal method)은 상전환 (phase inversion)을 유발하기 위해 이용될 수 있다. 이 방법들은 또한 좁은 입자 크기 분포를 갖는 서브미크론 에멀젼을 제공할 수 있다.
바람직한 에멀젼은 여과 멸균될 수 있다, 즉, 그것들의 방울은 220 nm 필터를 통과할 수 있다. 멸균을 제공할 뿐만 아니라, 이 공정은 또한 에멀젼의 어떤 큰 방울도 제거한다.
특정 구체예에서, 에멀젼의 양이온성 지질은 DOTAP이다. 양이온성 수중유 에멀젼은 약 0.5 mg/ml 내지 약 25 mg/ml DOTAP를 포함할 수도 있다. 예를 들어, 양이온성 수중유 에멀젼은 DOTAP를 약 0.5 mg/ml 내지 약 25 mg/ml, 약 0.6 mg/ml 내지 약 25 mg/ml, 약 0.7 mg/ml 내지 약 25 mg/ml, 약 0.8 mg/ml 내지 약 25 mg/ml, 약 0.9 mg/ml 내지 약 25 mg/ml, 약 1.0 mg/ml 내지 약 25 mg/ml, 약 1.1 mg/ml 내지 약 25 mg/ml, 약 1.2 mg/ml 내지 약 25 mg/ml, 약 1.3 mg/ml 내지 약 25 mg/ml, 약 1.4 mg/ml 내지 약 25 mg/ml, 약 1.5 mg/ml 내지 약 25 mg/ml, 약 1.6 mg/ml 내지 약 25 mg/ml, 약 1.7 mg/ml 내지 약 25 mg/ml, 약 0.5 mg/ml 내지 약 24 mg/ml, 약 0.5 mg/ml 내지 약 22 mg/ml, 약 0.5 mg/ml 내지 약 20 mg/ml, 약 0.5 mg/ml 내지 약 18 mg/ml, 약 0.5 mg/ml 내지 약 15 mg/ml, 약 0.5 mg/ml 내지 약 12 mg/ml, 약 0.5 mg/ml 내지 약 10 mg/ml, 약 0.5 mg/ml 내지 약 5 mg/ml, 약 0.5 mg/ml 내지 약 2 mg/ml, 약 0.5 mg/ml 내지 약 1.9 mg/ml, 약 0.5 mg/ml 내지 약 1.8 mg/ml, 약 0.5 mg/ml 내지 약 1.7 mg/ml, 약 0.5 mg/ml 내지 약 1.6 mg/ml, 약 0.6 mg/ml 내지 약 1.6 mg/ml, 약 0.7 mg/ml 내지 약 1.6 mg/ml, 약 0.8 mg/ml 내지 약 1.6 mg/ml, 약 0.5 mg/ml, 약 0.6 mg/ml, 약 0.7 mg/ml, 약 0.8 mg/ml, 약 0.9 mg/ml, 약 1.0 mg/ml, 약 1.1 mg/ml, 약 1.2 mg/ml, 약 1.3 mg/ml, 약 1.4 mg/ml, 약 1.5 mg/ml, 약 1.6 mg/ml, 약 12 mg/ml, 약 18 mg/ml, 약 20 mg/ml, 약 21.8 mg/ml, 약 24 mg/ml, 등으로 포함할 수도 있다. 전형적인 구체예에서, 양이온성 수중유 에멀젼은 약 0.8 mg/ml 내지 약 1.6 mg/ml DOTAP, 예를 들어, 0.8 mg/ml, 1.2 mg/ml, 1.4 mg/ml 또는 1.6 mg/ml를 포함한다.
특정 구체예에서, 양이온성 지질은 DC 콜레스테롤이다. 양이온성 수중유 에멀젼은 DC 콜레스테롤을 약 0.1 mg/ml 내지 약 5 mg/ml DC 콜레스테롤로 포함할 수도 있다. 예를 들어, 양이온성 수중유 에멀젼은 DC 콜레스테롤을 약 0.1 mg/ml 내지 약 5 mg/ml, 약 0.2 mg/ml 내지 약 5 mg/ml, 약 0.3 mg/ml 내지 약 5 mg/ml, 약 0.4 mg/ml 내지 약 5 mg/ml, 약 0.5 mg/ml 내지 약 5 mg/ml, 약 0.62 mg/ml 내지 약 5 mg/ml, 약 1 mg/ml 내지 약 5 mg/ml, 약 1.5 mg/ml 내지 약 5 mg/ml, 약 2 mg/ml 내지 약 5 mg/ml, 약 2.46 mg/ml 내지 약 5 mg/ml, 약 3 mg/ml 내지 약 5 mg/ml, 약 3.5 mg/ml 내지 약 5 mg/ml, 약 4 mg/ml 내지 약 5 mg/ml, 약 4.5 mg/ml 내지 약 5 mg/ml, 약 0.1 mg/ml 내지 약 4.92 mg/ml, 약 0.1 mg/ml 내지 약 4.5 mg/ml, 약 0.1 mg/ml 내지 약 4 mg/ml, 약 0.1 mg/ml 내지 약 3.5 mg/ml, 약 0.1 mg/ml 내지 약 3 mg/ml, 약 0.1 mg/ml 내지 약 2.46 mg/ml, 약 0.1 mg/ml 내지 약 2 mg/ml, 약 0.1 mg/ml 내지 약 1.5 mg/ml, 약 0.1 mg/ml 내지 약 1 mg/ml, 약 0.1 mg/ml 내지 약 0.62 mg/ml, 약 0.15 mg/ml, 약 0.3 mg/ml, 약 0.6 mg/ml, 약 0.62 mg/ml, 약 0.9 mg/ml, 약 1.2 mg/ml, 약 2.46 mg/ml, 약 4.92 mg/ml, 등으로 포함할 수도 있다. 전형적인 구체예에서, 양이온성 수중유 에멀젼은 약 0.62 mg/ml 내지 약 4.92 mg/ml, 예를 들어, 2.46 mg/ml DC 콜레스테롤을 포함한다.
특정 구체예에서, 양이온성 지질은 DDA이다. 양이온성 수중유 에멀젼은 약 0.1 mg/ml 내지 약 5 mg/ml DDA이다. 예를 들어, 양이온성 수중유 에멀젼은 DDA를 약 0.1 mg/ml 내지 약 5 mg/ml, 약 0.1 mg/ml 내지 약 4.5 mg/ml, 약 0.1 mg/ml 내지 약 4 mg/ml, 약 0.1 mg/ml 내지 약 3.5 mg/ml, 약 0.1 mg/ml 내지 약 3 mg/ml, 약 0.1 mg/ml 내지 약 2.5 mg/ml, 약 0.1 mg/ml 내지 약 2 mg/ml, 약 0.1 mg/ml 내지 약 1.5 mg/ml, 약 0.1 mg/ml 내지 약 1.45 mg/ml, 약 0.2 mg/ml 내지 약 5 mg/ml, 약 0.3 mg/ml 내지 약 5 mg/ml, 약 0.4 mg/ml 내지 약 5 mg/ml, 약 0.5 mg/ml 내지 약 5 mg/ml, 약 0.6 mg/ml 내지 약 5 mg/ml, 약 0.73 mg/ml 내지 약 5 mg/ml, 약 0.8 mg/ml 내지 약 5 mg/ml, 약 0.9 mg/ml 내지 약 5 mg/ml, 약 1.0 mg/ml 내지 약 5 mg/ml, 약 1.2 mg/ml 내지 약 5 mg/ml, 약 1.45 mg/ml 내지 약 5 mg/ml, 약 2 mg/ml 내지 약 5 mg/ml, 약 2.5 mg/ml 내지 약 5 mg/ml, 약 3 mg/ml 내지 약 5 mg/ml, 약 3.5 mg/ml 내지 약 5 mg/ml, 약 4 mg/ml 내지 약 5 mg/ml, 약 4.5 mg/ml 내지 약 5 mg/ml, 약 1.2 mg/ml, 약 1.45 mg/ml, 등으로 포함할 수도 있다. 대안으로서, 양이온성 수중유 에멀젼은 DDA를 약 20 mg/ml, 약 21 mg/ml, 약 21.5 mg/ml, 약 21.6 mg/ml, 약 25 mg/ml으로 포함할 수도 있다. 전형적이 구체예에서, 양이온성 수중유 에멀젼은 약 0.73 mg/ml 내지 약 1.45 mg/ml, 예를 들어, 1.45 mg/ml DDA를 포함한다.
카테터 또는 유사한 장치는 본 발명의 자가 복제 RNA 분자를, 노출 RNA로서 또는 전달 시스템과 조합하여, 표적 장기 또는 조직으로 전달하기 위해 이용될 수도 있다. 적합한 카테터는, 예를 들어, 미국 특허 번호 4, 186, 745; 5, 397, 307; 5, 547, 472; 5, 674, 192; 및 6, 129, 705에 개시되며, 이것들 모두는 본원에 참고로 포함된다.
본 발명은, 예를 들어, 단독으로, 또는 또 다른 고 분자와 조합하여 면역 반응을 유도하기 위해, 둘 이상의 CMV 단백질을 암호화하는 자가 복제 RNA 분자를 전달하도록 캡슐화된 또는 흡착된 자가 복제 RNA를 갖는 리포솜, 폴리머 미세입자 또는 서브미크론 에멀젼 미세입자와 같은, 적합한 전달 시스템의 이용을 포함한다. 본 발명은 흡착된 및/또는 캡슐화된 자가 복제 RNA 분자, 및 이들의 조합을 갖는 리포솜, 미세입자 및 서브미크론 에멀젼을 포함한다.
리포솜 및 서브미크론 에멀젼 미세입자와 연관된 자가 복제 RNA 분자는 숙주 세포에 효율적으로 전달될 수 있고 자가 복제 RNA에 의해 암호화된 단백질에 대한 면역 반응을 유발할 수 있다.
CMV 단백질을 암호화하는 폴리시스트론성 자가 복제 RNA 분자, 폴리시스트론성 알파바이러스 레플리콘을 이용하여 생산된 VRP는 세포에서 CMV 단백질 복합체를 형성하기 위해 이용될 수 있다. 복합체는 gB/gH/gL; gH/gL; gH/gL/gO; gM/gN; gH/gL/UL128/UL130/UL131; 및 UL128/UL130/UL131을 포함하지만, 이에 제한되지 않는다.
일부 구체예에서, VRP의 조합은 세포에 전달된다. 조합은 다음을 포함하지만, 이에 제한되지 않는다:
1. gH/gL VRP 및 또 다른 VRP;
2. gH/gL VRP 및 gB VRP;
3. gH/gL/gO VRP 및 gB VRP;
4. gB VRP 및 gH/gL/UL128/UL130/UL131 VRP;
5. gB VRP 및 UL128/UL130/UL131 VRP;
6. gB VRP 및 gM/gN VRP;
7. gB VRP, gH/gL VRP, 및 UL128/UL130/UL131 VRP;
8. gB VRP, gH/gLgO VRP, 및 UL128/UL130/UL131 VRP;
9. gB VRP, gM/gN VRP, gH/gL VRP, 및 UL128/UL130/UL131 VRP;
10. gB VRP, gM/gN VRP, gH/gL/O VRP, 및 UL128/UL130/UL131 VRP;
11. gH/gL VRP 및 UL128/UL130/UL131 VRP; 및
일부 구체예에서, 자가 복제 RNA 분자의 조합은 세포에 전달된다. 조합은 다음을 포함하지만, 이에 제한되지 않는다:
1. gH/gL을 암호화하는 자가 복제 RNA 분자 및 또 다른 단백질을 암호화하는 자가 복제 RNA 분자;
2. gH 및 gL을 암호화하는 자가 복제 RNA 분자 및 gB를 암호화하는 자가 복제 RNA 분자;
3. gH, gL 및 gO를 암호화하는 자가 복제 RNA 분자 및 gB를 암호화하는 자가 복제 RNA 분자 ;
4. gB를 암호화하는 자가 복제 RNA 분자 및 gH, gL, UL128, UL130 및 UL131을 암호화하는 자가 복제 RNA 분자 ;
5. gB를 암호화하는 자가 복제 RNA 분자 및 UL128, UL130 및 UL131을 암호화하는 자가 복제 RNA 분자;
6. gB를 암호화하는 자가 복제 RNA 분자 및 gM 및 gN을 암호화하는 자가 복제 RNA 분자 ;
7. gB를 암호화하는 자가 복제 RNA 분자, gH 및 gL을 암호화하는 자가 복제 RNA 분자, 및 UL128, UL130 및 UL131을 암호화하는 자가 복제 RNA 분자;
8. gB를 암호화하는 자가 복제 RNA 분자, gH, gL, 및 gO를 암호화하는 자가 복제 RNA 분자, 및 UL128, UL130 및 UL131를 암호화하는 자가 복제 RNA 분자;
9. gB를 암호화하는 자가 복제 RNA 분자, gM 및 gN을 암호화하는 자가 복제 RNA 분자, gH 및 gL을 암호화하는 자가 복제 RNA 분자, 및 UL128, UL130 및 UL131을 암호화하는 자가 복제 RNA 분자;
10. gB를 암호화하는 자가 복제 RNA 분자, gM 및 gN을 암호화하는 자가 복제 RNA 분자, gH, gL 및 gO를 암호화하는 자가 복제 RNA 분자, 및 UL128, UL130 및 UL131를 암호화하는 자가 복제 RNA 분자;
11. gH 및 gL을 암호화하는 자가 복제 RNA 분자, 및 UL128, UL130 및 UL131을 암호화하는 자가 복제 RNA 분자; 및
CMV 단백질
적합한 CMV 단백질은 gB, gH, gL, gO를 포함하고, 어떤 CMV 균주의 것일 수 있다. 다른 적합한 CMV 단백질은 UL128, UL130 및 UL131을 포함하고, 어떤 CMV 균주의 것일 수 있다. 예를 들어, CMV 단백질은 CMV 단백질의 Merlin, AD 169, VR1814, Towne, Toledo, TR, PH, TB40, 또는 Fix 균주의 것일 수 있다. 전형적인 CMV 단백질 및 단편이 여기에 설명된다. 이 단백질 및 단편은 사람 세포와 같은, 원하는 숙주에서 발현을 위해 최적화 또는 탈최적화된 코돈인 서열을 포함하는, 어떤 적합한 뉴클레오티드 서열에 의해서도 암호화될 수 있다. CMV 단백질의 전형적인 서열 및 단백질을 암호화하는 핵산은 표 2에 제공된다.
표 2
Figure 112020102169690-pat00002
CMV gB 단백질
gB 단백질은 전체 길이일 수 있거나 단백질의 하나 이상의 지역을 생략할 수 있다. 대안으로는, gB 단백질의 단편이 이용될 수 있다. gB 아미노산은 SEQ ID NO:26로 나타나는 전체 길이 gB 아미노산 서열 (CMV gB FL)에 따라 번호가 매겨지며, 이것은 907 아미노산 길이이다. gB 단백질의 적합한 영역은 전체 길이 단백질로부터 제외될 수 있거나 단편으로서 포함될 수 있으며, 다음을 포함한다: 신호 서열 (아미노산 1-24), gB-DLD 디스인테그린-유사 도메인 (아미노산 57-146), 퓨린 분할 부위 (아미노산 459-460), 7가 반복 영역 (679-693), 막 스패닝 도메인 (아미노산 751-771), 및 아미노산 771-906의 세포질 도메인. 일부 구체예에서, gB 단백질은 아미노산 67-86 (중화 에피토프 AD2) 및/또는 아미노산 532-635 (면역 우성 에피토프 AD1)를 포함한다. gB 단편의 특정 예는 gB의 첫 번째 692 아미노산을 포함하는 "gB sol 692" 및 gB의 첫 번째 750 아미노산을 포함하는 "gB sol 750"을 포함한다. 신호 서열, 아미노산 1-24는 원하는 바와 같이 gB sol 692 및 gB sol 750으로부터 존재하거나 없을 수 있다. 임의로, gB 단백질은 10개 이상의 아미노산의 gB 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 또는 875개의 아미노산을 포함할 수 있다. gB 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 또는 897.
임의로, gB 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, gB 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV gH 단백질
일부 구체예에서, gH 단백질은 전체 길이 gH 단백질이다 (CMV gH FL, SEQ ID NO:32, 예를 들어, 이것은 742개의 아미노산 단백질이다). gH는 위치 716에서 743까지 시작하는 막 스패닝 도메인 및 세포질 도메인을 갖는다. 717 내지 743의 아미노산의 제거는 가용성 gH를 제공한다 (예를 들어, CMV gH sol, SEQ ID NO:34). 일부 구체예에서, gH 단백질은 10개 이상의 아미노산의 gH 단편일 수 있고, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 또는 725개의 아미노산을 포함할 수 있다. 임의로, gH 단백질은 10개 이상의 아미노산의 gH 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 또는 725개의 아미노산을 포함할 수 있다. gH 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 또는 732.
gH 잔기는 SEQ ID NO:32로 나타나는 전체 길이 gH 아미노산 서열 (CMV gH FL)에 따라 번호가 매겨진다. 임의로, gH 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, gH 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV gL 단백질
일부 구체예에서, gL 단백질은 전체 길이 gL 단백질이다 (CMV gL FL, SEQ ID NO:36, 예를 들어, 이것은 278개의 아미노산 단백질이다). 일부 구체예에서, gL 단편이 이용될 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 또는 250개의 아미노산을 포함할 수 있다. gL 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 또는 268.
gL 잔기는 SEQ ID NO:36로 나타나는 전체 길이 gL 아미노산 서열 (CMV gL FL)에 따라 번호가 매겨진다. 임의로, gL 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, gL 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV gO 단백질
일부 구체예에서, gO 단백질은 전체 길이 gO 단백질 (CMV gO FL, SEQ ID NO:42, 예를 들어, 이것은 472개의 아미노산 단백질이다). 일부 구체예에서, gO 단백질은 10개 이상의 아미노산의 gO 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 또는 450개의 아미노산을 포함할 수 있다. gO 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 또는 462.
gO 잔기는 SEQ ID NO:42로 나타나는 전체 길이 gO 아미노산 서열 (CMV gO FL)에 따라 번호가 매겨진다. 임의로, gO 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, gO 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV gM 단백질
일부 구체예에서, gM 단백질은 전체 길이 gM 단백질이다 (CMV gM FL, SEQ ID NO:38, 예를 들어, 이것은 371개의 아미노산 단백질이다). 일부 구체예에서, gM 단백질은 10개 이상의 아미노산의 gM 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 또는 350개의 아미노산을 포함할 수 있다. gM 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 또는 361.
gM 잔기는 SEQ ID NO:38로 나타나는 전체 길이 gM 아미노산 서열 (CMV gM FL)에 따라 번호가 매겨진다. 임의로, gM 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, gM 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV gN 단백질
일부 구체예에서, gN 단백질은 전체 길이 gN 단백질이다 (CMV gN FL, SEQ ID NO:40, 예를 들어, 이것은 135개의 아미노산 단백질이다). 구체예에서, gN 단백질은 10개 이상의 아미노산의 gN 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 또는 125개의 아미노산을 포함할 수 있다. gN 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 또는 125.
gN 잔기는 SEQ ID NO:40로 나타나는 전체 길이 gN 아미노산 서열 (CMV gN FL)에 따라 번호가 매겨진다. 임의로, gN 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. gN 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV UL128 단백질
일부 구체예에서, UL128 단백질은 전체 길이 UL128 단백질이다 (CMV UL128 FL, SEQ ID NO:44, 예를 들어, 이것은 171개의 아미노산 단백질이다). 일부 구체예에서, UL128 단백질은 10개 이상의 아미노산의 UL128 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 또는 150개의 아미노산을 포함할 수 있다. UL128 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 또는 161.
UL128 잔기는 SEQ ID NO:44로 나타나는 전체 길이 UL128 아미노산 서열 (CMV UL128 FL)에 따라 번호가 매겨진다. 임의로, UL128 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, UL128 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV UL130 단백질
일부 구체예에서, UL130 단백질은 전체 길이 UL130 단백질이다 (CMV UL130 FL, SEQ ID NO:46, 예를 들어, 이것은 214개의 아미노산 단백질이다). 일부 구체예에서, UL130 단백질은 10개 이상의 아미노산의 UL130 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 또는 200개의 아미노산을 포함할 수 있다. UL130 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 또는 204.
UL130 잔기는 SEQ ID NO:46로 나타나는 전체 길이 UL130 아미노산 서열 (CMV UL130 FL)에 따라 번호가 매겨진다. 임의로, UL130 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, UL130 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
CMV UL131 단백질
일부 구체예에서, UL131 단백질은 전체 길이 UL131 단백질이다 (CMV UL131 FL, SEQ ID NO:48, 예를 들어, 이것은 129개의 아미노산 단백질이다). 일부 구체예에서, UL131 단백질은 10개 이상의 아미노산의 UL131 단편일 수 있다. 예를 들어, 단편의 아미노산의 수는 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 또는 200개의 아미노산을 포함할 수 있다. UL131 단편은 잔기 번호 중 어느 것에서도 시작할 수 있다: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119.
UL131 잔기는 SEQ ID NO:48로 나타나는 전체 길이 UL131 아미노산 서열 (CMV UL131 FL)에 따라 번호가 매겨진다. 임의로, UL131 단편은 단편의 시작 잔기로부터 N-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다. 임의로, UL131 단편은 단편의 마지막 잔기로부터 C-말단으로 5, 10, 20, 또는 30개의 아미노산으로 추가로 연장될 수 있다.
상기 진술된 바와 같이, 본 발명은 첫 번째 헤르페스바이러스 단백질 또는 이들의 단편을 암호화하는 첫 번째 서열, 및 두 번째 헤르페스바이러스 단백질 또는 이들의 단편을 암호화하는 두 번째 서열을 함유하는 재조합 폴리시스트론성 핵산 분자와 관련된다. 따라서, 알파바이러스 VRP 및 둘 이상의 CMV 단백질 또는 이들의 단편을 암호화하는 서열을 함유하는 자가 복제 RNA와 같은, 특정 바람직한 구체예의 전술된 설명은 본 발명의 예시이지만 본 발명의 범위를 제한하지 않는다. 이러한 바람직한 구체예에서 CMV 단백질을 암호화하는 서열은 gH 및 gL, 또는 10개 이상의 아미노산 길이인 이들의 단편과 같이, 다른 헤르페스바이러스, 예를 들어, HHV-1, HHV-2, HHV-3, HHV-4, HHV-6, HHV-7 및 HHV-8의 단백질을 암호화하는 서열로 대체될 수 있는 것으로 이해될 것이다. 예를 들어, 적합한 VZV (HHV-3) 단백질은 gB, gE, gH, gI, 및 gL, 및 10개 이상의 아미노산 길이인 이들의 단편을 포함하고, 어떤 VZV 균주의 것일 수도 있다. 예를 들어, VZV 단백질 또는 이들의 단편은 VZV의 pOka, Dumas, HJO, CA123, 또는 DR 균주일 수 있다. 이 전형적인 VZV 단백질 및 이들의 단편은 사람 세포와 같이, 원하는 숙주에서 발현에 최적화된 또는 탈최적화된 코돈인 서열을 포함하는 어떤 적합한 뉴클레오티드 서열에 의해서도 암호화될 수 있다. VZV 단백질의 전형적인 서열은 여기에 제공된다.
예를 들어, 한 구체예에서, 폴리시스트론성 핵산 분자는 VZV gH 단백질 또는 이들의 단편을 암호화하는 첫 번째 서열, 및 VZV gL 단백질 또는 이들의 단편을 암호화하는 두 번째 서열을 함유한다.
일부 구체예에서, 폴리시스트론성 핵산 분자에 존재하는 헤르페스바이러스 단백질 또는 단편을 암호화하는 각각의 서열은 그것의 자체 조절 요소와 작동 가능하게 연결된다. 예를 들어, 헤르페스바이러스 단백질 또는 단편을 암호화하는 각각의 서열은 그것의 자체 서브게놈 프로모터와 작동 가능하게 연결된다. 따라서 알파바이러스 레플리콘과 같은, 폴리시스트론성 핵산 분자는 둘, 셋, 넷 또는 다섯 개의 서브게놈 프로모터를 함유할 수 있으며, 이것들 각각은 헤르페스바이러스 단백질 또는 단편의 발현을 조절한다. 이 타입의 폴리시스트론성 핵산 분자가 알파바이러스 레플리콘과 같은, 자가 복제 RNA일 때, 그것은 VRP로서 포장될 수 있거나, RNA 전달 시스템과 관련되거나 이로 조제될 수 있다.
방법 및 이용
일부 구체예에서, 자가 복제 RNA 분자 또는 VRP는 면역 반응을 자극하기 위해 개인에게 투여된다. 이러한 구체예에서, 자가 복제 RNA 분자 또는 VRP는 전형적으로 약학적으로 허용 가능한 담체 및, 임의로, 보조제를 포함할 수도 있는 조성물에 존재한다. 예를 들어, U.S. 6,299,884; U.S. 7,641,911; U.S. 7,306,805; 및 US 2007/0207090 참조.
면역 반응은 체액 면역 반응, 세포-매개 면역 반응, 또는 둘 다를 포함할 수 있다. 일부 구체예에서, 면역 반응은 각각 전달된 CMV 단백질에 대하여 유발된다. 세포-매개 면역 반응은 헬퍼 T-세포 (Th) 반응, CD8+ 세포 독성 T-세포 (CTL) 반응, 또는 둘 다를 포함할 수 있다. 일부 구체예에서, 면역 반응은 체액 면역 반응이고, 항체는 중화 항체이다. 중화 항체는 세포의 바이러스 감염을 차단한다. CMV는 상피 세포 및 또한 섬유아세포를 감염시킨다. 일부 구체예에서, 면역 반응은 두 세포 타입의 감염을 감소시키거나 방지한다. 중화 항체 반응은 보체-의존적 또는 보체-독립적일 수 있다. 일부 구체예에서, 중화 항체 반응은 보체-독립적이다. 일부 구체예에서, 중화 항체 반응은 교차-중화이다; 즉, 투여된 조성물에 대하여 발생한 항체는 조성물에 이용된 균주 이외의 균주의 CMV 바이러스를 중화시킨다.
업계에서 항체 효능의 유용한 측정값은 "50% 중화 역가"이다. 50% 중화 역가를 결정하기 위해, 면역화된 동물의 혈청은 얼마나 희석된 혈청이 세포 내로 바이러스의 50%의 유입을 차단하는 능력을 유지할 수 있는지 평가하기 위해 희석된다. 예를 들어, 700의 역가는 혈청이 700배 희석된 후 바이러스의 50%를 중화시키는 능력을 유지하였다는 것을 의미한다. 따라서, 더 높은 역가는 더 효능 있는 중화 항체 반응을 나타낸다. 일부 구체예에서, 이 역가는 약 200, 약 400, 약 600, 약 800, 약 1000, 약 1500, 약 2000, 약 2500, 약 3000, 약 3500, 약 4000, 약 4500, 약 5000, 약 5500, 약 6000, 약 6500, 또는 약 7000의 하한을 갖는 범위에 있다. 50% 중화 역가 범위는 약 400, 약 600, 약 800, 약 1000, 약 1500, 약 200, 약 2500, 약 3000, 약 3500, 약 4000, 약 4500, 약 5000, 약 5500, 약 6000, 약 6500, 약 7000, 약 8000, 약 9000, 약 10000, 약 11000, 약 12000, 약 13000, 약 14000, 약 15000, 약 16000, 약 17000, 약 18000, 약 19000, 약 20000, 약 21000, 약 22000, 약 23000, 약 24000, 약 25000, 약 26000, 약 27000, 약 28000, 약 29000, 또는 약 30000의 상한을 가질 수 있다. 예를 들어, 50% 중화 역가는 약 3000 내지 약 6500일 수 있다. "약"은 나열된 값의 플러스 또는 마이너스 10%를 의미한다. 중화 역가는 하기, 특정 예에서 설명된 바와 같이 측정될 수 있다.
면역 반응은 VRP 또는 자가 복제 RNA를 개인, 전형적으로 사람을 포함하는, 포유동물에게 투여함으로써 자극될 수 있다. 일부 구체예에서, 유발된 면역 반응은 보호 면역 반응이다, 즉, 반응은 CMV 감염의 위험 또는 심각도를 감소시킨다. 보호 면역 자극을 자극하는 것은 특히 CMV 감염 및 질환의 위험에 있는 일부 개체군에서 특히 바람직하다. 예를 들어, 위험에 있는 개체군은 고체 장기 이식 (SOT) 환자, 골수 이식 환자, 및 조혈모세포 이식 (HSCT) 환자를 포함한다. VRP는 이식 전 이식 기증자, 또는 이식 전 및/또는 후 이식 수령체에게 투여될 수 있다. 모체로부터 아이에게 수직 전달은 유아를 감염시키는 일반적인 근원이기 때문에, 임신할 수 있는 여성에게 VRP 또는 자가 복제 RNA를 투여하는 것은 특히 유용하다.
투여의 어떤 적합한 루트도 이용될 수 있다. 예를 들어, 조성물은 근육 내로, 복강 내로, 피하로, 또는 경피성으로 투여될 수 있다. 일부 구체예는 점막 내 루트를 통해, 예를 들어, 구강 내로, 비강내로, 질 내로, 및 직장 내로 투여될 것이다. 조성물은 어떤 적합한 계획에 따라서도 투여될 수 있다.
수탁 번호로 나타나는 뉴클레오티드 및 아미노산 서열을 포함하는, 이 개시에 인용된 모든 특허, 특허 출원, 및 참고는 표현적으로 본원에 참고로 포함된다. 상기 개시된 내용은 일반적인 설명이다. 더 완벽한 이해는 다음 특정 실시예에 대한 참고에 의해 얻어질 수 있으며, 이것은 예시의 목적으로만 제공된다.
실시예 1
VRP 플랫폼을 이용하여 개개의 CMV 항원의 전달
각각의 CMV 당단백질 gB 및 gH는 중화 반응을 유발하고, gB는 섬유아세포의 감염을 중화시키는 사람 혈청의 항체 사이에서 우성 항원이다 (Britt et al. (1990) J. Virol. 64(3): 1079-85). 다음 실험은 마우스에서 vRP 플랫폼을 이용하여 전달된 이 항원들에 대한 중화 반응을 입증한다.
각각의 CMV 항원을 pcDNA-6His 벡터 (Invitrogen) 내로 클로닝하였고 알파바이러스 레플리콘 벡터, 도 2에 나타난 구조물을 생산하는, Perri et al. (J. Virol 77(19)10394-10403 (2003))에 의해 설명된 플라스미드로부터 유도된 pVCR 2.1 SalI/XbaI 내로 클로닝하기 전 단백질 발현에 대하여 테스트하였다. pVCR 2.1 SalI/XbaI는 자가 복제 RNA 벡터이며, 이것은 결함 헬퍼 캡시드 및 당단백질 RNA로 전기 천공될 때, 감염성 알파바이러스 입자를 형성한다. pVCR 벡터를 베네수엘라 말 뇌염 바이러스 (VEE)로부터 유도된 결함 헬퍼 캡시드 및 당단백질 RNA의 존재시 아기 햄스터 신장 (BHKV) 세포 내로 전기 천공되는 RNA를 만들기 위해 이용하였다. 전기 천공 후, 분비된 알파바이러스 벡터 입자 (VRP)를 함유하는 상층액을 마우스 면역화 연구를 위해 수거, 정제, 적정, 및 이용하였다. 마우스는 3주 간격으로, 연속적인 두 번의 면역화에서 1 x 106 감염 유닛 (IU)/마우스로 면역화되었다. 2차 면역화 3주 후에 마지막 채혈을 하였다.
모노시스트론성 gB, gH 및 gL VRP
두 개의 다른 버젼의 가용성 gB를 구성하였다: "gB sol 750"은 막 통과 스패닝 도메인 및 세포질 도메인이 없고; "gB sol 692"는 또한 소수성 영역이 없고 (도 2a) Reap et al. 구조와 유사하다. 막 통과 스패닝 도메인 및 세포질 도메인이 없는 가용성 gH ("gH sol 716")을 또한 제조하였다 (도 2c). 면역화된 마우스의 혈청을 다수의 검정으로 선별하였다. 면역블롯 (데이터 미도시) 및 면역형광 검정을 항원에 대한 특정 항체 반응을 확인하기 위해 이용하였다. 유도된 항체 반응이 CMV 감염을 중화시킬 수 있다는 것을 입증하기 위해 중화 검정을 이용하였다.
면역화된 마우스의 혈청을 gB-6His를 발현하는 구조물로 트랜스펙션된 293T 세포에서 gB의 인식을 위해 면역형광법으로 조사하였다. 세포를 항-His 항체 ("항-6His"), 단클론성 gB 항체 ("항-gB 27-156"), 또는 수거된 풀 마우스 항체로 탐침하였다. 사전 면역화된 혈청은 모든 경우에 음성이었다. gB FL-6His를 발현하는 구조물로 트랜스펙션되고, 고정되고, 통과된 세포에서, 항-6His 염색은 엔도사이트/엑소사이트 트래피킹 경로 (endocytic/exocytic trafficking pathway)에 대부분 해당하는 반점 세포질 패턴으로 표면 발현의 발현 패턴을 나타내었다. 항-gB 27-156 및 풀 마우스 혈청은 유사한 발현 패턴을 나타내었다. gB FL VRP, gB sol 750 VRP, 및 gB sol 692 VRP 각각으로 면역화된 마우스의 혈청은 같은 발현 패턴을 나타내었다.
gH FL VRP 및 gH sol 716 VRP로 면역화된 마우스는 gH에 특이적인 항체를 생산하였다. gH FL-6His를 발현하는 구조물로 트랜스펙션된 293T 세포의 면역형광 분석은 항-6His, 항-gH, 및 풀 마우스 혈청에 의해 gH의 강한 인식을 검출하였다. gL VRP로 면역화된 마우스로부터 수거한 혈청은 면역블롯 분석 및 면역형광법으로 결정된 바와 같은 특이적 항체 반응을 생산하였다. gL VRP는 중화 반응을 유도하는데 실패하였다.
gB VRP 또는 gH VRP로 면역화된 마우스의 혈청을 중화 항체의 존재에 대하여 CMV 중화 검정을 이용하여 분석하였다. 다양하게 희석된 혈청을 CMV 바이러스 TB40UL32EGFP ("TB40-GFP," GFP를 발현하도록 설계된 임상 분리체)와 함께 사전 배양하였고 ARPE-19 상피 세포에 추가하였고 5일 동안 배양하였다. 감염 5일 후에, GFP-양성 세포를 계산하였다. 이 검정에서, 중화 항체를 함유하는 혈청과 함께 배양된 세포는 바이러스 단독과 함께 또는 사전 면역 혈청과 함께 배양된 바이러스와 함께 배양된 세포에 비해 더 적은 GFP-양성 세포를 갖는다. gB VRP, gB FL VRP, gB sol 750 VRP, 또는 gB sol 692 VRP로 면역화된 마우스의 혈청은 기니피그 보체의 존재시 강한 중화 활성이 있었다 (1:1280-1:2560의 혈청 희석시 50% 중화 역가; 도 3). gH FL VRP 또는 gH sol VRP로 면역화된 마우스의 혈청은 기니피그 보체에 독립적인, 일부 중화 활성이 있었다 (도 3).
실시예 2
폴리시스트론성 알파바이러스 벡터의 구조
CMV는 감염 중에 다수의 다단백질 복합체를 생산한다. 대상체에서 CMV 복합체를 생산하기 위해 원하는 복합체의 모든 성분을 발현하는 단일 레플리콘이 이용될 수 있는지, 또는 복합체의 성분이 다수의 레플리콘 벡터로부터 동시전달될 수 있는지 결정하기 위하여, 우리는 다수의 CMV 단백질의 제어된 발현을 허용하는 플랫폼을 디자인하였다.
알파바이러스 벡터 (pVCR 2.1 SalI/XbaI)를 다수의 서브게놈 프로모터 (SGP) 및 원하는 유전자 (GOI)의 조립체를 허용하도록 변형하였다. 11026-31 bp의 pVCR 2.1SalI/XbaI ApaI 부위를 GGGCCC (SEQ ID NO:7)에서 GGCGCC (SEQ ID NO:8)로 바꿨다. ClaI 및 PmlI 제한 부위는 첫 번째 서브게놈 프로모터 및 SalI-XbaI 삽입 부위의 다운스트림 근처 영역에 추가된다. 7727-7754 bp의 서열을 ctcgatgtacttccgaggaactgatgtg (SEQ ID NO:9)에서 ATCGATGTACTTCCGAGGAACTCACGTG (SEQ ID NO:10)로 바꿨다.
셔틀 (shuttling) 벡터 시스템을 SalI-XbaI 부위를 이용하여 SGP의 다운스트림에 직접 GOI의 삽입을 허용하기 위해 디자인하였다. pcDNA 3.1 (-) C를 다음과 같이 변형시켰다. 세 개의 SalI 부위, 위치 1046-1051 bp, 3332-3337 bp 및 5519-21, 1-3 bp가 GTCGAC (SEQ ID NO:11)에서 GTCTAC (SEQ ID NO:12)로 삭제되었다.
위치 916-921 bp에 XbaI 부위의 돌연변이를 일으키기 위해 TCTAGA (SEQ ID NO:13)에서 pcDNA 3.1 (-) C를 TCAAGA (SEQ ID NO:14)로 변형하였다. 위치 942-947 (ClaI) 및 950-955 (SacII) bp에 ClaI 부위 및 SacII 부위를 추가하기 위해 pcDNA 3.1 (-) C를 ctggatatctgcag (SEQ ID NO:15)에서 ATCGATATCCGCGG (SEQ ID NO:16)로 변형시켰다.
제한 부위가 추가되었고 결과 서열이 입증되었고, bp 7611-7689 (ctataactctctacggctaacctgaatggactacgacatagtctagtcgaccaagcctctagacggc gcgcccaccca) (SEQ ID NO:17)의 영역은 다음 프라이머를 이용하여 변형된 pVCR 2.1 알파바이러스 벡터로부터 증폭되었다
정방향 SGP S-X Not F:
5'ATAAGAATGCGGCCGCCTATAACTCTCTACGGCTAACC3' (SEQ ID NO:18) 및
역방향 SGP S-X Cla R:
5'CCATCGATTGGGTGGGCGCGCCGTCTAG3' (SEQ ID NO:19) 또는
정방향 SGP S-X Cla F:
5'CCATCGATCTATAACTCTCTACGGCTAACC3' (SEQ ID NO:20) 및
역방향 SGP S-X Sac R:
5'TCCCCGCGGTGGGTGGGCGCGCCGTCTAG3' (SEQ ID NO:21).
적절한 부위의 사이에 (NotI-ClaI 또는 ClaI-SacII) 셔틀 벡터 (pcDNA SV)를 만들기 위해 증폭된 영역을 변형된 pcDNA 3.1 (-) C 벡터 내로 추가하였다. NotI-SGP Sal-Xba-ClaI의 삽입은 pcDNA SV 카세트 2를 형성하고, ClaI-SGP Sal-Xba-SacII의 삽입은 pcDNA SV 카세트 3을 형성한다. 이 SV 카세트를 배열하였다. pcDNA SV 카세트 2는 ClaI 부위가 pcDNA SV 카세트 2 벡터에서 절단되지 않았기 때문에 XbaI 부위 및 ClaI 부위 사이에 추가적인 12 bp (CCACTGTGATCG) (SEQ ID NO:22)를 함유한다. 그러므로 PmlI 부위를 추가하였다. pcDNA SV 카세트 2에 대하여, PmlI 부위를 bp 1012 (CACGTG) (SEQ ID NO:23)에 삽입하였다. 카세트 3에 대하여, PmlI 부위를 bp 935-940 (ACTGTG (SEQ ID NO:24)에 추가하였고 CACGTG (SEQ ID NO:23)로 바꾸었다.
각각의 폴리시스트론성 벡터에 대하여, 첫 번째 유전자를 SalI-XbaI 부위를 이용하여 pVCR 2.1 변형된 벡터 내로 직접 삽입하였다. 두 번째 유전자를 SalI-XbaI를 이용하여 pcDNA SV 카세트 2로 결찰하였고 NotI-PmlI, NotI-SacII를 이용하여 잘라내거나 NotI-ClaI에 대한 프라이머를 이용하여 PCR하였고 NotI 및 ClaI를 이용하여 촉진하였다. 결과 삽입물 SGP-SalI-GOI-Xba을 NotI-PmlI, NotI-SacII, 또는 NotI-ClaI 부위를 이용하여 변형된 pVCR 2.1 벡터에 결찰하였다. NotI-ClaI 삽입물은 구조물에서 원하는 유전자가 PmlI 부위를 함유할 때만 이용되었다.
일부 경우에서, 세 번째 유전자를 SalI-XbaI를 이용하여 pcDNA SV 카세트 3에 결찰하였고 PmlI-SacII를 이용하여 잘라내거나 ClaI-SacII에 대한 프라이머를 이용하여 PCR하였고 ClaI 및 SacII를 이용하여 촉진하였다. 결과 삽입물 SGP-SalI-GOI-XbaI을 PmlI-SacII 또는 ClaI-SacII를 이용하여 변형된 pVCR 2.1로 결찰하였다.
SalI-XbaI 촉진을 폴리시스트론성 벡터 DNA의 구조물을 입증하기 위해 이용하였다. SalI-XbaI으로 촉진 후, GOI의 존재를 확인하기 위해 아가로스 겔 전기영동을 수행하였다. 폴리시스틀노성 벡터 DNA를 PmeI로 하룻밤 동안 선형화하였고, Qiagen의 PCR 정제 키트를 사용하여 정제하였고, Ambion mMessage mMachine 키트를 사용하여 RNA를 만들기 위해 주형으로 사용하였다. RNA 질을 RNA 아가로스 겔 상에 샘플 앨리쿼트를 실행함으로써 체크하였다.
폴리시시트론성 벡터로부터 발현
폴리시스트론성 벡터의 두 개의 단백질을 발현하는 능력을 평가하기 위하여 형광 발광 단백질 GFP (녹색 형광 단백질) 및 mCherry (적색 형광 단백질)을 이용하였다. 우리는 첫 번째 서브게놈 프로모터를 사용하여 GFP가 발현되고 두 번째 서브게놈 프로모터를 사용하여 mCherry가 발현되는 바이시스트론성 벡터를 제조하였다 (도 4a). 이 단백질에 대한 암호화 서열을 함유하는 폴리뉴클레오티드를 SalI-XbaI 부위를 사용하여 삽입하였다. 첫 번째 폴리뉴클레오티드 (GFP)를 변형된 알파바이러스 레플리콘 벡터로 직접 삽입하였다. 두 번째 폴리뉴클레오티드 (mCherry)를 암호화 서열의 직접적으로 업스트림인 서브게놈 프로모터를 함유하는 tu틀 벡터로 먼저 삽입하였다. 두 번째 서브게놈 프로모터 및 두 번째 폴리뉴클레오티드 둘 다를 함유하는 단편을 분리하였고 첫 번째 폴리뉴클레오티드를 함유하는 변형된 알파바이러스 레플리콘 벡터에 결찰하였으며, 다수의 서브게놈 프로모터를 갖는 알파바이러스 레플리콘을 제공한다.
Cap 및 Gly에 대하여 결함 헬퍼 RNA와 함께 레플리콘 RNA를 전기 천공함으로써 BHKV 세포에서 VRP를 생산하였다. VRP를 전기 천공 24 시간 후 수확하였고 세포 당 20개의 감염 유닛 (IU)의 감염 다중도 (MOI)로 BHKV 세포를 감염시키기 위해 이용하였다.
실험은 네 개의 세트의 VRP를 테스트하였다: GFP만을 발현하는 한 VRP; mCherry를 발현하는 한 VRP; 둘 다 20 IU/세포의 MOI에서, GFP만을 발현하는 한 VRP 및 mCherry만을 발현하는 한 VRP; 및 바이시스트론성 벡터 GFP (1)-SGPmCherry(2)를 함유하는 한 VRP. VRP-감염된 BHKV 세포를 공존의 퍼센트를 결정하기 위해 감염 24 시간 후 조사하였다. 거의 모든 세포는 개별적으로 감염될 때 GFP 또는 mCherry에 대해 양성이었다. 두 개의 별도으이 VRP로 감염된 세포는 녹색 또는 적색을 나타냈다. 극소수의 세포는 황색이었고, 소수의 세포가 동등한 수준으로 GFP 및 mCherry를 나타내고 동시-감염의 수준이 낮다는 것을 나타낸다. 이 데이터를 FACS 분석법을 사용하여 확인하였다 (도 4b).
반대로, 바이시스트론성 벡터 GFP(1)-SGPmCherry(2)를 함유하는 알파바이러스로 감염된 세포는 모두 황색이었으며, 이것은 GFP 및 mCherry의 거의 동일한 발현을 나타낸다. 이 연구는 다수의 단백질이 단일 폴리시스트론성 알파바이러스 레플리콘 벡터로부터 성공적으로 발현될 수 있다는 것을 입증한다.
실시예 3
CMV 복합체의 생산
이 실시예는 폴리시스트론성 알파바이러스 레플리콘 벡터의 복합체 성분의 전달 후 세포에서 CMV 단백질 복합체가 형성될 수 있다는 것을 입증한다.
gH/gL 및 gH/gL/gO 복합체
폴리시스트론성 gH/gL 및 gH/gL/gO 알파바이러스 레플리콘을 상기 설명된 바와 같이 구성하였다 (도 5a에 도면으로 나타남). 레플리콘을 암호화하는 gH, gL, gO, gH/gL 및 gH/gL/gO를 함유하는 VRP를 상기 설명된 바와 같이 BHKV tph에서 생산하였고 시험관 내에서 복합체 형성을 입증하기 위해 BHKV 세포를 감염시키는데 사용하였다. VRP 감염된 ARPE-19 세포들은 gH/gL의 이황화 결합된 복합체를 생성하였다. gO는 gH/gL 결합을 검출 가능하게 변화시키지 않았다 (도 5b).
단독으로 전달된 gH 및 gL의 국부화를 평가하기 위해 및 동시발현될 때 단백질의 재국부화를 관찰하기 위해 폴리시스트론성 알파바이러스를 사용하여 전달될 때 면역형광 연구를 수행하였다. gH 국부화는 gL, 또는 gL/gO의 존재시 또는 부재시 바뀌지 않는 것으로 보였다. gL 국부화는 gH 및 gH/gO의 존재시 바뀌지 않았다.
최종적으로, gH/gL 결합을 면역침강법을 통해 검사하였다. 상업적인 gH 항체 (Genway)를 gH 및 gL의 결합을 조사하기 위해 사용하였다. 모든 경우에서, gH 항체는 gH를 효율적으로 면역침강하였다 (도 5c). gH가 존재하지 않을 때, gL은 면역침강되지 않았다. gH 또는 gH/gO의 존재시 gL이 발현될 때, gL과 gH의 결합이 있었다 (도 5c).
gH의 존재시 gL의 재국부화 및 gH/gL의 결합은 (gO의 유무에 상관없이) 폴리시스트론성 알파바이러스 레플리콘의 모든 성분이 발현되고 복합체를 형성하기 위해 결합된다는 것을 나타낸다.
실시예 4
시험관 내에서 gH/gL 복합체 형성에 영향을 미치는 VRP는 gB VRP에 대하여 유도된 면역 반응에 비해 질적으로 및 양적으로 뛰어난 효능 있는 면역 반응을 유발한다.
이 실시예는 폴리시스트론성 gH/gL VRP 또는 gH/gL/gO VRP를 전달함으로써 형성되는 강한 면역 반응의 유발이 조합으로 투여된 단일 성분들을 전달하는 VRP 및 단일 성분 VRP를 사용하여 얻어진 면역 반응 또는 gB VRP에 의해 유도된 반응과 비교된다는 것을 입증한다.
마우스를 3주 간격으로 투여된 VRP로 세 번 감염시켰다 (마우스 당 106 IU; 5 마리 BalbC 마우스/그룹). 단일 및 폴리시스트론성 VRP로 면역화로부터 수거된 혈청을 상기 설명된 바와 같이 CMV 중화 검정을 사용하여 중화 항체에 대하여 선별하였다. 중화 역가를 다음과 같이 측정하였다. 다양한 희석의 혈청을 기니피그 보체의 존재시 또는 부재시 TB40-UL32-EGFP와 함께 사전 배양하였고 ARPE-19 상피 세포 또는 MRC-5 섬유아세포에 추가하였고 5일 동안 배양하였다. 바이러스로 감염 5일 후, GFP-양성 세포를 계산하였다. ARPE-19 세포에 대한 결과는 도 6a, 도 6b, 및 도 6c에 나타난다. MRC-5 세포에 대한 결과는 도 7a 및 도 7b에 나타난다.
gH FL VRP로 면역화된 마우스의 혈청은 낮은 보체-독립적 중화 활성이 있었다 (도 6a 및 도 6b). 기니피그 보체의 존재시 또는 부재시 gL 또는 gO만으로 면역화된 마우스의 혈청을 사용하여 중화 활성이 관찰되지 않았다 (도 6c). 다수의 CMV gB 단백질 (gB FL, gB sol 750, 및 gB sol 692)로 면역화된 풀 혈청은 기니피그 보체의 존재시 1:1280 혈청 희석시 50% 중화 역가를 갖는, 강한 중화 활성을 입증하였다. 하지만, 풀 gB 혈청에 대하여 ARPE-19 세포에서 기니피그 보체의 부재시 중화 활성이 없었다. 단일 CMV 단백질을 발현하는 VRP (106 IU/마우스/VRP로 gH-또는 gL-VRP 또는 동시투여 gH-, gL-, 및 gO-VRP)는 gH 단독의 그것 이상으로 중화 활성을 향상시키지 않았다.
반대로, 바이시스트론성 gH/gL 또는 트리시스트론성 gH/gL/gO VRP로 면역화된 마우스의 혈청 (1x106 IU/마우스)은 강한 중화 반응을 입증하였다. 게다가, 반응은 기니피그 보체의 존재시 및 부재시 유사하였으며, 폴리시스트론성 VRP가 보체-독립적 면역 반응을 성공적으로 유발하였다는 것을 나타낸다 (도 6c). 50% 중화 역가는 TB40-GFP CM 바이러스를 갖는 ARPE-19 세포에서 1:3500-6400+ 혈청 희석이었다. 이 역가는 gB 풀 혈청에 대하여 50% 보체-의존적 중화 역가보다 대략 3-4배 더 높은 역가이다.
MRC-5 섬유아세포에서 결과는 ARPE-19 세포의 그것과 유사하였다 (도 7a 및 도 7b). 바이시스트론성 gH/gL 또는 트리시스트론성 gH/gL/gO VRP로 면역화된 마우스의 혈청은 gH 단독, gL 단독, 또는 gO 단독을 암호화하는 VRP로 면역화된 마우스의 혈청 및 gH VRP 및 gL VRP의 동시투여, 또는 gH VRP, gL VRP, 및 gO VRP의 동시투여에 의해 면역화된 마우스의 혈청에 비해 강한 중화 활성을 입증하였다. 이 결과들은 폴리시스트론성 VRP의 투여가 섬유아세포의 CMV 감염의 양호한 보체-독립적 중화를 제공하는 면역 반응을 유발한다는 것을 입증한다. CMV의 다른 균주에 대한 gH/gL 면역 혈청의 범위 및 효능을 평가하기 위해, 우리는 혈청의 섬유아세포 및 상피 세포의 감염을 차단하는 능력과 CMV의 6개의 다른 균주를 비교하였다. 도 8은 gH/gL 혈청이 광범위한 균주로 세포 타입 둘 다의 감염을 효능 있게 중화시킨다는 것을 나타낸다.
이 데이터는 또한 폴리시스트론성 VRP로 면역화되지만 단지 하나의 단백질을 발현하는 VRP의 혼합된 풀이 아닌 마우스의 혈청에 대한 강한 중화 활성을 입증한다. 이는 단일 레플리콘에서 단백질 복합체의 성분을 암호화하는 폴리시스트론성 레플리콘이 제자리에서 복합체의 효율적인 생산을 일으킨다는 것을 나타낸다. 게다가, Merlin 균주 CMV 단백질을 이 반응들을 자극하기 위해 사용하였고, TB40 균주 CMV 바이러스를 사용하여 얻어진 시험관 내 데이터는 폴리시스트론성 VRP의 전달에 의해 유발된 중화 항체가 교차-중화 항체인 것을 입증한다.
실시예 5
RNA 합성
알파바이러스 레플리콘을 암호화하는 플라스미드 DNA (도 14-16 참조)는 시험관 내에서 RNA의 합성을 위한 주형의 역할을 하였다. 알파바이러스 레플리콘은 RNA 복제에 필요한 유전적 요소를 함유하지만 입자성 조립체에 필요한 유전자 생성물을 암호화하는 것이 없다; 알파바이러스 게놈의 구조 유전자는 이종 기원 단백질을 암호화하는 서열에 의해 대체된다. 진핵세포에 레플리콘의 전달시, 양성-가닥 RNA는 네 개의 비구조 단백질을 생산하기 위해 번역되며, 이것은 함께 게놈 RNA를 복제하고 이종 기원 유전자 생성물 또는 원하는 유전자 (GOI)를 암호화하는 풍부한 서브게놈 mRNA를 전사한다. 알파바이러스 구조 단백질의 발현의 결핍으로 인해, 레플리콘은 감염성 입자의 발생을 유발할 수 없다. 알파바이러스 cDNA의 박테리오파지 (T7 또는 SP6) 프로모터 업스트림은 시험관 내에서 레플리콘 RNA의 합성을 용이하게 하고 폴리(A)-꼬리의, 델타 간염 바이러스 (hepatitis delta virus; HDV) 다운스트림은 그것의 자체-분할 활성을 통해 정확한 3'-말단을 발생시킨다.
항원성 단백질 복합체의 형성을 허용하기 위해, 같은 세포에서 상기 복합체의 개개의 성분의 발현이 가장 중요하다. 이론상으로, 이것은 개개의 성분을 암호화하는 유전자를 갖는 세포를 동시트랜스펙션함으로써 이루어질 수 있다. 하지만, 비-바이러스성 또는 VRP 전달 알파바이러스 레플리콘 RNA의 경우에, 이 계획은 불다수의 RNA의 같은 세포에 충분한 동시전달에 의해 또는, 대안으로서, 개개의 세포에서 다수의 자가 복제 RNA의 불충분한 론치에 의해 방해된다. 단백질 복합체의 성분의 동시발현을 용이하게 하는 잠재적으로 더 효율적인 방법은 같은 자가 복제 RNA 분자의 일부로서 각각의 유전자를 전달하는 것이다. 이를 위해, 우리는 원하는 다수의 유전자를 암호화하는 알파바이러스 레플리콘 구조물을 설계하였다. 모든 GOI는 알파바이러스 전사 장치에 의해 인식되는 그것 자체의 서브게놈 프로모터에 의해 진행된다. 그 때문에, 다수의 서브게놈 메신저 RNA 종은 다성분 단백질 복합체의 조립체를 허용하는 개개의 세포에서 합성된다.
적합한 제한 엔도뉴클레아제를 갖는 HDV 리보자임의 플라스미드 DNA 다운스트림의 선형화에 따라, 유출 전사물 (run-off transcript)을 T7 박테리오파지 유도 DNA-의존적 RNA 폴리머라제를 사용하여 시험관 내에서 합성하였다. 전사를 제조사 (Ambion, Austin, TX)에 의해 제공된 지시에 따라 각각 7.5 mM의 뉴클레오시드 트리포스페이트 (ATP, CTP, GTP 및 UTP)의 존재시 37 ℃에서 2 시간 동안 수행하였다. 전사 후, 주형 DNA를 TURBO DN아제로 소화시켰다. 레플리콘 RNA를 LiCl로 침전시켰고 뉴클레아제 없는 물로 재구성하였다. 캐핑되지 않은 RNA를 사용자 매뉴얼에 설명된 바와 같이 ScriptCap m7G Capping System (Epicentre Biotechnologies, Madison, WI)을 사용하여 Vaccinia Capping Enzyme (VCE)로 전사 후 캐핑하였다. 전사 후 캐핑된 RNA를 LiCl로 침전시켰고 뉴클레아제 없는 물로 재구성하였다. RNA 샘플의 농도를 250 nm에서 흡광도를 측정함으로써 결정하였다. 시험관 내 전사의 무결성을 아가로스 겔 전기 영동을 변성시킴으로써 확인하였다.
지질 나노입자 (LNP) 조제
1,2-디리놀레일옥시-N,N-디메틸-3-아미노프로판 (DlinDMA)을 이전에 출판된 공정 [Heyes, J., Palmer, L., Bremner, K., MacLachlan, I. Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. Journal of Controlled Release, 107: 276-287 (2005)]을 사용하여 합성하였다. 1,2-디아스테아로일-sn-글리세로-3-포스포콜린 (DSPC)을 Genzyme에서 구입하였다. 콜레스테롤을 Sigma-Aldrich (St. Lois, MO)에서 얻었다. 1,2-디미리스토일-sn-글리세로-3-포스포에탄올아민-N-[메톡시(폴리에틸렌 글리콜)-2000] (암모늄 염) (PEG DMG 2000)을 Avanti Polar Lipids에서 얻었다.
LNP (RV01(14))를 다음 방법을 사용하여 조제하였다. 150 μg 배치, (PES 유공 섬유 및 무스탕 없음): 에탄올 중에 신선한 지질 스톡 (stock) 용액을 제조하였다. 37 mg DlinDMA, 11.8 mg DSPC, 27.8 mg 콜레스테롤 및 8.07 mg PEG DMG 2000을 계량하였고 7.55 mL 에탄올에 용해시켰다. 신선하게 제조된 지질 스톡 용액을 균질한 혼합물을 형성하기 위해 37 ℃에서 약 15 분 동안 부드럽게 흔들었다. 이후에, 2 mL의 작용 지질 스톡 용액을 만들기 위해 453 μL의 스톡을 1.547 mL 에탄올에 추가하였다. 이 지질의 양을 8:1 N:P (질소 대 인)에서 150 μg RNA로 LNP를 형성하기 위해 사용하였다. 이 계산을 위해 DlinDMA 상에 양성자성 질소 (양이온성 지질) 및 RNA 상에 인산이 사용된다. 자가 복제 RNA 분자의 각각의 μg이 음이온성 인의 3 nmole을 함유하는 것으로 가정하였고, DlinDMA의 각각의 μg은 양이온성 질소의 1.6 nmole을 함유하는 것으로 가정하였다. 2 mL의 RNA 작용 용액을 또한 100 mM 시트레이트 완충액 (pH 6) (Teknova)중의 1 μg/μL 이하의 스톡 용액으로부터 제조하였다. 세 개의 20 mL 유리 바이알 (스터 바 (stir bar)와 함께)을 RNase Away 용액 (Molecular BioProducts)으로 헹구고 RN아제로 바이알을 정화하기 위해 사용 전 충분한 MilliQ 물로 세척하였다. 바이알 중 하나를 RNA 작용 용액을 위해 사용하였고 다른 것을 지질 및 RNA 혼합물을 수거하기 위해 사용하였다 (하기 설명된 바와 같음). 작용 지질 및 RNA 용액을 3 cc 루어록 (luer-lok) 주사기 (BD Medical)에 로딩하기 전에 37 ℃에서 10 분 동안 가열하였다. 2 mL의 시트레이트 완충액 (pH 6)을 또 다른 3 cc 주사기에 로딩하였다. RNA 및 지질을 함유하는 주사기를 FEP 튜빙 ([불소화 에틸렌-프로필렌] 2mm ID x 3mm OD, Idex Health Science, Oak Harbor, WA)을 사용하여 T 믹서 (PEEK™ 500 μm ID 접합)에 연결하였다. T 믹서의 배출구는 또한 FEP 튜빙 (2mm ID x 3mm)이었다. 세트레이트 완충액을 함유하는 세 번째 주사기를 별도의 조각의 튜빙 (2mm ID x 3mm OD)에 연결하였다. 모든 주사기를 주사기 펌프 (kdScientific의 것, 모델 번호 KDS-220)를 사용하여 7 mL/ 분의 유속으로 구동하였다. 혼합물을 수거하기 위해 튜브 배출구를 20 mL 유리 바이알에 배치하였다 (교반하면서). 스터 바를 꺼내고 에탄올/수용액을 1 시간 동안 상온과 평형을 허용하였다. 혼합물을 5 cc 주사기 (BD Medical)에 로딩하였으며, 이것은 FEP 튜빙 (2mm ID x 3mm OD)의 조각에 맞춰졌고 같은 길이의 FEP 튜빙을 갖는 또 다른 5 cc 주사기에서, 같은 양의 100 mM 시트레이트 완충액 (pH 6)을 로딩하였다. 두 개의 주사기를 주사기 펌프를 사용하여 7 mL/ 분의 유속으로 구동하였고 최종 혼합물을 20 mL 유리 바이알에 수거하였다 (교반하면서). 그 다음, LNP를 2 mL로 농축하였고 최종 생성물을 회수하기 전에 접선 유동 여과 (Tangential Flow Filtration; TFF) 시스템을 사용하여 10-15배의 1X PBS (Teknova의 것)에 대하여 투석하였다. TFF 시스템 및 유공 섬유 여과막을 Spectrum Labs에서 구입하였고 제조사의 가이드라인에 따라 사용하였다. 100 kD 기공 크기 컷오프 및 20 cm2 표면적을 갖는 폴리에테르술폰 (PES) 유공 섬유 여과막 (부품 번호 P-C1-1OOE-100-O1N)을 사용하였다. 시험관 내 및 생체 내 실험에 대하여, 제형을 1X PBS (Teknova의 것)를 가지고 필요한 RNA 농도로 희석하였다.
입자 크기
입자 크기를 제조사의 지시에 따라 Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK)를 사용하여 측정하였다. 입자 크기는 다 분산 지수 (pdi)와 함께 Z 평균으로 보고된다. 측정 전 리포솜을 1X PBS로 희석하였다.
캡슐화 효능 및 RNA 농도
캡슐화된 RNA의 퍼센트 및 RNA 농도를 Quant-iT RiboGreen RNA 시약 키트 (Invitrogen)으로 결정하였다. 검정시 제조사의 지시를 따랐다. 키트에 제공된 리보솜 RNA 표준을 표준 곡선을 발생시키기 위해 사용하였다. 염료의 추가 전에, 방법 1 또는 방법 2-5로부터 얻어진 LNP를 1X TE 완충액 (키트의 것)으로 각각 10배 또는 100배 희석하였다. 별도로, 염료의 추가 전에, LNP를 0.5% Triton X (Sigma-Aldrich)를 함유하는 1X TE 완충액으로 10배 또는 100배 희석하였다. 그 후에 같은 양의 염료를 각각의 용액에 추가하였고 염료 추가 후에 180 μL 이하의 각 용액을 96 웰 조직 배양 플레이트에 두 번 로딩하였다 (VWR에서 얻어짐, 카탈로그 # 353072). 형광발광 (Ex 485 nm, Em 528 nm)을 미크로플레이트 리더 (BioTek Instruments, Inc.의 것)에서 측정하였다.
LNP를 방해하기 위해 Triton X를 사용하였으며, 총 RNA 양에 해당하는 형광발광 측정값을 제공하고 Triton X가 없는 샘플은 캡슐화되지 않은 RNA에 해당하는 형광발광을 제공한다. % RNA 캡슐화를 다음과 같이 결정하였다: LNP RNA 캡슐화 (%) = [(Ft-Fi)/Ft] X 100, 여기에서 Ft는 Triton X가 추가된 LNP의 형광 강도이고 Fi는 세제 추가 없는 LNP의 형광 강도이다. 이 값들 (Ft 및 Fi)은 블랭크 (blank) (1X TE 완충액) 형광 강도에서 뺀 후에 얻어진다. 캡슐화된 RNA의 농도를 Ft-Fi를 발생된 표준 곡선과 비교함으로써 얻어졌다. 모든 LNP 제형을 캡슐화된 용량에 기초하여 생체 내에 투여하였다.
바이러스 레플리콘 입자 (VRP)
RNA 백신을 리포터 유전자 또는 항원의 생체 내 발현을 달성하기 위한 전통적인 RNA-벡터 접근법과 비교하기 위하여, 우리는 Perri et al. (J. Virol 77(19): 10394-10403 (2003))에 의해 설명된 방법으로 BHK 세포에서 생산되고, 해당하는 RNA 구조물과 같은 항원의 발현을 위해 암호화하는 바이러스 레플리콘 입자 (VRP)를 활용하였다. 이 시스템에서, 항원은 신드비스 바이러스의 3' 말단 서열 (3' UTR) 및 신드비스 바이러스 패키징 신호 (PS)를 함유하도록 설계된 베네수엘라 말 뇌염 바이러스 (VEEV)의 게놈으로부터 유도된 알파바이러스 키메라 레플리콘 (VCR)로 구성되었다 (Perri et al의 도 2 참조). 그것들을 신드비스 바이러스 캡시드 및 당단백질 유전자를 암호화하는 결함 헬퍼 RNA로 아기 햄스터 신장 (BHK) 세포에 동시전기천공함으로써 레플리콘을 VRP 내로 포장하였다 (Perri et al의 도 2 참조). 이후 VRP를 수거하였고 수크로스 쿠션에서 초원심 분리에 의해 부 분적으로 정제하였고 Amicon 농축기에서 농축하였다. 결과 VRP 스톡을 표준 방법에 의해 적정하였고 배양 유동체 또는 다른 등장성 완충액의 동물에 접종하였다. 베네수엘라 말 뇌염 및 신드비스 바이러스로부터 유도된 알파바이러스 레플리콘 입자 키메라는 효능 있는 유전자-기반 백신 전달 벡터이다. J. Virol 77, 10394-10403.
쥐 면역원성 연구
10마리의 8-10주령 및 약 20 g 중량의 BALB/c 마우스 그룹을 제 0일, 제 21일 및 제 42일에 1x106 IU (VRP) 또는 1.0 μg (RNA)로 면역화하였으며, 두 번째 백신 접종 3주 후에 및 세 번째 백신 접종 3주 후에 채혈하였다. 모든 동물은 두 개의 뒷다리의 사두근에 주사되었고 각각 동등한 양 (부위 당 50 μl)을 얻었다.
미크로 중화 검정
혈청 샘플을 중화 항체에 대하여 감염 감소 중화 테스트로 테스트하였다. 두 배의 단계 희석된 HI-혈청 (10% HI FBS가 첨가된 DMEM으로)을 약 200 IU/50 μl를 제공하도록 이전에 적정된 동량의 CMV (균주 TB40 또는 임상 분리체 8819)에 추가하였다. VR1814, Towne, AD 169 균주 및 임상 분리체 8822를 또한 사용하였다. 바이러스 중화가 발생하는 것을 허용하기 위해 혈청/바이러스 혼합물을 37 ℃ 및 5% CO2에서 2 시간 동안 배양하였고, 이후 이 혼합물의 50 μl (약 200 IU 함유)를 96 하프 웰 플레이트의 ARPE-19 세포의 웰에 두 번 접종하였다. 플레이트를 40-44 시간 동안 배양하였다. 달리 지시되지 않으면, 양성 감염된 병소의 수를 AlexaFluor 488 접합 IE1 CMV 단클론성 항체로 면역염색 후 이어서 자동화 계산에 의해 결정하였다. 중화 역가는 대조군 (혈청 없음)에 비해, 웰 당 양성 바이러스 병소의 수의 50% 감소를 생산하는 혈청 희석의 역수로서 정의된다.
gH/gL VRP의 면역원성 및 LNP 조제 RNA
CMV의 표면 당단백질 B (gB)를 발현하는 A323 레플리콘, 전체 길이 당단백질 H 및 L (gH/gL)의 막 복합체를 발현하는 A160 레플리콘 및 가용성 형태의 당단백질 H 및 L (gHsol/gL)의 막 복합체를 발현하는 A322 레플리콘을 이 실험에 사용하였다. BALB/c 마우스, 그룹 당 10마리의 동물에 제 0일, 제 21일 및 제 42일에 gB를 발현하는 VRP (1x106 IU), gH/gL을 발현하는 VRP (1x106 IU), gHsol/gL을 발현하는 VRP (1x106 IU) 및 대조군으로서 PBS로 양측 근육 내 백신 접종 (다리 당 50 μl)을 제공하였다. 세 개의 테스트 그룹 (A160, A322 또는 A323)은 LNP (RV01(14))에서 조제된 자가 복제 RNA를 받았다. 제 39일 (3wp2) 및 제 63일 (3wp3)에 면역학적 분석을 위해 혈청을 수거하였다.
결과
실험을 위해 만들어진 RV01(14) 조제시 캡슐화된 RNA의 시브 (sive) 및 퍼센트는 표 3에 나타난다.
Figure 112020102169690-pat00003
마지막 혈청 (제 63일, 최종 백신 접종 3주 후)에 대한 50% 중화 역가는 표 4에 나타난다.
Figure 112020102169690-pat00004
두 개의 다른 HCMV 균주를 사용하여 상피 세포에서 검정된 바와 같이, HCMV gH/gL 복합체의 전체 길이 또는 추정 가용성 형태를 발현하는 RNA는 중화 항체의 높은 역가를 유도한다. gH/gL RNA에 의해 유도된 평균 역가는 적어도 해당하는 gH/gL VRP에 대한 평균 역가만큼 높다 (도 17 참조)
실시예 6 CMV 단백질을 암호화하는 바이시스트론성 및 펜타시스트론성 핵산
사람 시토메갈로바이러스 (HCMV)의 당단백질 복합체를 발현하는 추가적인 바이시스트론성 및 펜타시스트론성 알파바이러스 레플리콘을 제조하였고, 도 18 및 20에 개략적으로 나타난다. 알파바이러스 레플리콘은 베네수엘라 말 뇌염 바이러스 (VEE)에 기초하였다. 레플리콘은 바이러스 레플리콘 입자 (VRP) 내로 포장되었고, 지질 입자 (LNP)로 캡슐화되거나 양이온성 나노에멀젼 (CNE)을 가지고 조제되었다. 각각의 레플리콘의 암호화된 HCMV 단백질 및 단백질 복합체의 발현을 면역블롯, 동시면역침강법, 및 유동 세포 분석법으로 확인하였다. 펜타머 복합체에 존재하는 구조 에피토프에 특이적인 사람 단클론성 항체를 사용하여, 복합체의 단백질 성분을 암호화하는 펜타머 레플리콘의 펜타머 gH/gL/UL128/UL130/UL131 복합체의 발현을 입증하기 위해 유동 세포 분석법을 사용하였다 (Macagno et al (2010), J. Virol. 84(2): 1005-13). 도 19는 이 항체들이 HCMV gH/gL/UL128/UL130/UL131 펜타머 복합체 (A527)를 발현하는 레플리콘 RNA로 트랜스펙션된 BHKV 세포에 결합한다는 것을 나타낸다. 세포가 같은 레플리콘 구조물로 만들어진 VRP로 감염되었을 때 유사한 결과를 얻었다. 이는 펜타머 복합체를 발현하도록 설계된 레플리콘이 원하는 항원을 정말로 발현하지만 잠재적 부산물 gH/gL은 아니라는 것을 나타낸다.
LNP에 캡슐화된 RNA인, 및 CNE로 조제된 RNA인, VRP는 후방 사두근의 근육 내 주사로 Balb/c 마우스를 면역화하기 위해 사용하였다. 마우스를 세 번, 3주 간격으로 면역화하였고, 혈청 샘플을 면역화 이전에 뿐만 아니라 세 번째 및 최종 면역화 3주 후에 각각 수거하였다. 혈청을 평가하였다. 혈청을 백신 접종에 의해 유도된 중화 항체 반응의 효능을 측정하기 위해 미크로중화 검정으로 평가하였다. 역가는 50% 중화 역가로서 발현된다.
가용성 HCMV gH/gL 복합체에 대한 바이시스트론성 발현 카세트의 많은 다른 배열의 면역원성을 평가하였다. 도 20은 막-고정된, 전체 길이 gH/gL 복합체를 발현하는 VRP가 효능 있는 중화 항체를 유사한 바이시스트론성 발현 카세트에서 발현되는 가용성 복합체 (gHsol/gL)보다 약간 더 높은 역가로 발현하였다는 것을 나타낸다. gHsol 및 gL을 암호화하는 유전자의 순서를 바꾸거나 서브게놈 프로모터 중 하나를 IRES 또는 FMDV 2A 부위로 대체하는 것은 실질적으로 면역원성을 개선하지 않았다.
gH/gL을 발현하는 VEE/SIN VRP로 면역화된 마우스의 혈청의 HCMV 중화 활성의 범위 및 효능을 다른 균주의 HCMV로 섬유아세포 및 상피 세포의 감염을 차단하기 위해 혈청을 사용함으로써 평가하였다. 표 5는 보체의 부재시 두 가지 세포 타입에서 gH/gL 면역 혈청이 여섯 가지의 다른 균주의 HCMV에 대하여 광범위하고 유효하게 중화하였다는 것을 나타낸다. 보체의 추가는 혈청의 중화 효능에 대하여 약간 부정적인 효과가 있었다.
Figure 112020102169690-pat00005
LNP-캡슐화된 RNA (A160)에 비해 펜타머 복합체 (A526 및 A527)를 암호화하는 LNP-캡슐화된 RNA 및 VRP (pVCR 변형된 gH-SGPgL)의 면역원성을 평가하였다. 표 6은 펜타머 복합체를 발현하는 레플리콘이 gH/gL을 발현하는 레플리콘 보다 더 많은 효능 있는 중화 항체를 유도하였다는 것을 나타낸다.
Figure 112020102169690-pat00006
가장 높은 역가의 중화 항체 (A527)를 유도하는 펜타시스트론성 VEE-기반 RNA 레플리콘을 VRP로 포장하였고 VRP의 면역원성을 gH/gL-발현 VRP 및 gH/gL 및 펜타머 복합체를 발현하는 LNP-캡슐화된 레플리콘에 비교하였다. 표 7은 펜타머 복합체를 발현하는 VRP가 gH/gL을 발현하는 VRP보다 더 높은 역가의 중화 항체를 유도하였다는 것을 나타낸다. 게다가, VRP의 106개의 감염성 유닛은 VRP 및 RNA가 같은 단백질 복합체를 암호화할 때 적어도 1 μg의 LNP-캡슐화된 RNA만큼 효과가 있다.
Figure 112020102169690-pat00007
펜타머 복합체 (A527)을 암호화하는 VEE-기반 RNA로 면역화된 마우스 혈청의 HCMV 중화 활성의 범위 및 효능을 HCMV의 다른 균주로 섬유아세포 및 상피 세포의 감염을 차단하기 위해 혈청을 사용함으로써 평가하였다. 표 8은 항-gH/gL/UL128/UL130/UL131 면역 혈청이 광범위하고 상피 세포의 감염을 효능있게 중화하였다는 것을 나타낸다. 이 노력은 보체 독립적이었다. 반대로, 혈청은 섬유아세포의 감염에 대하여 감소된 또는 검출 불가능한 효과가 있었다. 펜타머 복합체는 섬유아세포의 감염이 필요하지 않기 때문에, 이 결과들은 주로 gH/gL/UL128/UL130/UL131 펜타머 복합체에 대해 특이적인 항체를 함유하는 면역 혈청에 대하여 예상된 것이고, 그 결과로서, UL128, UL130, 및 UL131에 대한 항체는 섬유아세포의 감염을 차단하지 않는다 (Adler et al (2006), J. Gen. Virol. 87(Pt.9):2451-60; Wang and Shenk (2005), Proc. Natl. Acad. Sci. USA 102(50): 18153-8). 따라서, 이 데이터는 gH/gL/UL128/UL130/UL131 펜타머 복합체를 암호화하는 펜타머 레플리콘은 특이적으로 생체 내에서 복합체에 대한 항체를 유도한다.
Figure 112020102169690-pat00008
gH/gL 및 펜타머 복합체를 발현하는 바이시스트론성 및 펜타시스트론성 레플리콘이 다른 제형에서 중화 항체를 유도할 것인지 알기 위해서, 코튼 래트 (cotton rat)를 양이온성 나노에멀젼 (CNE)과 혼합된 바이시스트론성 또는 펜타시스트론성 레플리콘으로 면역화하였다. 표 9는 CNE 중의 레플리콘이 LNP에서 캡슐화된 같은 레플리콘에 비교 가능한 중화 항체 역가를 유도하였다는 것을 나타낸다.
Figure 112020102169690-pat00009
실시예 7. VZV 단백질을 암호화하는 레플리콘
gB, gH, gL, gE, 및 gI를 암호화하는 모노시스트론성 레플리콘을 생산하기 위해 및 gH/gL 또는 gE/gI를 암호화하는 바이시스트론성 레플리콘을 생산하기 위해 VZV 단백질을 암호화하는 핵산을 VEE 레플리콘 벡터에 클로닝하였다. 바이시스트론성 레플리콘에서, 각각의 VZV 오픈 리딩 프레임의 발현은 별도의 서브게놈 프로모터에 의해 구동되었다.
레플리콘 RNA를 제조하기 위해, 레플리콘을 암호화하는 플라스미드를 PmeI로 소화에 의해 선형화하였고, 선형화된 플라스미드를 페놀/클로로포름/이소아밀알콜로 추출하였고, 나트륨 아세테이트/에탄올에서 침전시켰고 20μl의 RN아제 없는 물에 재현탁시켰다.
MEGAscript T7 키트 (AMBION# AM1333)를 사용하여 1 μg의 선형화된 DNA의 시험관 내 전사에 의해 RNA를 제조하였다. 20 μ1 반응물을 캡 유사체 없이 제조사의 지시에 따라 셋업하였고 32 ℃에서 2 시간 동안 배양하였다. TURBO DN아제 (1 μl)을 추가하였고 혼합물을 32 ℃에서 30 분 동안 배양하였다. RN아제 없는 물 (30 μl) 및 암모늄 아세테이트 (30 μl)를 추가하였다. 용액을 혼합하였고-20 ℃에서 적어도 30 분 동안 냉각하였다. 이후 용액을 4 ℃에서 25 분 동안 최대 속도로 원심 분리하였다. 상층액을 제거하였고, 펠렛을 70% 에탄올로 헹궜고, 다시 4 ℃에서 10 분 동안 최대 속도로 원심 분리 하였다. 펠렛을 공기 건조하였고 50 μl의 RN아제-없는 물로 재현탁하였다. RNA의 농도를 측정하였고 품질을 변성 겔 상에서 체크하였다.
ScriptCap m7G Capping System (Epicentre #SCCE0625)을 사용하여 RNA를 캐핑하였다. 반응물은 RNA 및 RN아제-없는 물을 결합시킴으로써 양을 조정하였다. 이후 RNA를 65 ℃에서 5-10 분 동안 변성시켰다. 변성된 RNA를 신속하게 얼음으로 옮겼고 다음 시약을 다음 순서로 추가하였다: ScriptCap Capping Buffer, 10 mM GTP, 새로 제조된 2 mM SAM, ScriptGuard RN아제 억제제, 및 ScriptCap Capping Enzyme. 반응은 RN아제-없는 물 및 7.5 M LiCl을 추가하고, 잘 혼합하고-20 ℃에서 적어도 30 분 동안 혼합물을 저장함으로써 중단되었다. 이후, 혼합물을 4 ℃에서 25 분 동안 최대 속도로 원심 분리하였고, 펠렛을 70% 에탄올로 헹궜고, 다시 4 ℃에서 10 분 동안 최대 속도로 원심 분리하였고 펠렛을 공기 건조하였다. 펠렛을 RN아제-아제 없는 물로 재현탁하였다. RNA의 농도를 측정하였고 품질을 변성 겔 상에서 체크하였다.
RNA 트랜스펙션
세포 (BHK-V 세포)를 트랜스펙션 시점에 90-95% 포화되도록 6-웰 플레이트에 분주하였다. 각각의 트랜스펙션을 위해 3 g의 RNA를 첫 번째 튜브의 50 mL OPTIMEM 배지에 희석하였다. Lipofectamine 2000을 50 mL OPTIMEM 배지가 함유된 두 번째 튜브에 추가하였다. 첫 번째 및 두 번째 튜브를 결합하였고 상온에서 20 분 동안 유지하였다. 6-웰 플레이트의 배양 배지를 새로운 배지로 교체하였고, RNA-리포펙타민 복합체를 세포에 배치하였고, 부드럽게 흔들어서 혼합시켰다. 플레이트를 CO2 배양기에서 37 ℃에서 24 시간 동안 배양하였다.
트랜스펙션된 세포에서 VZV 단백질의 발현을 웨스턴 블롯 및 면역형광법에 의해 평가하였다. 웨스턴 블롯을 위해, 트랜스펙션된 세포의 용해물을 전기영동법에 의해 분류하였고 (5 μg 총 단백질/레인) 블롯하였다. OKA/Merck 백신 균주로부터 유도된 온전한 바이러스 현탁액 (7 μg 총 단백질/레인)을 양성 대조군으로서 사용하였다. VZV 단백질과 결합하는 상업적으로 이용 가능한 항체 (1:1000 희석)를 사용하여 블롯을 프로빙하였다.
면역형광법을 위해, 트랜스펙션된 세포를 수확하였고 96 웰 플레이트에 분주하였고, 상업적으로 이용 가능한 마우스 mAb (희석 범위 1:100 1:400)를 사용하여 세포 내 염색을 수행하였다. 세포 펠렛을 고정하였고 Citofix-Citoperm 용액으로 통과시켰다. 두 번째 시약, 염소 항-마우스 F(ab')2 표지된 Alexa488 (1:400 최종 희석)을 사용하였다.
상업적으로 이용 가능한 마우스 항체, gE에 대하여 13B1 및 gI에 대하여 8C4를 사용하여 VZV 단백질 gE 및 gI의 발현은 모노시스트론성 구조물 (gE 또는 gI)로 트랜스펙션된 세포에서 검출되었고, gE 및 gI 둘 다의 발현은 바이시스트론성 gE/gI 구조물로 트랜스펙션된 세포에서 검출되었다. 상업적으로 이용 가능한 항체 10G6을 사용하는 면역형광법에 의해, VZV 단백질 gB의 발현은 gB를 암호화하는 모노시스트론성 구조물로 트랜스펙션된 세포에서 검출되었다. VZV 단백질 복합체 gH/gL의 발현은 모노시스트론성 gH 및 모노시스트론성 gL, 또는 바이시스트론성 gH/gL 구조물로 트랜스펙션된 세포에서 면역형광법에 의해 검출되었다. gH/gL 복합체는 상업적으로 이용 가능한 항체 SG3을 사용하여 검출되었다.
쥐 면역원성 연구
8마리의 6-8주령 및 약 20 g 중량의 암컷 BALB/c 마우스의 그룹을 제 0일, 제 21일 및 제 42일에 CNE 또는 LNP (RV01)로 조제된, 7.0 또는 1.0 μg의 레플리콘 RNA로 근육 내 면역화하였다. 혈액 샘플을 면역화된 동물로부터 두 번째 면역화 3주 후 및 세 번째 면역화 3주 후 채취하였다. 그룹은 표 10에 나타난다.
Figure 112020102169690-pat00010
VZV 항원에 대한 면역 반응
혈청 샘플을 VZV-레플리콘 트랜스펙션된 MRC-5 세포의 세포 내 염색으로 gB에 대한 항체의 존재에 대하여 테스트하였다. MRC-5 세포를 10% 태아 소 혈청이 들어있는 Dulbeco Modified Eagle's Medium에서 유지하였다. VZV Oka 균주 접종원 (ATCC로부터 얻어짐)을 MRC-5 세포 배양액을 감염시키기 위해 사용하였고 감염된 전체 세포를 바이러스의 서브계대 (subpassage)에 사용하였다. 감염된 및 감염되지 않은 세포 사이의 비율은 1:10이었다. 감염 30 시간 후 면역화 후 얻어진 마우스 혈청 (희석 범위 1:200 내지 1:800)의 풀로 세포 내 염색을 수행하기 위해 96 웰 플레이트에 분주를 위해 세포를 트립신-분산시켰다. 상업적인 mAb를 감염 수준을 정량하기 위한 대조군으로서 사용하였다. 세포 펠렛을 고정하였고 Citofix-Citoperm 용액으로 통과시켰다. 두 번째 시약, 염소 항-마우스 F(ab')2 표지된 Alexa488 (1:400 최종 희석)을 사용하였다.
gB (10G6), gH (SG3), 및 gE (13B1 (SBA) 및 8612 (Millipore))에 대한 상업적인 항체를 양성 대조군으로서 사용하였고, 각각 감염된 MRC-5 세포를 세포 내 염색하였다. CNE 또는 LNP로 조제된 1 또는 7 μg의 RNA로 세 번째 면역화 3주 후 얻어진 면역 혈청을 1/200, 1/400 및 1/800로 희석하였고 감염된 MRC-5 세포를 세포 내 염색하기 위해 사용하였다. 결과는 도 21 (연구 1, 그룹 1, 5, 7, 9, 11, 13 및 15, CNE 제형) 및 도 22 (연구 2, 그룹 1-7, LNP 제형)에 나타난다.
중화 검정
각각의 면역화된 마우스 혈청을 표준 배양 배지에서 1:20에서 시작하여 2배 증가로 단계적으로 희석하였고, 기니피그 보체의 존재시 동량의 VZV 현탁액에 추가하였다. 37 ℃에서 1시간 동안 배양 후, 사람 상피 세포주 A549를 추가하였다. 감염된 세포를 배양의 일주일 후 현미경 하에 배양액에서 형성된 플라크를 계산함으로써 측정할 수 있다. 플라크 수로부터, 각각의 혈청 희석시 % 억제를 계산하였다. 로그 눈금, 희석 인자에 대하여 % 억제의 값을 플로팅함으로써 각각의 혈청 샘플의 차트를 만들었다. 그 결과 희석 인자 및 % 억제 사이의 관계의 근사한 선이 그려졌다. 이후 선이 50% 억제의 값에서 교차되는 경우 희석 인자로서 50% 중화 역가를 결정하였다.
표 11은 모노시스트론성 gE, 바이시스트론성 gE/gI, 및 바이시스트론성 gH/gL로 면역화된 마우스로부터 얻어진 혈청이 강한 중화 항체 역가를 함유하였다는 것을 나타낸다.
Figure 112020102169690-pat00011
참고문헌
Britt WJ, Alford CA. Cytomegalovirus. In Fields BN, Knipe DM, Howley PM (ed.). Fields Virology, 3rd edition, Philadelphia, PA: Lippincott/Raven; 1996. p. 2493-523.
Chee MS, Bankier AT, Beck S, Bohni R, Brown CM, Cerny R, Horsnell T,
Hutchinson CA, Kouzarides T, Martignetti JA, Preddie E, Satchwell SC, Tomlinson P, Weston KM and Barrell BG. 1990. Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD 169. Curr. Top. Microbiol. Immunol. 154: 125-70.
Davison AJ, Dolan A, Akter P, Addison C, Dargan DJ, Alcendor DJ, McGeoch DJ and Hayward GS. 2003. The human cytomegalovirus genome revisited: comparison with the chimpanzee cytomegalovirus genome. J. Gen. Virol. 84: 17-28. (Erratum, 84: 1053).
Crumpacker CS and Wadhwa S. 2005. Cytomegalovirus, p 1786-1800. In G.L.
Mandell, J.E. Bennett, and R. Dolin (ed.), Principles and practice of infectious diseases, vol 2. Elsevier, Philadelphia, PA.
Pomeroy C and Englund JA. 1987. Cyotmegalo virus: epidemiology and infection control. Am J Infect Control 15: 107-119.
Murphy E, Yu D, Grimwood J, Schmutz J, Dickson M, Jarvis MA, Nelson JA, Myers RM and Shenk TE. 2003. Coding potential of laboratory and clinical strains of cytomegalovirus. Proc. Natl. Acad. Sci. USA 100: 14976-81.
Mocarski ES and Tan Courcelle C. 2001. Cytomegalovirus and their replication, p. 2629-73. In DM Knipe and PM Howley (ed.) Fields Virology, 4th edition, vol. 2. Lippincott Williams and Wilkins, Philadelphia, PA.
Compton T. 2004. Receptors and immune sensors: the complex entry path of human cytomegalovirus. Trends Cell. Bio. 14(1): 5-8.
Britt WJ and Alford CA. 2004. Human cytomegalovirus virion proteins. Hum. Immunol. 65:395-402.
Varnum SM, Streblow DN, Monroe ME, Smith P, Auberry KJ, Pasa-Tolic L, Wang D, Camp II DG, Rodland K, Wiley, Britt W, Shenk T, Smith RD and Nelson JA. 2004. Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J. Virol. 78: 10960-66. (Erratum, 78: 13395).
Ljungman P, Griffiths P and Paya C. 2002. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin. Infect. Dis. 34: 1094-97.
Rubin R. 2002. Clinical approach to infection in the compromised host, p. 573-679. In R. Rubin and LS Young (ed), Infection in the organ transplant recipient. Kluwer Academic Press, New York, NY.
Stagno S and Britt WJ. 2005. Cytomegalovirus, p. 389-424. In JS Remington and JO Klein (ed), Infectious diseases of the fetus and newborn infant, 6htt edition. WB Saunders, Philadelphia, PA.
Britt WJ, Vugler L, Butfiloski EJ and Stephens EB. 1990. Cell surface expression of human cytomegalovirus (HCMV) gp55-l 16 (gB): use of HCMV-vaccinia recombinant virus infected cells in analysis of the human neutralizing antibody response. J. Virol. 64: 1079-85.
Reap EA, Dryga SA, Morris J, Rivers B, Norberg PK, Olmsted RA and Chulay JD. 2007. Cellular and Humoral Immune Responses to Alphavirus Replicon Vaccines expressing Cytomegalovirus pp65, IL1 and gB proteins. Clin. Vacc. Immunol. 14:748-55.
Balasuriya UBR, Heidner HW, Hedges JF, Williams JC, Davis NL, Johnston RE and MacLachlan NJ. 2000. Expression of the two major envelope proteins of equine arteritis virus as a heterodimer is necessary for induction of neutralizing antibodies in mice immunized with recombinant Venezuelan equine encephalitis virus replicon particles. J. Virol. 74: 10623-30.
Dunn W, Chou C, Li H, Hai R, Patterson D, Stoic V, Zhu H and Liu F. 2003.
Functional profiling of a human cytomegalovirus genome. Proc. Natl. Acad. Sci USA 100: 14223-28.
Hobom U, Brune W, Messerle M, Hahn G and Kosinowski UH. 2000. Fast screening procedures for random transposon llibraries of cloned herpesvirus genomes: mutational analysis of human cytomegalovirus envelope glycoprotein genes. J. Virol. 74:7720-29.
Ryckman BJ, Chase MC and Johnson DC. 2009. HCMV TR strain glycoprotein O acts as a chaperone promoting gH/gL incorporation into virions, but is not present in virions. J. Virol.
Wille PT, Knoche AJ, Nelson JA, Jarvis MA and Johnson JC. 2009. An HCMV gO-null mutant fails to incorporate gH/gL into the virion envelope and is unable to enter fibroblasts, epithelial, and endothelial cells. J. Virol.
Shimamura M, Mach M and Britt WJ. 2006. Human Cytomegalovirus infection elicits a glycoprotein M (gM)/gN-specific virus-neutralizing antibody response. J. Virol. 80:4591-4600.
Cha TA, Tom E, Kemble GW, Duke GM, Mocarski ES and Spaete RR. 1996. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J. Virol. 70:78-83.
Wang D and Shenk T. 2005. Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc. Natl. Acad. Sci. USA 102: 18153-58.
Adler B, Scrivano L, Ruzcics Z, Rupp B, Sinzger C and Kosinowski U. 2006. Role of human cytomegalovirus UL131A in cell type-specific virus entry and release. J. Gen. Virol. 87:2451-60.
Ryckman BJ, Rainish BL, Chase MC, Borton JA, Nelson JA, Jarvis JA and Johnson DC. 2008. Characterization of the human cytomegalovirus gH/gL/UL128-UL131 complex that mediates entry into epithelial and endothelial cells. J. Virol. 82: 60-70.
서열
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SEQUENCE LISTING <110> GLAXOSMITHKLINE BIOLOGICALS SA <120> ANTIGEN DELIVERY PLATFORMS <130> VN54076C1 <140> US 16/114,621 <141> 2018-08-28 <150> US 13/878835 <151> 2013-10-10 <150> PCT/US2011/055834 <151> 2011-10-11 <150> US 61/391,960 <151> 2010-10-11 <160> 85 <170> PatentIn version 3.5 <210> 1 <211> 24 <212> DNA <213> Venezuelan equine encephalitis virus <400> 1 ctctctacgg ctaacctgaa tgga 24 <210> 2 <211> 8 <212> PRT <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic consensus sequence" <220> <221> VARIANT <222> (2)..(2) <223> /replace="Ile" <220> <221> MOD_RES <222> (4)..(4) <223> Any amino acid <400> 2 Asp Val Glu Xaa Asn Pro Gly Pro 1 5 <210> 3 <211> 8 <212> PRT <213> Foot and mouth disease virus <400> 3 Asp Val Glu Ser Asn Pro Gly Pro 1 5 <210> 4 <211> 100 <212> PRT <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polypeptide" <220> <221> misc_feature <222> (1)..(100) <223> /note="This sequence may encompass 3 to 100 'Lys' residues" <400> 4 Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys 1 5 10 15 Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys 20 25 30 Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys 35 40 45 Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys 50 55 60 Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys 65 70 75 80 Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys 85 90 95 Lys Lys Lys Lys 100 <210> 5 <211> 3 <212> PRT <213> Unknown <220> <221> source <223> /note="Description of Unknown: integrin receptor-binding moiety peptide" <400> 5 Arg Gly Asp 1 <210> 6 <211> 6 <212> PRT <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic 6xHis tag" <400> 6 His His His His His His 1 5 <210> 7 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 7 gggccc 6 <210> 8 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 8 ggcgcc 6 <210> 9 <211> 28 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 9 ctcgatgtac ttccgaggaa ctgatgtg 28 <210> 10 <211> 28 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 10 atcgatgtac ttccgaggaa ctcacgtg 28 <210> 11 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 11 gtcgac 6 <210> 12 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 12 gtctac 6 <210> 13 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 13 tctaga 6 <210> 14 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 14 tcaaga 6 <210> 15 <211> 14 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 15 ctggatatct gcag 14 <210> 16 <211> 14 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 16 atcgatatcc gcgg 14 <210> 17 <211> 78 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 17 ctataactct ctacggctaa cctgaatgga ctacgacata gtctagtcga ccaagcctct 60 agacggcgcg cccaccca 78 <210> 18 <211> 38 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic primer" <400> 18 ataagaatgc ggccgcctat aactctctac ggctaacc 38 <210> 19 <211> 28 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic primer" <400> 19 ccatcgattg ggtgggcgcg ccgtctag 28 <210> 20 <211> 30 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic primer" <400> 20 ccatcgatct ataactctct acggctaacc 30 <210> 21 <211> 29 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic primer" <400> 21 tccccgcggt gggtgggcgc gccgtctag 29 <210> 22 <211> 12 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 22 ccactgtgat cg 12 <210> 23 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 23 cacgtg 6 <210> 24 <211> 6 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic oligonucleotide" <400> 24 actgtg 6 <210> 25 <211> 2727 <212> DNA <213> Human herpesvirus 5 <400> 25 atggaaagcc ggatctggtg cctggtcgtg tgcgtgaacc tgtgcatcgt gtgcctggga 60 gccgccgtga gcagcagcag caccagaggc accagcgcca cacacagcca ccacagcagc 120 cacaccacct ctgccgccca cagcagatcc ggcagcgtgt cccagagagt gaccagcagc 180 cagaccgtgt cccacggcgt gaacgagaca atctacaaca ccaccctgaa gtacggcgac 240 gtcgtgggcg tgaataccac caagtacccc tacagagtgt gcagcatggc ccagggcacc 300 gacctgatca gattcgagcg gaacatcgtg tgcaccagca tgaagcccat caacgaggac 360 ctggacgagg gcatcatggt ggtgtacaag agaaacatcg tggcccacac cttcaaagtg 420 cgggtgtacc agaaggtgct gaccttccgg cggagctacg cctacatcca caccacatac 480 ctgctgggca gcaacaccga gtacgtggcc cctcccatgt gggagatcca ccacatcaac 540 agccacagcc agtgctacag cagctacagc cgcgtgatcg ccggcacagt gttcgtggcc 600 taccaccggg acagctacga gaacaagacc atgcagctga tgcccgacga ctacagcaac 660 acccacagca ccagatacgt gaccgtgaag gaccagtggc acagcagagg cagcacctgg 720 ctgtaccggg agacatgcaa cctgaactgc atggtcacca tcaccaccgc cagaagcaag 780 tacccttacc acttcttcgc cacctccacc ggcgacgtgg tggacatcag ccccttctac 840 aacggcacca accggaacgc cagctacttc ggcgagaacg ccgacaagtt cttcatcttc 900 cccaactaca ccatcgtgtc cgacttcggc agacccaaca gcgctctgga aacccacaga 960 ctggtggcct ttctggaacg ggccgacagc gtgatcagct gggacatcca ggacgagaag 1020 aacgtgacct gccagctgac cttctgggag gcctctgaga gaaccatcag aagcgaggcc 1080 gaggacagct accacttcag cagcgccaag atgaccgcca ccttcctgag caagaaacag 1140 gaagtgaaca tgagcgactc cgccctggac tgcgtgaggg acgaggccat caacaagctg 1200 cagcagatct tcaacaccag ctacaaccag acctacgaga agtatggcaa tgtgtccgtg 1260 ttcgagacaa caggcggcct ggtggtgttc tggcagggca tcaagcagaa aagcctggtg 1320 gagctggaac ggctcgccaa ccggtccagc ctgaacctga cccacaaccg gaccaagcgg 1380 agcaccgacg gcaacaacgc aacccacctg tccaacatgg aaagcgtgca caacctggtg 1440 tacgcacagc tgcagttcac ctacgacacc ctgcggggct acatcaacag agccctggcc 1500 cagatcgccg aggcttggtg cgtggaccag cggcggaccc tggaagtgtt caaagagctg 1560 tccaagatca accccagcgc catcctgagc gccatctaca acaagcctat cgccgccaga 1620 ttcatgggcg acgtgctggg cctggccagc tgcgtgacca tcaaccagac cagcgtgaag 1680 gtgctgcggg acatgaacgt gaaagagagc ccaggccgct gctactccag acccgtggtc 1740 atcttcaact tcgccaacag ctcctacgtg cagtacggcc agctgggcga ggacaacgag 1800 atcctgctgg ggaaccaccg gaccgaggaa tgccagctgc ccagcctgaa gatctttatc 1860 gccggcaaca gcgcctacga gtatgtggac tacctgttca agcggatgat cgacctgagc 1920 agcatctcca ccgtggacag catgatcgcc ctggacatcg accccctgga aaacaccgac 1980 ttccgggtgc tggaactgta cagccagaaa gagctgcgga gcagcaacgt gttcgacctg 2040 gaagagatca tgcgggagtt caacagctac aagcagcgcg tgaaatacgt ggaggacaag 2100 gtggtggacc ccctgcctcc ttacctgaag ggcctggacg acctgatgag cggactgggc 2160 gctgccggaa aagccgtggg agtggccatt ggagctgtgg gcggagctgt ggcctctgtc 2220 gtggaaggcg tcgccacctt tctgaagaac cccttcggcg ccttcaccat catcctggtg 2280 gccattgccg tcgtgatcat cacctacctg atctacaccc ggcagcggag actgtgtacc 2340 cagcccctgc agaacctgtt cccctacctg gtgtccgccg atggcaccac agtgaccagc 2400 ggctccacca aggataccag cctgcaggcc ccacccagct acgaagagag cgtgtacaac 2460 agcggcagaa agggccctgg ccctcccagc tctgatgcca gcacagccgc ccctccctac 2520 accaacgagc aggcctacca gatgctgctg gccctggcta gactggatgc cgagcagagg 2580 gcccagcaga acggcaccga cagcctggat ggcagaaccg gcacccagga caagggccag 2640 aagcccaacc tgctggaccg gctgcggcac cggaagaacg gctaccggca cctgaaggac 2700 agcgacgagg aagagaacgt ctgataa 2727 <210> 26 <211> 907 <212> PRT <213> Human herpesvirus 5 <400> 26 Met Glu Ser Arg Ile Trp Cys Leu Val Val Cys Val Asn Leu Cys Ile 1 5 10 15 Val Cys Leu Gly Ala Ala Val Ser Ser Ser Ser Thr Arg Gly Thr Ser 20 25 30 Ala Thr His Ser His His Ser Ser His Thr Thr Ser Ala Ala His Ser 35 40 45 Arg Ser Gly Ser Val Ser Gln Arg Val Thr Ser Ser Gln Thr Val Ser 50 55 60 His Gly Val Asn Glu Thr Ile Tyr Asn Thr Thr Leu Lys Tyr Gly Asp 65 70 75 80 Val Val Gly Val Asn Thr Thr Lys Tyr Pro Tyr Arg Val Cys Ser Met 85 90 95 Ala Gln Gly Thr Asp Leu Ile Arg Phe Glu Arg Asn Ile Val Cys Thr 100 105 110 Ser Met Lys Pro Ile Asn Glu Asp Leu Asp Glu Gly Ile Met Val Val 115 120 125 Tyr Lys Arg Asn Ile Val Ala His Thr Phe Lys Val Arg Val Tyr Gln 130 135 140 Lys Val Leu Thr Phe Arg Arg Ser Tyr Ala Tyr Ile His Thr Thr Tyr 145 150 155 160 Leu Leu Gly Ser Asn Thr Glu Tyr Val Ala Pro Pro Met Trp Glu Ile 165 170 175 His His Ile Asn Ser His Ser Gln Cys Tyr Ser Ser Tyr Ser Arg Val 180 185 190 Ile Ala Gly Thr Val Phe Val Ala Tyr His Arg Asp Ser Tyr Glu Asn 195 200 205 Lys Thr Met Gln Leu Met Pro Asp Asp Tyr Ser Asn Thr His Ser Thr 210 215 220 Arg Tyr Val Thr Val Lys Asp Gln Trp His Ser Arg Gly Ser Thr Trp 225 230 235 240 Leu Tyr Arg Glu Thr Cys Asn Leu Asn Cys Met Val Thr Ile Thr Thr 245 250 255 Ala Arg Ser Lys Tyr Pro Tyr His Phe Phe Ala Thr Ser Thr Gly Asp 260 265 270 Val Val Asp Ile Ser Pro Phe Tyr Asn Gly Thr Asn Arg Asn Ala Ser 275 280 285 Tyr Phe Gly Glu Asn Ala Asp Lys Phe Phe Ile Phe Pro Asn Tyr Thr 290 295 300 Ile Val Ser Asp Phe Gly Arg Pro Asn Ser Ala Leu Glu Thr His Arg 305 310 315 320 Leu Val Ala Phe Leu Glu Arg Ala Asp Ser Val Ile Ser Trp Asp Ile 325 330 335 Gln Asp Glu Lys Asn Val Thr Cys Gln Leu Thr Phe Trp Glu Ala Ser 340 345 350 Glu Arg Thr Ile Arg Ser Glu Ala Glu Asp Ser Tyr His Phe Ser Ser 355 360 365 Ala Lys Met Thr Ala Thr Phe Leu Ser Lys Lys Gln Glu Val Asn Met 370 375 380 Ser Asp Ser Ala Leu Asp Cys Val Arg Asp Glu Ala Ile Asn Lys Leu 385 390 395 400 Gln Gln Ile Phe Asn Thr Ser Tyr Asn Gln Thr Tyr Glu Lys Tyr Gly 405 410 415 Asn Val Ser Val Phe Glu Thr Thr Gly Gly Leu Val Val Phe Trp Gln 420 425 430 Gly Ile Lys Gln Lys Ser Leu Val Glu Leu Glu Arg Leu Ala Asn Arg 435 440 445 Ser Ser Leu Asn Leu Thr His Asn Arg Thr Lys Arg Ser Thr Asp Gly 450 455 460 Asn Asn Ala Thr His Leu Ser Asn Met Glu Ser Val His Asn Leu Val 465 470 475 480 Tyr Ala Gln Leu Gln Phe Thr Tyr Asp Thr Leu Arg Gly Tyr Ile Asn 485 490 495 Arg Ala Leu Ala Gln Ile Ala Glu Ala Trp Cys Val Asp Gln Arg Arg 500 505 510 Thr Leu Glu Val Phe Lys Glu Leu Ser Lys Ile Asn Pro Ser Ala Ile 515 520 525 Leu Ser Ala Ile Tyr Asn Lys Pro Ile Ala Ala Arg Phe Met Gly Asp 530 535 540 Val Leu Gly Leu Ala Ser Cys Val Thr Ile Asn Gln Thr Ser Val Lys 545 550 555 560 Val Leu Arg Asp Met Asn Val Lys Glu Ser Pro Gly Arg Cys Tyr Ser 565 570 575 Arg Pro Val Val Ile Phe Asn Phe Ala Asn Ser Ser Tyr Val Gln Tyr 580 585 590 Gly Gln Leu Gly Glu Asp Asn Glu Ile Leu Leu Gly Asn His Arg Thr 595 600 605 Glu Glu Cys Gln Leu Pro Ser Leu Lys Ile Phe Ile Ala Gly Asn Ser 610 615 620 Ala Tyr Glu Tyr Val Asp Tyr Leu Phe Lys Arg Met Ile Asp Leu Ser 625 630 635 640 Ser Ile Ser Thr Val Asp Ser Met Ile Ala Leu Asp Ile Asp Pro Leu 645 650 655 Glu Asn Thr Asp Phe Arg Val Leu Glu Leu Tyr Ser Gln Lys Glu Leu 660 665 670 Arg Ser Ser Asn Val Phe Asp Leu Glu Glu Ile Met Arg Glu Phe Asn 675 680 685 Ser Tyr Lys Gln Arg Val Lys Tyr Val Glu Asp Lys Val Val Asp Pro 690 695 700 Leu Pro Pro Tyr Leu Lys Gly Leu Asp Asp Leu Met Ser Gly Leu Gly 705 710 715 720 Ala Ala Gly Lys Ala Val Gly Val Ala Ile Gly Ala Val Gly Gly Ala 725 730 735 Val Ala Ser Val Val Glu Gly Val Ala Thr Phe Leu Lys Asn Pro Phe 740 745 750 Gly Ala Phe Thr Ile Ile Leu Val Ala Ile Ala Val Val Ile Ile Thr 755 760 765 Tyr Leu Ile Tyr Thr Arg Gln Arg Arg Leu Cys Thr Gln Pro Leu Gln 770 775 780 Asn Leu Phe Pro Tyr Leu Val Ser Ala Asp Gly Thr Thr Val Thr Ser 785 790 795 800 Gly Ser Thr Lys Asp Thr Ser Leu Gln Ala Pro Pro Ser Tyr Glu Glu 805 810 815 Ser Val Tyr Asn Ser Gly Arg Lys Gly Pro Gly Pro Pro Ser Ser Asp 820 825 830 Ala Ser Thr Ala Ala Pro Pro Tyr Thr Asn Glu Gln Ala Tyr Gln Met 835 840 845 Leu Leu Ala Leu Ala Arg Leu Asp Ala Glu Gln Arg Ala Gln Gln Asn 850 855 860 Gly Thr Asp Ser Leu Asp Gly Arg Thr Gly Thr Gln Asp Lys Gly Gln 865 870 875 880 Lys Pro Asn Leu Leu Asp Arg Leu Arg His Arg Lys Asn Gly Tyr Arg 885 890 895 His Leu Lys Asp Ser Asp Glu Glu Glu Asn Val 900 905 <210> 27 <211> 2256 <212> DNA <213> Human herpesvirus 5 <400> 27 atggaaagcc ggatctggtg cctggtcgtg tgcgtgaacc tgtgcatcgt gtgcctggga 60 gccgccgtga gcagcagcag caccagaggc accagcgcca cacacagcca ccacagcagc 120 cacaccacct ctgccgccca cagcagatcc ggcagcgtgt cccagagagt gaccagcagc 180 cagaccgtgt cccacggcgt gaacgagaca atctacaaca ccaccctgaa gtacggcgac 240 gtcgtgggcg tgaataccac caagtacccc tacagagtgt gcagcatggc ccagggcacc 300 gacctgatca gattcgagcg gaacatcgtg tgcaccagca tgaagcccat caacgaggac 360 ctggacgagg gcatcatggt ggtgtacaag agaaacatcg tggcccacac cttcaaagtg 420 cgggtgtacc agaaggtgct gaccttccgg cggagctacg cctacatcca caccacatac 480 ctgctgggca gcaacaccga gtacgtggcc cctcccatgt gggagatcca ccacatcaac 540 agccacagcc agtgctacag cagctacagc cgcgtgatcg ccggcacagt gttcgtggcc 600 taccaccggg acagctacga gaacaagacc atgcagctga tgcccgacga ctacagcaac 660 acccacagca ccagatacgt gaccgtgaag gaccagtggc acagcagagg cagcacctgg 720 ctgtaccggg agacatgcaa cctgaactgc atggtcacca tcaccaccgc cagaagcaag 780 tacccttacc acttcttcgc cacctccacc ggcgacgtgg tggacatcag ccccttctac 840 aacggcacca accggaacgc cagctacttc ggcgagaacg ccgacaagtt cttcatcttc 900 cccaactaca ccatcgtgtc cgacttcggc agacccaaca gcgctctgga aacccacaga 960 ctggtggcct ttctggaacg ggccgacagc gtgatcagct gggacatcca ggacgagaag 1020 aacgtgacct gccagctgac cttctgggag gcctctgaga gaaccatcag aagcgaggcc 1080 gaggacagct accacttcag cagcgccaag atgaccgcca ccttcctgag caagaaacag 1140 gaagtgaaca tgagcgactc cgccctggac tgcgtgaggg acgaggccat caacaagctg 1200 cagcagatct tcaacaccag ctacaaccag acctacgaga agtatggcaa tgtgtccgtg 1260 ttcgagacaa caggcggcct ggtggtgttc tggcagggca tcaagcagaa aagcctggtg 1320 gagctggaac ggctcgccaa ccggtccagc ctgaacctga cccacaaccg gaccaagcgg 1380 agcaccgacg gcaacaacgc aacccacctg tccaacatgg aaagcgtgca caacctggtg 1440 tacgcacagc tgcagttcac ctacgacacc ctgcggggct acatcaacag agccctggcc 1500 cagatcgccg aggcttggtg cgtggaccag cggcggaccc tggaagtgtt caaagagctg 1560 tccaagatca accccagcgc catcctgagc gccatctaca acaagcctat cgccgccaga 1620 ttcatgggcg acgtgctggg cctggccagc tgcgtgacca tcaaccagac cagcgtgaag 1680 gtgctgcggg acatgaacgt gaaagagagc ccaggccgct gctactccag acccgtggtc 1740 atcttcaact tcgccaacag ctcctacgtg cagtacggcc agctgggcga ggacaacgag 1800 atcctgctgg ggaaccaccg gaccgaggaa tgccagctgc ccagcctgaa gatctttatc 1860 gccggcaaca gcgcctacga gtatgtggac tacctgttca agcggatgat cgacctgagc 1920 agcatctcca ccgtggacag catgatcgcc ctggacatcg accccctgga aaacaccgac 1980 ttccgggtgc tggaactgta cagccagaaa gagctgcgga gcagcaacgt gttcgacctg 2040 gaagagatca tgcgggagtt caacagctac aagcagcgcg tgaaatacgt ggaggacaag 2100 gtggtggacc ccctgcctcc ttacctgaag ggcctggacg acctgatgag cggactgggc 2160 gctgccggaa aagccgtggg agtggccatt ggagctgtgg gcggagctgt ggcctctgtc 2220 gtggaaggcg tcgccacctt tctgaagaac tgataa 2256 <210> 28 <211> 750 <212> PRT <213> Human herpesvirus 5 <400> 28 Met Glu Ser Arg Ile Trp Cys Leu Val Val Cys Val Asn Leu Cys Ile 1 5 10 15 Val Cys Leu Gly Ala Ala Val Ser Ser Ser Ser Thr Arg Gly Thr Ser 20 25 30 Ala Thr His Ser His His Ser Ser His Thr Thr Ser Ala Ala His Ser 35 40 45 Arg Ser Gly Ser Val Ser Gln Arg Val Thr Ser Ser Gln Thr Val Ser 50 55 60 His Gly Val Asn Glu Thr Ile Tyr Asn Thr Thr Leu Lys Tyr Gly Asp 65 70 75 80 Val Val Gly Val Asn Thr Thr Lys Tyr Pro Tyr Arg Val Cys Ser Met 85 90 95 Ala Gln Gly Thr Asp Leu Ile Arg Phe Glu Arg Asn Ile Val Cys Thr 100 105 110 Ser Met Lys Pro Ile Asn Glu Asp Leu Asp Glu Gly Ile Met Val Val 115 120 125 Tyr Lys Arg Asn Ile Val Ala His Thr Phe Lys Val Arg Val Tyr Gln 130 135 140 Lys Val Leu Thr Phe Arg Arg Ser Tyr Ala Tyr Ile His Thr Thr Tyr 145 150 155 160 Leu Leu Gly Ser Asn Thr Glu Tyr Val Ala Pro Pro Met Trp Glu Ile 165 170 175 His His Ile Asn Ser His Ser Gln Cys Tyr Ser Ser Tyr Ser Arg Val 180 185 190 Ile Ala Gly Thr Val Phe Val Ala Tyr His Arg Asp Ser Tyr Glu Asn 195 200 205 Lys Thr Met Gln Leu Met Pro Asp Asp Tyr Ser Asn Thr His Ser Thr 210 215 220 Arg Tyr Val Thr Val Lys Asp Gln Trp His Ser Arg Gly Ser Thr Trp 225 230 235 240 Leu Tyr Arg Glu Thr Cys Asn Leu Asn Cys Met Val Thr Ile Thr Thr 245 250 255 Ala Arg Ser Lys Tyr Pro Tyr His Phe Phe Ala Thr Ser Thr Gly Asp 260 265 270 Val Val Asp Ile Ser Pro Phe Tyr Asn Gly Thr Asn Arg Asn Ala Ser 275 280 285 Tyr Phe Gly Glu Asn Ala Asp Lys Phe Phe Ile Phe Pro Asn Tyr Thr 290 295 300 Ile Val Ser Asp Phe Gly Arg Pro Asn Ser Ala Leu Glu Thr His Arg 305 310 315 320 Leu Val Ala Phe Leu Glu Arg Ala Asp Ser Val Ile Ser Trp Asp Ile 325 330 335 Gln Asp Glu Lys Asn Val Thr Cys Gln Leu Thr Phe Trp Glu Ala Ser 340 345 350 Glu Arg Thr Ile Arg Ser Glu Ala Glu Asp Ser Tyr His Phe Ser Ser 355 360 365 Ala Lys Met Thr Ala Thr Phe Leu Ser Lys Lys Gln Glu Val Asn Met 370 375 380 Ser Asp Ser Ala Leu Asp Cys Val Arg Asp Glu Ala Ile Asn Lys Leu 385 390 395 400 Gln Gln Ile Phe Asn Thr Ser Tyr Asn Gln Thr Tyr Glu Lys Tyr Gly 405 410 415 Asn Val Ser Val Phe Glu Thr Thr Gly Gly Leu Val Val Phe Trp Gln 420 425 430 Gly Ile Lys Gln Lys Ser Leu Val Glu Leu Glu Arg Leu Ala Asn Arg 435 440 445 Ser Ser Leu Asn Leu Thr His Asn Arg Thr Lys Arg Ser Thr Asp Gly 450 455 460 Asn Asn Ala Thr His Leu Ser Asn Met Glu Ser Val His Asn Leu Val 465 470 475 480 Tyr Ala Gln Leu Gln Phe Thr Tyr Asp Thr Leu Arg Gly Tyr Ile Asn 485 490 495 Arg Ala Leu Ala Gln Ile Ala Glu Ala Trp Cys Val Asp Gln Arg Arg 500 505 510 Thr Leu Glu Val Phe Lys Glu Leu Ser Lys Ile Asn Pro Ser Ala Ile 515 520 525 Leu Ser Ala Ile Tyr Asn Lys Pro Ile Ala Ala Arg Phe Met Gly Asp 530 535 540 Val Leu Gly Leu Ala Ser Cys Val Thr Ile Asn Gln Thr Ser Val Lys 545 550 555 560 Val Leu Arg Asp Met Asn Val Lys Glu Ser Pro Gly Arg Cys Tyr Ser 565 570 575 Arg Pro Val Val Ile Phe Asn Phe Ala Asn Ser Ser Tyr Val Gln Tyr 580 585 590 Gly Gln Leu Gly Glu Asp Asn Glu Ile Leu Leu Gly Asn His Arg Thr 595 600 605 Glu Glu Cys Gln Leu Pro Ser Leu Lys Ile Phe Ile Ala Gly Asn Ser 610 615 620 Ala Tyr Glu Tyr Val Asp Tyr Leu Phe Lys Arg Met Ile Asp Leu Ser 625 630 635 640 Ser Ile Ser Thr Val Asp Ser Met Ile Ala Leu Asp Ile Asp Pro Leu 645 650 655 Glu Asn Thr Asp Phe Arg Val Leu Glu Leu Tyr Ser Gln Lys Glu Leu 660 665 670 Arg Ser Ser Asn Val Phe Asp Leu Glu Glu Ile Met Arg Glu Phe Asn 675 680 685 Ser Tyr Lys Gln Arg Val Lys Tyr Val Glu Asp Lys Val Val Asp Pro 690 695 700 Leu Pro Pro Tyr Leu Lys Gly Leu Asp Asp Leu Met Ser Gly Leu Gly 705 710 715 720 Ala Ala Gly Lys Ala Val Gly Val Ala Ile Gly Ala Val Gly Gly Ala 725 730 735 Val Ala Ser Val Val Glu Gly Val Ala Thr Phe Leu Lys Asn 740 745 750 <210> 29 <211> 2082 <212> DNA <213> Human herpesvirus 5 <400> 29 atggaaagcc ggatctggtg cctggtcgtg tgcgtgaacc tgtgcatcgt gtgcctggga 60 gccgccgtga gcagcagcag caccagaggc accagcgcca cacacagcca ccacagcagc 120 cacaccacct ctgccgccca cagcagatcc ggcagcgtgt cccagagagt gaccagcagc 180 cagaccgtgt cccacggcgt gaacgagaca atctacaaca ccaccctgaa gtacggcgac 240 gtcgtgggcg tgaataccac caagtacccc tacagagtgt gcagcatggc ccagggcacc 300 gacctgatca gattcgagcg gaacatcgtg tgcaccagca tgaagcccat caacgaggac 360 ctggacgagg gcatcatggt ggtgtacaag agaaacatcg tggcccacac cttcaaagtg 420 cgggtgtacc agaaggtgct gaccttccgg cggagctacg cctacatcca caccacatac 480 ctgctgggca gcaacaccga gtacgtggcc cctcccatgt gggagatcca ccacatcaac 540 agccacagcc agtgctacag cagctacagc cgcgtgatcg ccggcacagt gttcgtggcc 600 taccaccggg acagctacga gaacaagacc atgcagctga tgcccgacga ctacagcaac 660 acccacagca ccagatacgt gaccgtgaag gaccagtggc acagcagagg cagcacctgg 720 ctgtaccggg agacatgcaa cctgaactgc atggtcacca tcaccaccgc cagaagcaag 780 tacccttacc acttcttcgc cacctccacc ggcgacgtgg tggacatcag ccccttctac 840 aacggcacca accggaacgc cagctacttc ggcgagaacg ccgacaagtt cttcatcttc 900 cccaactaca ccatcgtgtc cgacttcggc agacccaaca gcgctctgga aacccacaga 960 ctggtggcct ttctggaacg ggccgacagc gtgatcagct gggacatcca ggacgagaag 1020 aacgtgacct gccagctgac cttctgggag gcctctgaga gaaccatcag aagcgaggcc 1080 gaggacagct accacttcag cagcgccaag atgaccgcca ccttcctgag caagaaacag 1140 gaagtgaaca tgagcgactc cgccctggac tgcgtgaggg acgaggccat caacaagctg 1200 cagcagatct tcaacaccag ctacaaccag acctacgaga agtatggcaa tgtgtccgtg 1260 ttcgagacaa caggcggcct ggtggtgttc tggcagggca tcaagcagaa aagcctggtg 1320 gagctggaac ggctcgccaa ccggtccagc ctgaacctga cccacaaccg gaccaagcgg 1380 agcaccgacg gcaacaacgc aacccacctg tccaacatgg aaagcgtgca caacctggtg 1440 tacgcacagc tgcagttcac ctacgacacc ctgcggggct acatcaacag agccctggcc 1500 cagatcgccg aggcttggtg cgtggaccag cggcggaccc tggaagtgtt caaagagctg 1560 tccaagatca accccagcgc catcctgagc gccatctaca acaagcctat cgccgccaga 1620 ttcatgggcg acgtgctggg cctggccagc tgcgtgacca tcaaccagac cagcgtgaag 1680 gtgctgcggg acatgaacgt gaaagagagc ccaggccgct gctactccag acccgtggtc 1740 atcttcaact tcgccaacag ctcctacgtg cagtacggcc agctgggcga ggacaacgag 1800 atcctgctgg ggaaccaccg gaccgaggaa tgccagctgc ccagcctgaa gatctttatc 1860 gccggcaaca gcgcctacga gtatgtggac tacctgttca agcggatgat cgacctgagc 1920 agcatctcca ccgtggacag catgatcgcc ctggacatcg accccctgga aaacaccgac 1980 ttccgggtgc tggaactgta cagccagaaa gagctgcgga gcagcaacgt gttcgacctg 2040 gaagagatca tgcgggagtt caacagctac aagcagtgat aa 2082 <210> 30 <211> 692 <212> PRT <213> Human herpesvirus 5 <400> 30 Met Glu Ser Arg Ile Trp Cys Leu Val Val Cys Val Asn Leu Cys Ile 1 5 10 15 Val Cys Leu Gly Ala Ala Val Ser Ser Ser Ser Thr Arg Gly Thr Ser 20 25 30 Ala Thr His Ser His His Ser Ser His Thr Thr Ser Ala Ala His Ser 35 40 45 Arg Ser Gly Ser Val Ser Gln Arg Val Thr Ser Ser Gln Thr Val Ser 50 55 60 His Gly Val Asn Glu Thr Ile Tyr Asn Thr Thr Leu Lys Tyr Gly Asp 65 70 75 80 Val Val Gly Val Asn Thr Thr Lys Tyr Pro Tyr Arg Val Cys Ser Met 85 90 95 Ala Gln Gly Thr Asp Leu Ile Arg Phe Glu Arg Asn Ile Val Cys Thr 100 105 110 Ser Met Lys Pro Ile Asn Glu Asp Leu Asp Glu Gly Ile Met Val Val 115 120 125 Tyr Lys Arg Asn Ile Val Ala His Thr Phe Lys Val Arg Val Tyr Gln 130 135 140 Lys Val Leu Thr Phe Arg Arg Ser Tyr Ala Tyr Ile His Thr Thr Tyr 145 150 155 160 Leu Leu Gly Ser Asn Thr Glu Tyr Val Ala Pro Pro Met Trp Glu Ile 165 170 175 His His Ile Asn Ser His Ser Gln Cys Tyr Ser Ser Tyr Ser Arg Val 180 185 190 Ile Ala Gly Thr Val Phe Val Ala Tyr His Arg Asp Ser Tyr Glu Asn 195 200 205 Lys Thr Met Gln Leu Met Pro Asp Asp Tyr Ser Asn Thr His Ser Thr 210 215 220 Arg Tyr Val Thr Val Lys Asp Gln Trp His Ser Arg Gly Ser Thr Trp 225 230 235 240 Leu Tyr Arg Glu Thr Cys Asn Leu Asn Cys Met Val Thr Ile Thr Thr 245 250 255 Ala Arg Ser Lys Tyr Pro Tyr His Phe Phe Ala Thr Ser Thr Gly Asp 260 265 270 Val Val Asp Ile Ser Pro Phe Tyr Asn Gly Thr Asn Arg Asn Ala Ser 275 280 285 Tyr Phe Gly Glu Asn Ala Asp Lys Phe Phe Ile Phe Pro Asn Tyr Thr 290 295 300 Ile Val Ser Asp Phe Gly Arg Pro Asn Ser Ala Leu Glu Thr His Arg 305 310 315 320 Leu Val Ala Phe Leu Glu Arg Ala Asp Ser Val Ile Ser Trp Asp Ile 325 330 335 Gln Asp Glu Lys Asn Val Thr Cys Gln Leu Thr Phe Trp Glu Ala Ser 340 345 350 Glu Arg Thr Ile Arg Ser Glu Ala Glu Asp Ser Tyr His Phe Ser Ser 355 360 365 Ala Lys Met Thr Ala Thr Phe Leu Ser Lys Lys Gln Glu Val Asn Met 370 375 380 Ser Asp Ser Ala Leu Asp Cys Val Arg Asp Glu Ala Ile Asn Lys Leu 385 390 395 400 Gln Gln Ile Phe Asn Thr Ser Tyr Asn Gln Thr Tyr Glu Lys Tyr Gly 405 410 415 Asn Val Ser Val Phe Glu Thr Thr Gly Gly Leu Val Val Phe Trp Gln 420 425 430 Gly Ile Lys Gln Lys Ser Leu Val Glu Leu Glu Arg Leu Ala Asn Arg 435 440 445 Ser Ser Leu Asn Leu Thr His Asn Arg Thr Lys Arg Ser Thr Asp Gly 450 455 460 Asn Asn Ala Thr His Leu Ser Asn Met Glu Ser Val His Asn Leu Val 465 470 475 480 Tyr Ala Gln Leu Gln Phe Thr Tyr Asp Thr Leu Arg Gly Tyr Ile Asn 485 490 495 Arg Ala Leu Ala Gln Ile Ala Glu Ala Trp Cys Val Asp Gln Arg Arg 500 505 510 Thr Leu Glu Val Phe Lys Glu Leu Ser Lys Ile Asn Pro Ser Ala Ile 515 520 525 Leu Ser Ala Ile Tyr Asn Lys Pro Ile Ala Ala Arg Phe Met Gly Asp 530 535 540 Val Leu Gly Leu Ala Ser Cys Val Thr Ile Asn Gln Thr Ser Val Lys 545 550 555 560 Val Leu Arg Asp Met Asn Val Lys Glu Ser Pro Gly Arg Cys Tyr Ser 565 570 575 Arg Pro Val Val Ile Phe Asn Phe Ala Asn Ser Ser Tyr Val Gln Tyr 580 585 590 Gly Gln Leu Gly Glu Asp Asn Glu Ile Leu Leu Gly Asn His Arg Thr 595 600 605 Glu Glu Cys Gln Leu Pro Ser Leu Lys Ile Phe Ile Ala Gly Asn Ser 610 615 620 Ala Tyr Glu Tyr Val Asp Tyr Leu Phe Lys Arg Met Ile Asp Leu Ser 625 630 635 640 Ser Ile Ser Thr Val Asp Ser Met Ile Ala Leu Asp Ile Asp Pro Leu 645 650 655 Glu Asn Thr Asp Phe Arg Val Leu Glu Leu Tyr Ser Gln Lys Glu Leu 660 665 670 Arg Ser Ser Asn Val Phe Asp Leu Glu Glu Ile Met Arg Glu Phe Asn 675 680 685 Ser Tyr Lys Gln 690 <210> 31 <211> 2232 <212> DNA <213> Human herpesvirus 5 <400> 31 atgaggcctg gcctgccctc ctacctgatc atcctggccg tgtgcctgtt cagccacctg 60 ctgtccagca gatacggcgc cgaggccgtg agcgagcccc tggacaaggc tttccacctg 120 ctgctgaaca cctacggcag acccatccgg tttctgcggg agaacaccac ccagtgcacc 180 tacaacagca gcctgcggaa cagcaccgtc gtgagagaga acgccatcag cttcaacttt 240 ttccagagct acaaccagta ctacgtgttc cacatgccca gatgcctgtt tgccggccct 300 ctggccgagc agttcctgaa ccaggtggac ctgaccgaga cactggaaag ataccagcag 360 cggctgaata cctacgccct ggtgtccaag gacctggcca gctaccggtc ctttagccag 420 cagctcaagg ctcaggatag cctcggcgag cagcctacca ccgtgccccc tcccatcgac 480 ctgagcatcc cccacgtgtg gatgcctccc cagaccaccc ctcacggctg gaccgagagc 540 cacaccacct ccggcctgca cagaccccac ttcaaccaga cctgcatcct gttcgacggc 600 cacgacctgc tgtttagcac cgtgaccccc tgcctgcacc agggcttcta cctgatcgac 660 gagctgagat acgtgaagat caccctgacc gaggatttct tcgtggtcac cgtgtccatc 720 gacgacgaca cccccatgct gctgatcttc ggccacctgc ccagagtgct gttcaaggcc 780 ccctaccagc gggacaactt catcctgcgg cagaccgaga agcacgagct gctggtgctg 840 gtcaagaagg accagctgaa ccggcactcc tacctgaagg accccgactt cctggacgcc 900 gccctggact tcaactacct ggacctgagc gccctgctga gaaacagctt ccacagatac 960 gccgtggacg tgctgaagtc cggacggtgc cagatgctcg atcggcggac cgtggagatg 1020 gccttcgcct atgccctcgc cctgttcgcc gctgccagac aggaagaggc tggcgcccag 1080 gtgtcagtgc ccagagccct ggatagacag gccgccctgc tgcagatcca ggaattcatg 1140 atcacctgcc tgagccagac cccccctaga accaccctgc tgctgtaccc cacagccgtg 1200 gatctggcca agagggccct gtggaccccc aaccagatca ccgacatcac aagcctcgtg 1260 cggctcgtgt acatcctgag caagcagaac cagcagcacc tgatccccca gtgggccctg 1320 agacagatcg ccgacttcgc cctgaagctg cacaagaccc atctggccag ctttctgagc 1380 gccttcgcca ggcaggaact gtacctgatg ggcagcctgg tccacagcat gctggtgcat 1440 accaccgagc ggcgggagat cttcatcgtg gagacaggcc tgtgtagcct ggccgagctg 1500 tcccacttta cccagctgct ggcccaccct caccacgagt acctgagcga cctgtacacc 1560 ccctgcagca gcagcggcag acgggaccac agcctggaac ggctgaccag actgttcccc 1620 gatgccaccg tgcctgctac agtgcctgcc gccctgtcca tcctgtccac catgcagccc 1680 agcaccctgg aaaccttccc cgacctgttc tgcctgcccc tgggcgagag ctttagcgcc 1740 ctgaccgtgt ccgagcacgt gtcctacatc gtgaccaatc agtacctgat caagggcatc 1800 agctaccccg tgtccaccac agtcgtgggc cagagcctga tcatcaccca gaccgacagc 1860 cagaccaagt gcgagctgac ccggaacatg cacaccacac acagcatcac cgtggccctg 1920 aacatcagcc tggaaaactg cgctttctgt cagtctgccc tgctggaata cgacgatacc 1980 cagggcgtga tcaacatcat gtacatgcac gacagcgacg acgtgctgtt cgccctggac 2040 ccctacaacg aggtggtggt gtccagcccc cggacccact acctgatgct gctgaagaac 2100 ggcaccgtgc tggaagtgac cgacgtggtg gtggacgcca ccgacagcag actgctgatg 2160 atgagcgtgt acgccctgag cgccatcatc ggcatctacc tgctgtaccg gatgctgaaa 2220 acctgctgat aa 2232 <210> 32 <211> 742 <212> PRT <213> Human herpesvirus 5 <400> 32 Met Arg Pro Gly Leu Pro Ser Tyr Leu Ile Ile Leu Ala Val Cys Leu 1 5 10 15 Phe Ser His Leu Leu Ser Ser Arg Tyr Gly Ala Glu Ala Val Ser Glu 20 25 30 Pro Leu Asp Lys Ala Phe His Leu Leu Leu Asn Thr Tyr Gly Arg Pro 35 40 45 Ile Arg Phe Leu Arg Glu Asn Thr Thr Gln Cys Thr Tyr Asn Ser Ser 50 55 60 Leu Arg Asn Ser Thr Val Val Arg Glu Asn Ala Ile Ser Phe Asn Phe 65 70 75 80 Phe Gln Ser Tyr Asn Gln Tyr Tyr Val Phe His Met Pro Arg Cys Leu 85 90 95 Phe Ala Gly Pro Leu Ala Glu Gln Phe Leu Asn Gln Val Asp Leu Thr 100 105 110 Glu Thr Leu Glu Arg Tyr Gln Gln Arg Leu Asn Thr Tyr Ala Leu Val 115 120 125 Ser Lys Asp Leu Ala Ser Tyr Arg Ser Phe Ser Gln Gln Leu Lys Ala 130 135 140 Gln Asp Ser Leu Gly Glu Gln Pro Thr Thr Val Pro Pro Pro Ile Asp 145 150 155 160 Leu Ser Ile Pro His Val Trp Met Pro Pro Gln Thr Thr Pro His Gly 165 170 175 Trp Thr Glu Ser His Thr Thr Ser Gly Leu His Arg Pro His Phe Asn 180 185 190 Gln Thr Cys Ile Leu Phe Asp Gly His Asp Leu Leu Phe Ser Thr Val 195 200 205 Thr Pro Cys Leu His Gln Gly Phe Tyr Leu Ile Asp Glu Leu Arg Tyr 210 215 220 Val Lys Ile Thr Leu Thr Glu Asp Phe Phe Val Val Thr Val Ser Ile 225 230 235 240 Asp Asp Asp Thr Pro Met Leu Leu Ile Phe Gly His Leu Pro Arg Val 245 250 255 Leu Phe Lys Ala Pro Tyr Gln Arg Asp Asn Phe Ile Leu Arg Gln Thr 260 265 270 Glu Lys His Glu Leu Leu Val Leu Val Lys Lys Asp Gln Leu Asn Arg 275 280 285 His Ser Tyr Leu Lys Asp Pro Asp Phe Leu Asp Ala Ala Leu Asp Phe 290 295 300 Asn Tyr Leu Asp Leu Ser Ala Leu Leu Arg Asn Ser Phe His Arg Tyr 305 310 315 320 Ala Val Asp Val Leu Lys Ser Gly Arg Cys Gln Met Leu Asp Arg Arg 325 330 335 Thr Val Glu Met Ala Phe Ala Tyr Ala Leu Ala Leu Phe Ala Ala Ala 340 345 350 Arg Gln Glu Glu Ala Gly Ala Gln Val Ser Val Pro Arg Ala Leu Asp 355 360 365 Arg Gln Ala Ala Leu Leu Gln Ile Gln Glu Phe Met Ile Thr Cys Leu 370 375 380 Ser Gln Thr Pro Pro Arg Thr Thr Leu Leu Leu Tyr Pro Thr Ala Val 385 390 395 400 Asp Leu Ala Lys Arg Ala Leu Trp Thr Pro Asn Gln Ile Thr Asp Ile 405 410 415 Thr Ser Leu Val Arg Leu Val Tyr Ile Leu Ser Lys Gln Asn Gln Gln 420 425 430 His Leu Ile Pro Gln Trp Ala Leu Arg Gln Ile Ala Asp Phe Ala Leu 435 440 445 Lys Leu His Lys Thr His Leu Ala Ser Phe Leu Ser Ala Phe Ala Arg 450 455 460 Gln Glu Leu Tyr Leu Met Gly Ser Leu Val His Ser Met Leu Val His 465 470 475 480 Thr Thr Glu Arg Arg Glu Ile Phe Ile Val Glu Thr Gly Leu Cys Ser 485 490 495 Leu Ala Glu Leu Ser His Phe Thr Gln Leu Leu Ala His Pro His His 500 505 510 Glu Tyr Leu Ser Asp Leu Tyr Thr Pro Cys Ser Ser Ser Gly Arg Arg 515 520 525 Asp His Ser Leu Glu Arg Leu Thr Arg Leu Phe Pro Asp Ala Thr Val 530 535 540 Pro Ala Thr Val Pro Ala Ala Leu Ser Ile Leu Ser Thr Met Gln Pro 545 550 555 560 Ser Thr Leu Glu Thr Phe Pro Asp Leu Phe Cys Leu Pro Leu Gly Glu 565 570 575 Ser Phe Ser Ala Leu Thr Val Ser Glu His Val Ser Tyr Ile Val Thr 580 585 590 Asn Gln Tyr Leu Ile Lys Gly Ile Ser Tyr Pro Val Ser Thr Thr Val 595 600 605 Val Gly Gln Ser Leu Ile Ile Thr Gln Thr Asp Ser Gln Thr Lys Cys 610 615 620 Glu Leu Thr Arg Asn Met His Thr Thr His Ser Ile Thr Val Ala Leu 625 630 635 640 Asn Ile Ser Leu Glu Asn Cys Ala Phe Cys Gln Ser Ala Leu Leu Glu 645 650 655 Tyr Asp Asp Thr Gln Gly Val Ile Asn Ile Met Tyr Met His Asp Ser 660 665 670 Asp Asp Val Leu Phe Ala Leu Asp Pro Tyr Asn Glu Val Val Val Ser 675 680 685 Ser Pro Arg Thr His Tyr Leu Met Leu Leu Lys Asn Gly Thr Val Leu 690 695 700 Glu Val Thr Asp Val Val Val Asp Ala Thr Asp Ser Arg Leu Leu Met 705 710 715 720 Met Ser Val Tyr Ala Leu Ser Ala Ile Ile Gly Ile Tyr Leu Leu Tyr 725 730 735 Arg Met Leu Lys Thr Cys 740 <210> 33 <211> 2151 <212> DNA <213> Human herpesvirus 5 <400> 33 atgaggcctg gcctgccctc ctacctgatc atcctggccg tgtgcctgtt cagccacctg 60 ctgtccagca gatacggcgc cgaggccgtg agcgagcccc tggacaaggc tttccacctg 120 ctgctgaaca cctacggcag acccatccgg tttctgcggg agaacaccac ccagtgcacc 180 tacaacagca gcctgcggaa cagcaccgtc gtgagagaga acgccatcag cttcaacttt 240 ttccagagct acaaccagta ctacgtgttc cacatgccca gatgcctgtt tgccggccct 300 ctggccgagc agttcctgaa ccaggtggac ctgaccgaga cactggaaag ataccagcag 360 cggctgaata cctacgccct ggtgtccaag gacctggcca gctaccggtc ctttagccag 420 cagctcaagg ctcaggatag cctcggcgag cagcctacca ccgtgccccc tcccatcgac 480 ctgagcatcc cccacgtgtg gatgcctccc cagaccaccc ctcacggctg gaccgagagc 540 cacaccacct ccggcctgca cagaccccac ttcaaccaga cctgcatcct gttcgacggc 600 cacgacctgc tgtttagcac cgtgaccccc tgcctgcacc agggcttcta cctgatcgac 660 gagctgagat acgtgaagat caccctgacc gaggatttct tcgtggtcac cgtgtccatc 720 gacgacgaca cccccatgct gctgatcttc ggccacctgc ccagagtgct gttcaaggcc 780 ccctaccagc gggacaactt catcctgcgg cagaccgaga agcacgagct gctggtgctg 840 gtcaagaagg accagctgaa ccggcactcc tacctgaagg accccgactt cctggacgcc 900 gccctggact tcaactacct ggacctgagc gccctgctga gaaacagctt ccacagatac 960 gccgtggacg tgctgaagtc cggacggtgc cagatgctcg atcggcggac cgtggagatg 1020 gccttcgcct atgccctcgc cctgttcgcc gctgccagac aggaagaggc tggcgcccag 1080 gtgtcagtgc ccagagccct ggatagacag gccgccctgc tgcagatcca ggaattcatg 1140 atcacctgcc tgagccagac cccccctaga accaccctgc tgctgtaccc cacagccgtg 1200 gatctggcca agagggccct gtggaccccc aaccagatca ccgacatcac aagcctcgtg 1260 cggctcgtgt acatcctgag caagcagaac cagcagcacc tgatccccca gtgggccctg 1320 agacagatcg ccgacttcgc cctgaagctg cacaagaccc atctggccag ctttctgagc 1380 gccttcgcca ggcaggaact gtacctgatg ggcagcctgg tccacagcat gctggtgcat 1440 accaccgagc ggcgggagat cttcatcgtg gagacaggcc tgtgtagcct ggccgagctg 1500 tcccacttta cccagctgct ggcccaccct caccacgagt acctgagcga cctgtacacc 1560 ccctgcagca gcagcggcag acgggaccac agcctggaac ggctgaccag actgttcccc 1620 gatgccaccg tgcctgctac agtgcctgcc gccctgtcca tcctgtccac catgcagccc 1680 agcaccctgg aaaccttccc cgacctgttc tgcctgcccc tgggcgagag ctttagcgcc 1740 ctgaccgtgt ccgagcacgt gtcctacatc gtgaccaatc agtacctgat caagggcatc 1800 agctaccccg tgtccaccac agtcgtgggc cagagcctga tcatcaccca gaccgacagc 1860 cagaccaagt gcgagctgac ccggaacatg cacaccacac acagcatcac cgtggccctg 1920 aacatcagcc tggaaaactg cgctttctgt cagtctgccc tgctggaata cgacgatacc 1980 cagggcgtga tcaacatcat gtacatgcac gacagcgacg acgtgctgtt cgccctggac 2040 ccctacaacg aggtggtggt gtccagcccc cggacccact acctgatgct gctgaagaac 2100 ggcaccgtgc tggaagtgac cgacgtggtg gtggacgcca ccgactgata a 2151 <210> 34 <211> 715 <212> PRT <213> Human herpesvirus 5 <400> 34 Met Arg Pro Gly Leu Pro Ser Tyr Leu Ile Ile Leu Ala Val Cys Leu 1 5 10 15 Phe Ser His Leu Leu Ser Ser Arg Tyr Gly Ala Glu Ala Val Ser Glu 20 25 30 Pro Leu Asp Lys Ala Phe His Leu Leu Leu Asn Thr Tyr Gly Arg Pro 35 40 45 Ile Arg Phe Leu Arg Glu Asn Thr Thr Gln Cys Thr Tyr Asn Ser Ser 50 55 60 Leu Arg Asn Ser Thr Val Val Arg Glu Asn Ala Ile Ser Phe Asn Phe 65 70 75 80 Phe Gln Ser Tyr Asn Gln Tyr Tyr Val Phe His Met Pro Arg Cys Leu 85 90 95 Phe Ala Gly Pro Leu Ala Glu Gln Phe Leu Asn Gln Val Asp Leu Thr 100 105 110 Glu Thr Leu Glu Arg Tyr Gln Gln Arg Leu Asn Thr Tyr Ala Leu Val 115 120 125 Ser Lys Asp Leu Ala Ser Tyr Arg Ser Phe Ser Gln Gln Leu Lys Ala 130 135 140 Gln Asp Ser Leu Gly Glu Gln Pro Thr Thr Val Pro Pro Pro Ile Asp 145 150 155 160 Leu Ser Ile Pro His Val Trp Met Pro Pro Gln Thr Thr Pro His Gly 165 170 175 Trp Thr Glu Ser His Thr Thr Ser Gly Leu His Arg Pro His Phe Asn 180 185 190 Gln Thr Cys Ile Leu Phe Asp Gly His Asp Leu Leu Phe Ser Thr Val 195 200 205 Thr Pro Cys Leu His Gln Gly Phe Tyr Leu Ile Asp Glu Leu Arg Tyr 210 215 220 Val Lys Ile Thr Leu Thr Glu Asp Phe Phe Val Val Thr Val Ser Ile 225 230 235 240 Asp Asp Asp Thr Pro Met Leu Leu Ile Phe Gly His Leu Pro Arg Val 245 250 255 Leu Phe Lys Ala Pro Tyr Gln Arg Asp Asn Phe Ile Leu Arg Gln Thr 260 265 270 Glu Lys His Glu Leu Leu Val Leu Val Lys Lys Asp Gln Leu Asn Arg 275 280 285 His Ser Tyr Leu Lys Asp Pro Asp Phe Leu Asp Ala Ala Leu Asp Phe 290 295 300 Asn Tyr Leu Asp Leu Ser Ala Leu Leu Arg Asn Ser Phe His Arg Tyr 305 310 315 320 Ala Val Asp Val Leu Lys Ser Gly Arg Cys Gln Met Leu Asp Arg Arg 325 330 335 Thr Val Glu Met Ala Phe Ala Tyr Ala Leu Ala Leu Phe Ala Ala Ala 340 345 350 Arg Gln Glu Glu Ala Gly Ala Gln Val Ser Val Pro Arg Ala Leu Asp 355 360 365 Arg Gln Ala Ala Leu Leu Gln Ile Gln Glu Phe Met Ile Thr Cys Leu 370 375 380 Ser Gln Thr Pro Pro Arg Thr Thr Leu Leu Leu Tyr Pro Thr Ala Val 385 390 395 400 Asp Leu Ala Lys Arg Ala Leu Trp Thr Pro Asn Gln Ile Thr Asp Ile 405 410 415 Thr Ser Leu Val Arg Leu Val Tyr Ile Leu Ser Lys Gln Asn Gln Gln 420 425 430 His Leu Ile Pro Gln Trp Ala Leu Arg Gln Ile Ala Asp Phe Ala Leu 435 440 445 Lys Leu His Lys Thr His Leu Ala Ser Phe Leu Ser Ala Phe Ala Arg 450 455 460 Gln Glu Leu Tyr Leu Met Gly Ser Leu Val His Ser Met Leu Val His 465 470 475 480 Thr Thr Glu Arg Arg Glu Ile Phe Ile Val Glu Thr Gly Leu Cys Ser 485 490 495 Leu Ala Glu Leu Ser His Phe Thr Gln Leu Leu Ala His Pro His His 500 505 510 Glu Tyr Leu Ser Asp Leu Tyr Thr Pro Cys Ser Ser Ser Gly Arg Arg 515 520 525 Asp His Ser Leu Glu Arg Leu Thr Arg Leu Phe Pro Asp Ala Thr Val 530 535 540 Pro Ala Thr Val Pro Ala Ala Leu Ser Ile Leu Ser Thr Met Gln Pro 545 550 555 560 Ser Thr Leu Glu Thr Phe Pro Asp Leu Phe Cys Leu Pro Leu Gly Glu 565 570 575 Ser Phe Ser Ala Leu Thr Val Ser Glu His Val Ser Tyr Ile Val Thr 580 585 590 Asn Gln Tyr Leu Ile Lys Gly Ile Ser Tyr Pro Val Ser Thr Thr Val 595 600 605 Val Gly Gln Ser Leu Ile Ile Thr Gln Thr Asp Ser Gln Thr Lys Cys 610 615 620 Glu Leu Thr Arg Asn Met His Thr Thr His Ser Ile Thr Val Ala Leu 625 630 635 640 Asn Ile Ser Leu Glu Asn Cys Ala Phe Cys Gln Ser Ala Leu Leu Glu 645 650 655 Tyr Asp Asp Thr Gln Gly Val Ile Asn Ile Met Tyr Met His Asp Ser 660 665 670 Asp Asp Val Leu Phe Ala Leu Asp Pro Tyr Asn Glu Val Val Val Ser 675 680 685 Ser Pro Arg Thr His Tyr Leu Met Leu Leu Lys Asn Gly Thr Val Leu 690 695 700 Glu Val Thr Asp Val Val Val Asp Ala Thr Asp 705 710 715 <210> 35 <211> 840 <212> DNA <213> Human herpesvirus 5 <400> 35 atgtgcagaa ggcccgactg cggcttcagc ttcagccctg gacccgtgat cctgctgtgg 60 tgctgcctgc tgctgcctat cgtgtcctct gccgccgtgt ctgtggcccc tacagccgcc 120 gagaaggtgc cagccgagtg ccccgagctg accagaagat gcctgctggg cgaggtgttc 180 gagggcgaca agtacgagag ctggctgcgg cccctggtca acgtgaccgg cagagatggc 240 cccctgagcc agctgatccg gtacagaccc gtgacccccg aggccgccaa tagcgtgctg 300 ctggacgagg ccttcctgga taccctggcc ctgctgtaca acaaccccga ccagctgaga 360 gccctgctga ccctgctgtc cagcgacacc gcccccagat ggatgaccgt gatgcggggc 420 tacagcgagt gtggagatgg cagccctgcc gtgtacacct gcgtggacga cctgtgcaga 480 ggctacgacc tgaccagact gagctacggc cggtccatct tcacagagca cgtgctgggc 540 ttcgagctgg tgccccccag cctgttcaac gtggtggtgg ccatccggaa cgaggccacc 600 agaaccaaca gagccgtgcg gctgcctgtg tctacagccg ctgcacctga gggcatcaca 660 ctgttctacg gcctgtacaa cgccgtgaaa gagttctgcc tccggcacca gctggatccc 720 cccctgctga gacacctgga caagtactac gccggcctgc ccccagagct gaagcagacc 780 agagtgaacc tgcccgccca cagcagatat ggccctcagg ccgtggacgc cagatgataa 840 <210> 36 <211> 278 <212> PRT <213> Human herpesvirus 5 <400> 36 Met Cys Arg Arg Pro Asp Cys Gly Phe Ser Phe Ser Pro Gly Pro Val 1 5 10 15 Ile Leu Leu Trp Cys Cys Leu Leu Leu Pro Ile Val Ser Ser Ala Ala 20 25 30 Val Ser Val Ala Pro Thr Ala Ala Glu Lys Val Pro Ala Glu Cys Pro 35 40 45 Glu Leu Thr Arg Arg Cys Leu Leu Gly Glu Val Phe Glu Gly Asp Lys 50 55 60 Tyr Glu Ser Trp Leu Arg Pro Leu Val Asn Val Thr Gly Arg Asp Gly 65 70 75 80 Pro Leu Ser Gln Leu Ile Arg Tyr Arg Pro Val Thr Pro Glu Ala Ala 85 90 95 Asn Ser Val Leu Leu Asp Glu Ala Phe Leu Asp Thr Leu Ala Leu Leu 100 105 110 Tyr Asn Asn Pro Asp Gln Leu Arg Ala Leu Leu Thr Leu Leu Ser Ser 115 120 125 Asp Thr Ala Pro Arg Trp Met Thr Val Met Arg Gly Tyr Ser Glu Cys 130 135 140 Gly Asp Gly Ser Pro Ala Val Tyr Thr Cys Val Asp Asp Leu Cys Arg 145 150 155 160 Gly Tyr Asp Leu Thr Arg Leu Ser Tyr Gly Arg Ser Ile Phe Thr Glu 165 170 175 His Val Leu Gly Phe Glu Leu Val Pro Pro Ser Leu Phe Asn Val Val 180 185 190 Val Ala Ile Arg Asn Glu Ala Thr Arg Thr Asn Arg Ala Val Arg Leu 195 200 205 Pro Val Ser Thr Ala Ala Ala Pro Glu Gly Ile Thr Leu Phe Tyr Gly 210 215 220 Leu Tyr Asn Ala Val Lys Glu Phe Cys Leu Arg His Gln Leu Asp Pro 225 230 235 240 Pro Leu Leu Arg His Leu Asp Lys Tyr Tyr Ala Gly Leu Pro Pro Glu 245 250 255 Leu Lys Gln Thr Arg Val Asn Leu Pro Ala His Ser Arg Tyr Gly Pro 260 265 270 Gln Ala Val Asp Ala Arg 275 <210> 37 <211> 1119 <212> DNA <213> Human herpesvirus 5 <400> 37 atggccccca gccacgtgga caaagtgaac acccggactt ggagcgccag catcgtgttc 60 atggtgctga ccttcgtgaa cgtgtccgtg cacctggtgc tgtccaactt cccccacctg 120 ggctacccct gcgtgtacta ccacgtggtg gacttcgagc ggctgaacat gagcgcctac 180 aacgtgatgc acctgcacac ccccatgctg tttctggaca gcgtgcagct cgtgtgctac 240 gccgtgttca tgcagctggt gtttctggcc gtgaccatct actacctcgt gtgctggatc 300 aagatcagca tgcggaagga caagggcatg agcctgaacc agagcacccg ggacatcagc 360 tacatgggcg acagcctgac cgccttcctg ttcatcctga gcatggacac cttccagctg 420 ttcaccctga ccatgagctt ccggctgccc agcatgatcg ccttcatggc cgccgtgcac 480 tttttctgtc tgaccatctt caacgtgtcc atggtcaccc agtaccggtc ctacaagcgg 540 agcctgttct tcttctcccg gctgcacccc aagctgaagg gcaccgtgca gttccggacc 600 ctgatcgtga acctggtgga ggtggccctg ggcttcaata ccaccgtggt ggctatggcc 660 ctgtgctacg gcttcggcaa caacttcttc gtgcggaccg gccatatggt gctggccgtg 720 ttcgtggtgt acgccatcat cagcatcatc tactttctgc tgatcgaggc cgtgttcttc 780 cagtacgtga aggtgcagtt cggctaccat ctgggcgcct ttttcggcct gtgcggcctg 840 atctacccca tcgtgcagta cgacaccttc ctgagcaacg agtaccggac cggcatcagc 900 tggtccttcg gaatgctgtt cttcatctgg gccatgttca ccacctgcag agccgtgcgg 960 tacttcagag gcagaggcag cggctccgtg aagtaccagg ccctggccac agcctctggc 1020 gaagaggtgg ccgccctgag ccaccacgac agcctggaaa gcagacggct gcgggaggaa 1080 gaggacgacg acgacgagga cttcgaggac gcctgataa 1119 <210> 38 <211> 371 <212> PRT <213> Human herpesvirus 5 <400> 38 Met Ala Pro Ser His Val Asp Lys Val Asn Thr Arg Thr Trp Ser Ala 1 5 10 15 Ser Ile Val Phe Met Val Leu Thr Phe Val Asn Val Ser Val His Leu 20 25 30 Val Leu Ser Asn Phe Pro His Leu Gly Tyr Pro Cys Val Tyr Tyr His 35 40 45 Val Val Asp Phe Glu Arg Leu Asn Met Ser Ala Tyr Asn Val Met His 50 55 60 Leu His Thr Pro Met Leu Phe Leu Asp Ser Val Gln Leu Val Cys Tyr 65 70 75 80 Ala Val Phe Met Gln Leu Val Phe Leu Ala Val Thr Ile Tyr Tyr Leu 85 90 95 Val Cys Trp Ile Lys Ile Ser Met Arg Lys Asp Lys Gly Met Ser Leu 100 105 110 Asn Gln Ser Thr Arg Asp Ile Ser Tyr Met Gly Asp Ser Leu Thr Ala 115 120 125 Phe Leu Phe Ile Leu Ser Met Asp Thr Phe Gln Leu Phe Thr Leu Thr 130 135 140 Met Ser Phe Arg Leu Pro Ser Met Ile Ala Phe Met Ala Ala Val His 145 150 155 160 Phe Phe Cys Leu Thr Ile Phe Asn Val Ser Met Val Thr Gln Tyr Arg 165 170 175 Ser Tyr Lys Arg Ser Leu Phe Phe Phe Ser Arg Leu His Pro Lys Leu 180 185 190 Lys Gly Thr Val Gln Phe Arg Thr Leu Ile Val Asn Leu Val Glu Val 195 200 205 Ala Leu Gly Phe Asn Thr Thr Val Val Ala Met Ala Leu Cys Tyr Gly 210 215 220 Phe Gly Asn Asn Phe Phe Val Arg Thr Gly His Met Val Leu Ala Val 225 230 235 240 Phe Val Val Tyr Ala Ile Ile Ser Ile Ile Tyr Phe Leu Leu Ile Glu 245 250 255 Ala Val Phe Phe Gln Tyr Val Lys Val Gln Phe Gly Tyr His Leu Gly 260 265 270 Ala Phe Phe Gly Leu Cys Gly Leu Ile Tyr Pro Ile Val Gln Tyr Asp 275 280 285 Thr Phe Leu Ser Asn Glu Tyr Arg Thr Gly Ile Ser Trp Ser Phe Gly 290 295 300 Met Leu Phe Phe Ile Trp Ala Met Phe Thr Thr Cys Arg Ala Val Arg 305 310 315 320 Tyr Phe Arg Gly Arg Gly Ser Gly Ser Val Lys Tyr Gln Ala Leu Ala 325 330 335 Thr Ala Ser Gly Glu Glu Val Ala Ala Leu Ser His His Asp Ser Leu 340 345 350 Glu Ser Arg Arg Leu Arg Glu Glu Glu Asp Asp Asp Asp Glu Asp Phe 355 360 365 Glu Asp Ala 370 <210> 39 <211> 411 <212> DNA <213> Human herpesvirus 5 <400> 39 atggaatgga acaccctggt cctgggcctg ctggtgctgt ctgtcgtggc cagcagcaac 60 aacacatcca cagccagcac ccctagacct agcagcagca cccacgccag cactaccgtg 120 aaggctacca ccgtggccac cacaagcacc accactgcta ccagcaccag ctccaccacc 180 tctgccaagc ctggctctac cacacacgac cccaacgtga tgaggcccca cgcccacaac 240 gacttctaca acgctcactg caccagccac atgtacgagc tgtccctgag cagctttgcc 300 gcctggtgga ccatgctgaa cgccctgatc ctgatgggcg ccttctgcat cgtgctgcgg 360 cactgctgct tccagaactt caccgccacc accaccaagg gctactgata a 411 <210> 40 <211> 135 <212> PRT <213> Human herpesvirus 5 <400> 40 Met Glu Trp Asn Thr Leu Val Leu Gly Leu Leu Val Leu Ser Val Val 1 5 10 15 Ala Ser Ser Asn Asn Thr Ser Thr Ala Ser Thr Pro Arg Pro Ser Ser 20 25 30 Ser Thr His Ala Ser Thr Thr Val Lys Ala Thr Thr Val Ala Thr Thr 35 40 45 Ser Thr Thr Thr Ala Thr Ser Thr Ser Ser Thr Thr Ser Ala Lys Pro 50 55 60 Gly Ser Thr Thr His Asp Pro Asn Val Met Arg Pro His Ala His Asn 65 70 75 80 Asp Phe Tyr Asn Ala His Cys Thr Ser His Met Tyr Glu Leu Ser Leu 85 90 95 Ser Ser Phe Ala Ala Trp Trp Thr Met Leu Asn Ala Leu Ile Leu Met 100 105 110 Gly Ala Phe Cys Ile Val Leu Arg His Cys Cys Phe Gln Asn Phe Thr 115 120 125 Ala Thr Thr Thr Lys Gly Tyr 130 135 <210> 41 <211> 1422 <212> DNA <213> Human herpesvirus 5 <400> 41 atgggcaaga aagaaatgat catggtcaag ggcatcccca agatcatgct gctgattagc 60 atcacctttc tgctgctgtc cctgatcaac tgcaacgtgc tggtcaacag ccggggcacc 120 agaagatcct ggccctacac cgtgctgtcc taccggggca aagagatcct gaagaagcag 180 aaagaggaca tcctgaagcg gctgatgagc accagcagcg acggctaccg gttcctgatg 240 taccccagcc agcagaaatt ccacgccatc gtgatcagca tggacaagtt cccccaggac 300 tacatcctgg ccggacccat ccggaacgac agcatcaccc acatgtggtt cgacttctac 360 agcacccagc tgcggaagcc cgccaaatac gtgtacagcg agtacaacca caccgcccac 420 aagatcaccc tgaggcctcc cccttgtggc accgtgccca gcatgaactg cctgagcgag 480 atgctgaacg tgtccaagcg gaacgacacc ggcgagaagg gctgcggcaa cttcaccacc 540 ttcaacccca tgttcttcaa cgtgccccgg tggaacacca agctgtacat cggcagcaac 600 aaagtgaacg tggacagcca gaccatctac tttctgggcc tgaccgccct gctgctgaga 660 tacgcccagc ggaactgcac ccggtccttc tacctggtca acgccatgag ccggaacctg 720 ttccgggtgc ccaagtacat caacggcacc aagctgaaga acaccatgcg gaagctgaag 780 cggaagcagg ccctggtcaa agagcagccc cagaagaaga acaagaagtc ccagagcacc 840 accaccccct acctgagcta caccacctcc accgccttca acgtgaccac caacgtgacc 900 tacagcgcca cagccgccgt gaccagagtg gccacaagca ccaccggcta ccggcccgac 960 agcaacttta tgaagtccat catggccacc cagctgagag atctggccac ctgggtgtac 1020 accaccctgc ggtacagaaa cgagcccttc tgcaagcccg accggaacag aaccgccgtg 1080 agcgagttca tgaagaatac ccacgtgctg atcagaaacg agacacccta caccatctac 1140 ggcaccctgg acatgagcag cctgtactac aacgagacaa tgagcgtgga gaacgagaca 1200 gccagcgaca acaacgaaac cacccccacc tcccccagca cccggttcca gcggaccttc 1260 atcgaccccc tgtgggacta cctggacagc ctgctgttcc tggacaagat ccggaacttc 1320 agcctgcagc tgcccgccta cggcaatctg accccccctg agcacagaag ggccgccaac 1380 ctgagcaccc tgaacagcct gtggtggtgg agccagtgat aa 1422 <210> 42 <211> 472 <212> PRT <213> Human herpesvirus 5 <400> 42 Met Gly Lys Lys Glu Met Ile Met Val Lys Gly Ile Pro Lys Ile Met 1 5 10 15 Leu Leu Ile Ser Ile Thr Phe Leu Leu Leu Ser Leu Ile Asn Cys Asn 20 25 30 Val Leu Val Asn Ser Arg Gly Thr Arg Arg Ser Trp Pro Tyr Thr Val 35 40 45 Leu Ser Tyr Arg Gly Lys Glu Ile Leu Lys Lys Gln Lys Glu Asp Ile 50 55 60 Leu Lys Arg Leu Met Ser Thr Ser Ser Asp Gly Tyr Arg Phe Leu Met 65 70 75 80 Tyr Pro Ser Gln Gln Lys Phe His Ala Ile Val Ile Ser Met Asp Lys 85 90 95 Phe Pro Gln Asp Tyr Ile Leu Ala Gly Pro Ile Arg Asn Asp Ser Ile 100 105 110 Thr His Met Trp Phe Asp Phe Tyr Ser Thr Gln Leu Arg Lys Pro Ala 115 120 125 Lys Tyr Val Tyr Ser Glu Tyr Asn His Thr Ala His Lys Ile Thr Leu 130 135 140 Arg Pro Pro Pro Cys Gly Thr Val Pro Ser Met Asn Cys Leu Ser Glu 145 150 155 160 Met Leu Asn Val Ser Lys Arg Asn Asp Thr Gly Glu Lys Gly Cys Gly 165 170 175 Asn Phe Thr Thr Phe Asn Pro Met Phe Phe Asn Val Pro Arg Trp Asn 180 185 190 Thr Lys Leu Tyr Ile Gly Ser Asn Lys Val Asn Val Asp Ser Gln Thr 195 200 205 Ile Tyr Phe Leu Gly Leu Thr Ala Leu Leu Leu Arg Tyr Ala Gln Arg 210 215 220 Asn Cys Thr Arg Ser Phe Tyr Leu Val Asn Ala Met Ser Arg Asn Leu 225 230 235 240 Phe Arg Val Pro Lys Tyr Ile Asn Gly Thr Lys Leu Lys Asn Thr Met 245 250 255 Arg Lys Leu Lys Arg Lys Gln Ala Leu Val Lys Glu Gln Pro Gln Lys 260 265 270 Lys Asn Lys Lys Ser Gln Ser Thr Thr Thr Pro Tyr Leu Ser Tyr Thr 275 280 285 Thr Ser Thr Ala Phe Asn Val Thr Thr Asn Val Thr Tyr Ser Ala Thr 290 295 300 Ala Ala Val Thr Arg Val Ala Thr Ser Thr Thr Gly Tyr Arg Pro Asp 305 310 315 320 Ser Asn Phe Met Lys Ser Ile Met Ala Thr Gln Leu Arg Asp Leu Ala 325 330 335 Thr Trp Val Tyr Thr Thr Leu Arg Tyr Arg Asn Glu Pro Phe Cys Lys 340 345 350 Pro Asp Arg Asn Arg Thr Ala Val Ser Glu Phe Met Lys Asn Thr His 355 360 365 Val Leu Ile Arg Asn Glu Thr Pro Tyr Thr Ile Tyr Gly Thr Leu Asp 370 375 380 Met Ser Ser Leu Tyr Tyr Asn Glu Thr Met Ser Val Glu Asn Glu Thr 385 390 395 400 Ala Ser Asp Asn Asn Glu Thr Thr Pro Thr Ser Pro Ser Thr Arg Phe 405 410 415 Gln Arg Thr Phe Ile Asp Pro Leu Trp Asp Tyr Leu Asp Ser Leu Leu 420 425 430 Phe Leu Asp Lys Ile Arg Asn Phe Ser Leu Gln Leu Pro Ala Tyr Gly 435 440 445 Asn Leu Thr Pro Pro Glu His Arg Arg Ala Ala Asn Leu Ser Thr Leu 450 455 460 Asn Ser Leu Trp Trp Trp Ser Gln 465 470 <210> 43 <211> 519 <212> DNA <213> Human herpesvirus 5 <400> 43 atgagcccca aggacctgac ccccttcctg acaaccctgt ggctgctcct gggccatagc 60 agagtgccta gagtgcgggc cgaggaatgc tgcgagttca tcaacgtgaa ccaccccccc 120 gagcggtgct acgacttcaa gatgtgcaac cggttcaccg tggccctgag atgccccgac 180 ggcgaagtgt gctacagccc cgagaaaacc gccgagatcc ggggcatcgt gaccaccatg 240 acccacagcc tgacccggca ggtggtgcac aacaagctga ccagctgcaa ctacaacccc 300 ctgtacctgg aagccgacgg ccggatcaga tgcggcaaag tgaacgacaa ggcccagtac 360 ctgctgggag ccgccggaag cgtgccctac cggtggatca acctggaata cgacaagatc 420 acccggatcg tgggcctgga ccagtacctg gaaagcgtga agaagcacaa gcggctggac 480 gtgtgcagag ccaagatggg ctacatgctg cagtgataa 519 <210> 44 <211> 171 <212> PRT <213> Human herpesvirus 5 <400> 44 Met Ser Pro Lys Asp Leu Thr Pro Phe Leu Thr Thr Leu Trp Leu Leu 1 5 10 15 Leu Gly His Ser Arg Val Pro Arg Val Arg Ala Glu Glu Cys Cys Glu 20 25 30 Phe Ile Asn Val Asn His Pro Pro Glu Arg Cys Tyr Asp Phe Lys Met 35 40 45 Cys Asn Arg Phe Thr Val Ala Leu Arg Cys Pro Asp Gly Glu Val Cys 50 55 60 Tyr Ser Pro Glu Lys Thr Ala Glu Ile Arg Gly Ile Val Thr Thr Met 65 70 75 80 Thr His Ser Leu Thr Arg Gln Val Val His Asn Lys Leu Thr Ser Cys 85 90 95 Asn Tyr Asn Pro Leu Tyr Leu Glu Ala Asp Gly Arg Ile Arg Cys Gly 100 105 110 Lys Val Asn Asp Lys Ala Gln Tyr Leu Leu Gly Ala Ala Gly Ser Val 115 120 125 Pro Tyr Arg Trp Ile Asn Leu Glu Tyr Asp Lys Ile Thr Arg Ile Val 130 135 140 Gly Leu Asp Gln Tyr Leu Glu Ser Val Lys Lys His Lys Arg Leu Asp 145 150 155 160 Val Cys Arg Ala Lys Met Gly Tyr Met Leu Gln 165 170 <210> 45 <211> 648 <212> DNA <213> Human herpesvirus 5 <400> 45 atgctgcggc tgctgctgag acaccacttc cactgcctgc tgctgtgtgc cgtgtgggcc 60 accccttgtc tggccagccc ttggagcacc ctgaccgcca accagaaccc tagcccccct 120 tggtccaagc tgacctacag caagccccac gacgccgcca ccttctactg cccctttctg 180 taccccagcc ctcccagaag ccccctgcag ttcagcggct tccagagagt gtccaccggc 240 cctgagtgcc ggaacgagac actgtacctg ctgtacaacc gggagggcca gacactggtg 300 gagcggagca gcacctgggt gaaaaaagtg atctggtatc tgagcggccg gaaccagacc 360 atcctgcagc ggatgcccag aaccgccagc aagcccagcg acggcaacgt gcagatcagc 420 gtggaggacg ccaaaatctt cggcgcccac atggtgccca agcagaccaa gctgctgaga 480 ttcgtggtca acgacggcac cagatatcag atgtgcgtga tgaagctgga aagctgggcc 540 cacgtgttcc gggactactc cgtgagcttc caggtccggc tgaccttcac cgaggccaac 600 aaccagacct acaccttctg cacccacccc aacctgatcg tgtgataa 648 <210> 46 <211> 214 <212> PRT <213> Human herpesvirus 5 <400> 46 Met Leu Arg Leu Leu Leu Arg His His Phe His Cys Leu Leu Leu Cys 1 5 10 15 Ala Val Trp Ala Thr Pro Cys Leu Ala Ser Pro Trp Ser Thr Leu Thr 20 25 30 Ala Asn Gln Asn Pro Ser Pro Pro Trp Ser Lys Leu Thr Tyr Ser Lys 35 40 45 Pro His Asp Ala Ala Thr Phe Tyr Cys Pro Phe Leu Tyr Pro Ser Pro 50 55 60 Pro Arg Ser Pro Leu Gln Phe Ser Gly Phe Gln Arg Val Ser Thr Gly 65 70 75 80 Pro Glu Cys Arg Asn Glu Thr Leu Tyr Leu Leu Tyr Asn Arg Glu Gly 85 90 95 Gln Thr Leu Val Glu Arg Ser Ser Thr Trp Val Lys Lys Val Ile Trp 100 105 110 Tyr Leu Ser Gly Arg Asn Gln Thr Ile Leu Gln Arg Met Pro Arg Thr 115 120 125 Ala Ser Lys Pro Ser Asp Gly Asn Val Gln Ile Ser Val Glu Asp Ala 130 135 140 Lys Ile Phe Gly Ala His Met Val Pro Lys Gln Thr Lys Leu Leu Arg 145 150 155 160 Phe Val Val Asn Asp Gly Thr Arg Tyr Gln Met Cys Val Met Lys Leu 165 170 175 Glu Ser Trp Ala His Val Phe Arg Asp Tyr Ser Val Ser Phe Gln Val 180 185 190 Arg Leu Thr Phe Thr Glu Ala Asn Asn Gln Thr Tyr Thr Phe Cys Thr 195 200 205 His Pro Asn Leu Ile Val 210 <210> 47 <211> 393 <212> DNA <213> Human herpesvirus 5 <400> 47 atgcggctgt gcagagtgtg gctgtccgtg tgcctgtgtg ccgtggtgct gggccagtgc 60 cagagagaga cagccgagaa gaacgactac taccgggtgc cccactactg ggatgcctgc 120 agcagagccc tgcccgacca gacccggtac aaatacgtgg agcagctcgt ggacctgacc 180 ctgaactacc actacgacgc cagccacggc ctggacaact tcgacgtgct gaagcggatc 240 aacgtgaccg aggtgtccct gctgatcagc gacttccggc ggcagaacag aagaggcggc 300 accaacaagc ggaccacctt caacgccgct ggctctctgg cccctcacgc cagatccctg 360 gaattcagcg tgcggctgtt cgccaactga taa 393 <210> 48 <211> 129 <212> PRT <213> Human herpesvirus 5 <400> 48 Met Arg Leu Cys Arg Val Trp Leu Ser Val Cys Leu Cys Ala Val Val 1 5 10 15 Leu Gly Gln Cys Gln Arg Glu Thr Ala Glu Lys Asn Asp Tyr Tyr Arg 20 25 30 Val Pro His Tyr Trp Asp Ala Cys Ser Arg Ala Leu Pro Asp Gln Thr 35 40 45 Arg Tyr Lys Tyr Val Glu Gln Leu Val Asp Leu Thr Leu Asn Tyr His 50 55 60 Tyr Asp Ala Ser His Gly Leu Asp Asn Phe Asp Val Leu Lys Arg Ile 65 70 75 80 Asn Val Thr Glu Val Ser Leu Leu Ile Ser Asp Phe Arg Arg Gln Asn 85 90 95 Arg Arg Gly Gly Thr Asn Lys Arg Thr Thr Phe Asn Ala Ala Gly Ser 100 105 110 Leu Ala Pro His Ala Arg Ser Leu Glu Phe Ser Val Arg Leu Phe Ala 115 120 125 Asn <210> 49 <211> 550 <212> DNA <213> Encephalomyocarditis virus <400> 49 aacgttactg gccgaagccg cttggaataa ggccggtgtg cgtttgtcta tatgttattt 60 tccaccatat tgccgtcttt tggcaatgtg agggcccgga aacctggccc tgtcttcttg 120 acgagcattc ctaggggtct ttcccctctc gccaaaggaa tgcaaggtct gttgaatgtc 180 gtgaaggaag cagttcctct ggaagcttct tgaagacaaa caacgtctgt agcgaccctt 240 tgcaggcagc ggaacccccc acctggcgac aggtgcctct gcggccaaaa gccacgtgta 300 taagatacac ctgcaaaggc ggcacaaccc cagtgccacg ttgtgagttg gatagttgtg 360 gaaagagtca aatggctctc ctcaagcgta ttcaacaagg ggctgaagga tgcccagaag 420 gtaccccatt gtatgggatc tgatctgggg cctcggtgca catgctttac atgtgtttag 480 tcgaggttaa aaaaacgtct aggccccccg aaccacgggg acgtggtttt cctttgaaaa 540 acacgataat 550 <210> 50 <211> 678 <212> DNA <213> Human enterovirus 71 <400> 50 gtacctttgt acgcctgttt tataccccct ccctgatttg caacttagaa gcaacgcaaa 60 ccagatcaat agtaggtgtg acataccagt cgcatcttga tcaagcactt ctgtatcccc 120 ggaccgagta tcaatagact gtgcacacgg ttgaaggaga aaacgtccgt tacccggcta 180 actacttcga gaagcctagt aacgccattg aagttgcaga gtgtttcgct cagcactccc 240 cccgtgtaga tcaggtcgat gagtcaccgc attccccacg ggcgaccgtg gcggtggctg 300 cgttggcggc ctgcctatgg ggtaacccat aggacgctct aatacggaca tggcgtgaag 360 agtctattga gctagttagt agtcctccgg cccctgaatg cggctaatcc taactgcgga 420 gcacataccc ttaatccaaa gggcagtgtg tcgtaacggg caactctgca gcggaaccga 480 ctactttggg tgtccgtgtt tctttttatt cttgtattgg ctgcttatgg tgacaattaa 540 agaattgtta ccatatagct attggattgg ccatccagtg tcaaacagag ctattgtata 600 tctctttgtt ggattcacac ctctcactct tgaaacgtta cacaccctca attacattat 660 actgctgaac acgaagcg 678 <210> 51 <211> 24 <212> DNA <213> Venezuelan equine encephalitis virus <400> 51 ctctctacgg ctaacctgaa tgga 24 <210> 52 <211> 14071 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 52 cgcgtcggct acaattaata cataacctta tgtatcatac acatacgatt taggtgacac 60 tatagatggg cggcgcatga gagaagccca gaccaattac ctacccaaaa tggagaaagt 120 tcacgttgac atcgaggaag acagcccatt cctcagagct ttgcagcgga gcttcccgca 180 gtttgaggta gaagccaagc aggtcactga taatgaccat gctaatgcca gagcgttttc 240 gcatctggct tcaaaactga tcgaaacgga ggtggaccca tccgacacga tccttgacat 300 tggaagtgcg cccgcccgca gaatgtattc taagcacaag tatcattgta tctgtccgat 360 gagatgtgcg gaagatccgg acagattgta taagtatgca actaagctga agaaaaactg 420 taaggaaata actgataagg aattggacaa gaaaatgaag gagctcgccg ccgtcatgag 480 cgaccctgac ctggaaactg agactatgtg cctccacgac gacgagtcgt gtcgctacga 540 agggcaagtc gctgtttacc aggatgtata cgcggttgac ggaccgacaa gtctctatca 600 ccaagccaat aagggagtta gagtcgccta ctggataggc tttgacacca ccccttttat 660 gtttaagaac ttggctggag catatccatc atactctacc aactgggccg acgaaaccgt 720 gttaacggct cgtaacatag gcctatgcag ctctgacgtt atggagcggt cacgtagagg 780 gatgtccatt cttagaaaga agtatttgaa accatccaac aatgttctat tctctgttgg 840 ctcgaccatc taccacgaga agagggactt actgaggagc tggcacctgc cgtctgtatt 900 tcacttacgt ggcaagcaaa attacacatg tcggtgtgag actatagtta gttgcgacgg 960 gtacgtcgtt aaaagaatag ctatcagtcc aggcctgtat gggaagcctt caggctatgc 1020 tgctacgatg caccgcgagg gattcttgtg ctgcaaagtg acagacacat tgaacgggga 1080 gagggtctct tttcccgtgt gcacgtatgt gccagctaca ttgtgtgacc aaatgactgg 1140 catactggca acagatgtca gtgcggacga cgcgcaaaaa ctgctggttg ggctcaacca 1200 gcgtatagtc gtcaacggtc gcacccagag aaacaccaat accatgaaaa attacctttt 1260 gcccgtagtg gcccaggcat ttgctaggtg ggcaaaggaa tataaggaag atcaagaaga 1320 tgaaaggcca ctaggactac gagatagaca gttagtcatg gggtgttgtt gggcttttag 1380 aaggcacaag ataacatcta tttataagcg cccggatacc caaaccatca tcaaagtgaa 1440 cagcgatttc cactcattcg tgctgcccag gataggcagt aacacattgg agatcgggct 1500 gagaacaaga atcaggaaaa tgttagagga gcacaaggag ccgtcacctc tcattaccgc 1560 cgaggacgta caagaagcta agtgcgcagc cgatgaggct aaggaggtgc gtgaagccga 1620 ggagttgcgc gcagctctac cacctttggc agctgatgtt gaggagccca ctctggaagc 1680 cgatgtagac ttgatgttac aagaggctgg ggccggctca gtggagacac ctcgtggctt 1740 gataaaggtt accagctacg ctggcgagga caagatcggc tcttacgctg tgctttctcc 1800 gcaggctgta ctcaagagtg aaaaattatc ttgcatccac cctctcgctg aacaagtcat 1860 agtgataaca cactctggcc gaaaagggcg ttatgccgtg gaaccatacc atggtaaagt 1920 agtggtgcca gagggacatg caatacccgt ccaggacttt caagctctga gtgaaagtgc 1980 caccattgtg tacaacgaac gtgagttcgt aaacaggtac ctgcaccata ttgccacaca 2040 tggaggagcg ctgaacactg atgaagaata ttacaaaact gtcaagccca gcgagcacga 2100 cggcgaatac ctgtacgaca tcgacaggaa acagtgcgtc aagaaagaac tagtcactgg 2160 gctagggctc acaggcgagc tggtggatcc tcccttccat gaattcgcct acgagagtct 2220 gagaacacga ccagccgctc cttaccaagt accaaccata ggggtgtatg gcgtgccagg 2280 atcaggcaag tctggcatca ttaaaagcgc agtcaccaaa aaagatctag tggtgagcgc 2340 caagaaagaa aactgtgcag aaattataag ggacgtcaag aaaatgaaag ggctggacgt 2400 caatgccaga actgtggact cagtgctctt gaatggatgc aaacaccccg tagagaccct 2460 gtatattgac gaagcttttg cttgtcatgc aggtactctc agagcgctca tagccattat 2520 aagacctaaa aaggcagtgc tctgcgggga tcccaaacag tgcggttttt ttaacatgat 2580 gtgcctgaaa gtgcatttta accacgagat ttgcacacaa gtcttccaca aaagcatctc 2640 tcgccgttgc actaaatctg tgacttcggt cgtctcaacc ttgttttacg acaaaaaaat 2700 gagaacgacg aatccgaaag agactaagat tgtgattgac actaccggca gtaccaaacc 2760 taagcaggac gatctcattc tcacttgttt cagagggtgg gtgaagcagt tgcaaataga 2820 ttacaaaggc aacgaaataa tgacggcagc tgcctctcaa gggctgaccc gtaaaggtgt 2880 gtatgccgtt cggtacaagg tgaatgaaaa tcctctgtac gcacccacct cagaacatgt 2940 gaacgtccta ctgacccgca cggaggaccg catcgtgtgg aaaacactag ccggcgaccc 3000 atggataaaa acactgactg ccaagtaccc tgggaatttc actgccacga tagaggagtg 3060 gcaagcagag catgatgcca tcatgaggca catcttggag agaccggacc ctaccgacgt 3120 cttccagaat aaggcaaacg tgtgttgggc caaggcttta gtgccggtgc tgaagaccgc 3180 tggcatagac atgaccactg aacaatggaa cactgtggat tattttgaaa cggacaaagc 3240 tcactcagca gagatagtat tgaaccaact atgcgtgagg ttctttggac tcgatctgga 3300 ctccggtcta ttttctgcac ccactgttcc gttatccatt aggaataatc actgggataa 3360 ctccccgtcg cctaacatgt acgggctgaa taaagaagtg gtccgtcagc tctctcgcag 3420 gtacccacaa ctgcctcggg cagttgccac tggaagagtc tatgacatga acactggtac 3480 actgcgcaat tatgatccgc gcataaacct agtacctgta aacagaagac tgcctcatgc 3540 tttagtcctc caccataatg aacacccaca gagtgacttt tcttcattcg tcagcaaatt 3600 gaagggcaga actgtcctgg tggtcgggga aaagttgtcc gtcccaggca aaatggttga 3660 ctggttgtca gaccggcctg aggctacctt cagagctcgg ctggatttag gcatcccagg 3720 tgatgtgccc aaatatgaca taatatttgt taatgtgagg accccatata aataccatca 3780 ctatcagcag tgtgaagacc atgccattaa gcttagcatg ttgaccaaga aagcttgtct 3840 gcatctgaat cccggcggaa cctgtgtcag cataggttat ggttacgctg acagggccag 3900 cgaaagcatc attggtgcta tagcgcggca gttcaagttt tcccgggtat gcaaaccgaa 3960 atcctcactt gaagagacgg aagttctgtt tgtattcatt gggtacgatc gcaaggcccg 4020 tacgcacaat ccttacaagc tttcatcaac cttgaccaac atttatacag gttccagact 4080 ccacgaagcc ggatgtgcac cctcatatca tgtggtgcga ggggatattg ccacggccac 4140 cgaaggagtg attataaatg ctgctaacag caaaggacaa cctggcggag gggtgtgcgg 4200 agcgctgtat aagaaattcc cggaaagctt cgatttacag ccgatcgaag taggaaaagc 4260 gcgactggtc aaaggtgcag ctaaacatat cattcatgcc gtaggaccaa acttcaacaa 4320 agtttcggag gttgaaggtg acaaacagtt ggcagaggct tatgagtcca tcgctaagat 4380 tgtcaacgat aacaattaca agtcagtagc gattccactg ttgtccaccg gcatcttttc 4440 cgggaacaaa gatcgactaa cccaatcatt gaaccatttg ctgacagctt tagacaccac 4500 tgatgcagat gtagccatat actgcaggga caagaaatgg gaaatgactc tcaaggaagc 4560 agtggctagg agagaagcag tggaggagat atgcatatcc gacgactctt cagtgacaga 4620 acctgatgca gagctggtga gggtgcatcc gaagagttct ttggctggaa ggaagggcta 4680 cagcacaagc gatggcaaaa ctttctcata tttggaaggg accaagtttc accaggcggc 4740 caaggatata gcagaaatta atgccatgtg gcccgttgca acggaggcca atgagcaggt 4800 atgcatgtat atcctcggag aaagcatgag cagtattagg tcgaaatgcc ccgtcgaaga 4860 gtcggaagcc tcctcaccac ctagcacgct gccttgcttg tgcatccatg ccatgactcc 4920 agaaagagta cagcgcctaa aagcctcacg tccagaacaa attactgtgt gctcatcctt 4980 tccattgccg aagtatagaa tcactggtgt gcagaagatc caatgctccc agcctatatt 5040 gttctcaccg aaagtgcctg cgtatattca tccaaggaag tatctcgtgg aaacaccacc 5100 ggtagacgag actccggagc catcggcaga gaaccaatcc acagagggga cacctgaaca 5160 accaccactt ataaccgagg atgagaccag gactagaacg cctgagccga tcatcatcga 5220 agaggaagaa gaggatagca taagtttgct gtcagatggc ccgacccacc aggtgctgca 5280 agtcgaggca gacattcacg ggccgccctc tgtatctagc tcatcctggt ccattcctca 5340 tgcatccgac tttgatgtgg acagtttatc catacttgac accctggagg gagctagcgt 5400 gaccagcggg gcaacgtcag ccgagactaa ctcttacttc gcaaagagta tggagtttct 5460 ggcgcgaccg gtgcctgcgc ctcgaacagt attcaggaac cctccacatc ccgctccgcg 5520 cacaagaaca ccgtcacttg cacccagcag ggcctgctcg agagggatca cgggagaaac 5580 cgtgggatac gcggttacac acaatagcga gggcttcttg ctatgcaaag ttactgacac 5640 agtaaaagga gaacgggtat cgttccctgt gtgcacgtac atcccggcca ccataaactc 5700 gagaaccagc ctggtctcca acccgccagg cgtaaatagg gtgattacaa gagaggagtt 5760 tgaggcgttc gtagcacaac aacaatgacg gtttgatgcg ggtgcataca tcttttcctc 5820 cgacaccggt caagggcatt tacaacaaaa atcagtaagg caaacggtgc tatccgaagt 5880 ggtgttggag aggaccgaat tggagatttc gtatgccccg cgcctcgacc aagaaaaaga 5940 agaattacta cgcaagaaat tacagttaaa tcccacacct gctaacagaa gcagatacca 6000 gtccaggaag gtggagaaca tgaaagccat aacagctaga cgtattctgc aaggcctagg 6060 gcattatttg aaggcagaag gaaaagtgga gtgctaccga accctgcatc ctgttccttt 6120 gtattcatct agtgtgaacc gtgccttttc aagccccaag gtcgcagtgg aagcctgtaa 6180 cgccatgttg aaagagaact ttccgactgt ggcttcttac tgtattattc cagagtacga 6240 tgcctatttg gacatggttg acggagcttc atgctgctta gacactgcca gtttttgccc 6300 tgcaaagctg cgcagctttc caaagaaaca ctcctatttg gaacccacaa tacgatcggc 6360 agtgccttca gcgatccaga acacgctcca gaacgtcctg gcagctgcca caaaaagaaa 6420 ttgcaatgtc acgcaaatga gagaattgcc cgtattggat tcggcggcct ttaatgtgga 6480 atgcttcaag aaatatgcgt gtaataatga atattgggaa acgtttaaag aaaaccccat 6540 caggcttact gaagaaaacg tggtaaatta cattaccaaa ttaaaaggac caaaagctgc 6600 tgctcttttt gcgaagacac ataatttgaa tatgttgcag gacataccaa tggacaggtt 6660 tgtaatggac ttaaagagag acgtgaaagt gactccagga acaaaacata ctgaagaacg 6720 gcccaaggta caggtgatcc aggctgccga tccgctagca acagcgtatc tgtgcggaat 6780 ccaccgagag ctggttagga gattaaatgc ggtcctgctt ccgaacattc atacactgtt 6840 tgatatgtcg gctgaagact ttgacgctat tatagccgag cacttccagc ctggggattg 6900 tgttctggaa actgacatcg cgtcgtttga taaaagtgag gacgacgcca tggctctgac 6960 cgcgttaatg attctggaag acttaggtgt ggacgcagag ctgttgacgc tgattgaggc 7020 ggctttcggc gaaatttcat caatacattt gcccactaaa actaaattta aattcggagc 7080 catgatgaaa tctggaatgt tcctcacact gtttgtgaac acagtcatta acattgtaat 7140 cgcaagcaga gtgttgagag aacggctaac cggatcacca tgtgcagcat tcattggaga 7200 tgacaatatc gtgaaaggag tcaaatcgga caaattaatg gcagacaggt gcgccacctg 7260 gttgaatatg gaagtcaaga ttatagatgc tgtggtgggc gagaaagcgc cttatttctg 7320 tggagggttt attttgtgtg actccgtgac cggcacagcg tgccgtgtgg cagaccccct 7380 aaaaaggctg tttaagcttg gcaaacctct ggcagcagac gatgaacatg atgatgacag 7440 gagaagggca ttgcatgaag agtcaacacg ctggaaccga gtgggtattc tttcagagct 7500 gtgcaaggca gtagaatcaa ggtatgaaac cgtaggaact tccatcatag ttatggccat 7560 gactactcta gctagcagtg ttaaatcatt cagctacctg agaggggccc ctataactct 7620 ctacggctaa cctgaatgga ctacgacata gtctagtcga cgccaccatg aggcctggcc 7680 tgccctccta cctgatcatc ctggccgtgt gcctgttcag ccacctgctg tccagcagat 7740 acggcgccga ggccgtgagc gagcccctgg acaaggcttt ccacctgctg ctgaacacct 7800 acggcagacc catccggttt ctgcgggaga acaccaccca gtgcacctac aacagcagcc 7860 tgcggaacag caccgtcgtg agagagaacg ccatcagctt caactttttc cagagctaca 7920 accagtacta cgtgttccac atgcccagat gcctgtttgc cggccctctg gccgagcagt 7980 tcctgaacca ggtggacctg accgagacac tggaaagata ccagcagcgg ctgaatacct 8040 acgccctggt gtccaaggac ctggccagct accggtcctt tagccagcag ctcaaggctc 8100 aggatagcct cggcgagcag cctaccaccg tgccccctcc catcgacctg agcatccccc 8160 acgtgtggat gcctccccag accacccctc acggctggac cgagagccac accacctccg 8220 gcctgcacag accccacttc aaccagacct gcatcctgtt cgacggccac gacctgctgt 8280 ttagcaccgt gaccccctgc ctgcaccagg gcttctacct gatcgacgag ctgagatacg 8340 tgaagatcac cctgaccgag gatttcttcg tggtcaccgt gtccatcgac gacgacaccc 8400 ccatgctgct gatcttcggc cacctgccca gagtgctgtt caaggccccc taccagcggg 8460 acaacttcat cctgcggcag accgagaagc acgagctgct ggtgctggtc aagaaggacc 8520 agctgaaccg gcactcctac ctgaaggacc ccgacttcct ggacgccgcc ctggacttca 8580 actacctgga cctgagcgcc ctgctgagaa acagcttcca cagatacgcc gtggacgtgc 8640 tgaagtccgg acggtgccag atgctcgatc ggcggaccgt ggagatggcc ttcgcctatg 8700 ccctcgccct gttcgccgct gccagacagg aagaggctgg cgcccaggtg tcagtgccca 8760 gagccctgga tagacaggcc gccctgctgc agatccagga attcatgatc acctgcctga 8820 gccagacccc ccctagaacc accctgctgc tgtaccccac agccgtggat ctggccaaga 8880 gggccctgtg gacccccaac cagatcaccg acatcacaag cctcgtgcgg ctcgtgtaca 8940 tcctgagcaa gcagaaccag cagcacctga tcccccagtg ggccctgaga cagatcgccg 9000 acttcgccct gaagctgcac aagacccatc tggccagctt tctgagcgcc ttcgccaggc 9060 aggaactgta cctgatgggc agcctggtcc acagcatgct ggtgcatacc accgagcggc 9120 gggagatctt catcgtggag acaggcctgt gtagcctggc cgagctgtcc cactttaccc 9180 agctgctggc ccaccctcac cacgagtacc tgagcgacct gtacaccccc tgcagcagca 9240 gcggcagacg ggaccacagc ctggaacggc tgaccagact gttccccgat gccaccgtgc 9300 ctgctacagt gcctgccgcc ctgtccatcc tgtccaccat gcagcccagc accctggaaa 9360 ccttccccga cctgttctgc ctgcccctgg gcgagagctt tagcgccctg accgtgtccg 9420 agcacgtgtc ctacatcgtg accaatcagt acctgatcaa gggcatcagc taccccgtgt 9480 ccaccacagt cgtgggccag agcctgatca tcacccagac cgacagccag accaagtgcg 9540 agctgacccg gaacatgcac accacacaca gcatcaccgt ggccctgaac atcagcctgg 9600 aaaactgcgc tttctgtcag tctgccctgc tggaatacga cgatacccag ggcgtgatca 9660 acatcatgta catgcacgac agcgacgacg tgctgttcgc cctggacccc tacaacgagg 9720 tggtggtgtc cagcccccgg acccactacc tgatgctgct gaagaacggc accgtgctgg 9780 aagtgaccga cgtggtggtg gacgccaccg actgataatc tagacggcgc gcccacccag 9840 cggccgccta taactctcta cggctaacct gaatggacta cgacatagtc tagtcgacgc 9900 caccatgtgc agaaggcccg actgcggctt cagcttcagc cctggacccg tgatcctgct 9960 gtggtgctgc ctgctgctgc ctatcgtgtc ctctgccgcc gtgtctgtgg cccctacagc 10020 cgccgagaag gtgccagccg agtgccccga gctgaccaga agatgcctgc tgggcgaggt 10080 gttcgagggc gacaagtacg agagctggct gcggcccctg gtcaacgtga ccggcagaga 10140 tggccccctg agccagctga tccggtacag acccgtgacc cccgaggccg ccaatagcgt 10200 gctgctggac gaggccttcc tggataccct ggccctgctg tacaacaacc ccgaccagct 10260 gagagccctg ctgaccctgc tgtccagcga caccgccccc agatggatga ccgtgatgcg 10320 gggctacagc gagtgtggag atggcagccc tgccgtgtac acctgcgtgg acgacctgtg 10380 cagaggctac gacctgacca gactgagcta cggccggtcc atcttcacag agcacgtgct 10440 gggcttcgag ctggtgcccc ccagcctgtt caacgtggtg gtggccatcc ggaacgaggc 10500 caccagaacc aacagagccg tgcggctgcc tgtgtctaca gccgctgcac ctgagggcat 10560 cacactgttc tacggcctgt acaacgccgt gaaagagttc tgcctccggc accagctgga 10620 tccccccctg ctgagacacc tggacaagta ctacgccggc ctgcccccag agctgaagca 10680 gaccagagtg aacctgcccg cccacagcag atatggccct caggccgtgg acgccagatg 10740 ataatctaga cggcgcgccc acccaatcga tgtacttccg aggaactcac gtgcataatg 10800 catcaggctg gtacattaga tccccgctta ccgcgggcaa tatagcaaca ctaaaaactc 10860 gatgtacttc cgaggaagcg cagtgcataa tgctgcgcag tgttgccaca taaccactat 10920 attaaccatt tatctagcgg acgccaaaaa ctcaatgtat ttctgaggaa gcgtggtgca 10980 taatgccacg cagcgtctgc ataactttta ttatttcttt tattaatcaa caaaattttg 11040 tttttaacat ttcaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaagggtcgg 11100 catggcatct ccacctcctc gcggtccgac ctgggcatcc gaaggaggac gcacgtccac 11160 tcggatggct aagggagagc cacgagctcc tgtttaaacc agctccaatt cgccctatag 11220 tgagtcgtat tacgcgcgct cactggccgt cgttttacaa cgtcgtgact gggaaaaccc 11280 tggcgttacc caacttaatc gccttgcagc acatccccct ttcgccagct ggcgtaatag 11340 cgaagaggcc cgcaccgatc gcccttccca acagttgcgc agcctgaatg gcgaatggga 11400 cgcgccctgt agcggcgcat taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc 11460 tacacttgcc agcgccctag cgcccgctcc tttcgctttc ttcccttcct ttctcgccac 11520 gttcgccggc tttccccgtc aagctctaaa tcgggggctc cctttagggt tccgatttag 11580 tgctttacgg cacctcgacc ccaaaaaact tgattagggt gatggttcac gtagtgggcc 11640 atcgccctga tagacggttt ttcgcccttt gacgttggag tccacgttct ttaatagtgg 11700 actcttgttc caaactggaa caacactcaa ccctatctcg gtctattctt ttgatttata 11760 agggattttg ccgatttcgg cctattggtt aaaaaatgag ctgatttaac aaaaatttaa 11820 cgcgaatttt aacaaaatat taacgcttac aatttaggtg gcacttttcg gggaaatgtg 11880 cgcggaaccc ctatttgttt atttttctaa atacattcaa atatgtatcc gctcatgaga 11940 caataaccct gataaatgct tcaataatat tgaaaaagga agagtatgag tattcaacat 12000 ttccgtgtcg cccttattcc cttttttgcg gcattttgcc ttcctgtttt tgctcaccca 12060 gaaacgctgg tgaaagtaaa agatgctgaa gatcagttgg gtgcacgagt gggttacatc 12120 gaactggatc tcaacagcgg taagatcctt gagagttttc gccccgaaga acgttttcca 12180 atgatgagca cttttaaagt tctgctatgt ggcgcggtat tatcccgtat tgacgccggg 12240 caagagcaac tcggtcgccg catacactat tctcagaatg acttggttga gtactcacca 12300 gtcacagaaa agcatcttac ggatggcatg acagtaagag aattatgcag tgctgccata 12360 accatgagtg ataacactgc ggccaactta cttctgacaa cgatcggagg accgaaggag 12420 ctaaccgctt ttttgcacaa catgggggat catgtaactc gccttgatcg ttgggaaccg 12480 gagctgaatg aagccatacc aaacgacgag cgtgacacca cgatgcctgt agcaatggca 12540 acaacgttgc gcaaactatt aactggcgaa ctacttactc tagcttcccg gcaacaatta 12600 atagactgga tggaggcgga taaagttgca ggaccacttc tgcgctcggc ccttccggct 12660 ggctggttta ttgctgataa atctggagcc ggtgagcgtg ggtctcgcgg tatcattgca 12720 gcactggggc cagatggtaa gccctcccgt atcgtagtta tctacacgac ggggagtcag 12780 gcaactatgg atgaacgaaa tagacagatc gctgagatag gtgcctcact gattaagcat 12840 tggtaactgt cagaccaagt ttactcatat atactttaga ttgatttaaa acttcatttt 12900 taatttaaaa ggatctaggt gaagatcctt tttgataatc tcatgaccaa aatcccttaa 12960 cgtgagtttt cgttccactg agcgtcagac cccgtagaaa agatcaaagg atcttcttga 13020 gatccttttt ttctgcgcgt aatctgctgc ttgcaaacaa aaaaaccacc gctaccagcg 13080 gtggtttgtt tgccggatca agagctacca actctttttc cgaaggtaac tggcttcagc 13140 agagcgcaga taccaaatac tgttcttcta gtgtagccgt agttaggcca ccacttcaag 13200 aactctgtag caccgcctac atacctcgct ctgctaatcc tgttaccagt ggctgctgcc 13260 agtggcgata agtcgtgtct taccgggttg gactcaagac gatagttacc ggataaggcg 13320 cagcggtcgg gctgaacggg gggttcgtgc acacagccca gcttggagcg aacgacctac 13380 accgaactga gatacctaca gcgtgagcta tgagaaagcg ccacgcttcc cgaagggaga 13440 aaggcggaca ggtatccggt aagcggcagg gtcggaacag gagagcgcac gagggagctt 13500 ccagggggaa acgcctggta tctttatagt cctgtcgggt ttcgccacct ctgacttgag 13560 cgtcgatttt tgtgatgctc gtcagggggg cggagcctat ggaaaaacgc cagcaacgcg 13620 gcctttttac ggttcctggc cttttgctgg ccttttgctc acatgttctt tcctgcgtta 13680 tcccctgatt ctgtggataa ccgtattacc gcctttgagt gagctgatac cgctcgccgc 13740 agccgaacga ccgagcgcag cgagtcagtg agcgaggaag cggaagagcg cccaatacgc 13800 aaaccgcctc tccccgcgcg ttggccgatt cattaatgca gctggcacga caggtttccc 13860 gactggaaag cgggcagtga gcgcaacgca attaatgtga gttagctcac tcattaggca 13920 ccccaggctt tacactttat gctcccggct cgtatgttgt gtggaattgt gagcggataa 13980 caatttcaca caggaaacag ctatgaccat gattacgcca agcgcgcaat taaccctcac 14040 taaagggaac aaaagctggg taccggcgcc a 14071 <210> 53 <211> 14152 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 53 cgcgtcggct acaattaata cataacctta tgtatcatac acatacgatt taggtgacac 60 tatagatggg cggcgcatga gagaagccca gaccaattac ctacccaaaa tggagaaagt 120 tcacgttgac atcgaggaag acagcccatt cctcagagct ttgcagcgga gcttcccgca 180 gtttgaggta gaagccaagc aggtcactga taatgaccat gctaatgcca gagcgttttc 240 gcatctggct tcaaaactga tcgaaacgga ggtggaccca tccgacacga tccttgacat 300 tggaagtgcg cccgcccgca gaatgtattc taagcacaag tatcattgta tctgtccgat 360 gagatgtgcg gaagatccgg acagattgta taagtatgca actaagctga agaaaaactg 420 taaggaaata actgataagg aattggacaa gaaaatgaag gagctcgccg ccgtcatgag 480 cgaccctgac ctggaaactg agactatgtg cctccacgac gacgagtcgt gtcgctacga 540 agggcaagtc gctgtttacc aggatgtata cgcggttgac ggaccgacaa gtctctatca 600 ccaagccaat aagggagtta gagtcgccta ctggataggc tttgacacca ccccttttat 660 gtttaagaac ttggctggag catatccatc atactctacc aactgggccg acgaaaccgt 720 gttaacggct cgtaacatag gcctatgcag ctctgacgtt atggagcggt cacgtagagg 780 gatgtccatt cttagaaaga agtatttgaa accatccaac aatgttctat tctctgttgg 840 ctcgaccatc taccacgaga agagggactt actgaggagc tggcacctgc cgtctgtatt 900 tcacttacgt ggcaagcaaa attacacatg tcggtgtgag actatagtta gttgcgacgg 960 gtacgtcgtt aaaagaatag ctatcagtcc aggcctgtat gggaagcctt caggctatgc 1020 tgctacgatg caccgcgagg gattcttgtg ctgcaaagtg acagacacat tgaacgggga 1080 gagggtctct tttcccgtgt gcacgtatgt gccagctaca ttgtgtgacc aaatgactgg 1140 catactggca acagatgtca gtgcggacga cgcgcaaaaa ctgctggttg ggctcaacca 1200 gcgtatagtc gtcaacggtc gcacccagag aaacaccaat accatgaaaa attacctttt 1260 gcccgtagtg gcccaggcat ttgctaggtg ggcaaaggaa tataaggaag atcaagaaga 1320 tgaaaggcca ctaggactac gagatagaca gttagtcatg gggtgttgtt gggcttttag 1380 aaggcacaag ataacatcta tttataagcg cccggatacc caaaccatca tcaaagtgaa 1440 cagcgatttc cactcattcg tgctgcccag gataggcagt aacacattgg agatcgggct 1500 gagaacaaga atcaggaaaa tgttagagga gcacaaggag ccgtcacctc tcattaccgc 1560 cgaggacgta caagaagcta agtgcgcagc cgatgaggct aaggaggtgc gtgaagccga 1620 ggagttgcgc gcagctctac cacctttggc agctgatgtt gaggagccca ctctggaagc 1680 cgatgtagac ttgatgttac aagaggctgg ggccggctca gtggagacac ctcgtggctt 1740 gataaaggtt accagctacg ctggcgagga caagatcggc tcttacgctg tgctttctcc 1800 gcaggctgta ctcaagagtg aaaaattatc ttgcatccac cctctcgctg aacaagtcat 1860 agtgataaca cactctggcc gaaaagggcg ttatgccgtg gaaccatacc atggtaaagt 1920 agtggtgcca gagggacatg caatacccgt ccaggacttt caagctctga gtgaaagtgc 1980 caccattgtg tacaacgaac gtgagttcgt aaacaggtac ctgcaccata ttgccacaca 2040 tggaggagcg ctgaacactg atgaagaata ttacaaaact gtcaagccca gcgagcacga 2100 cggcgaatac ctgtacgaca tcgacaggaa acagtgcgtc aagaaagaac tagtcactgg 2160 gctagggctc acaggcgagc tggtggatcc tcccttccat gaattcgcct acgagagtct 2220 gagaacacga ccagccgctc cttaccaagt accaaccata ggggtgtatg gcgtgccagg 2280 atcaggcaag tctggcatca ttaaaagcgc agtcaccaaa aaagatctag tggtgagcgc 2340 caagaaagaa aactgtgcag aaattataag ggacgtcaag aaaatgaaag ggctggacgt 2400 caatgccaga actgtggact cagtgctctt gaatggatgc aaacaccccg tagagaccct 2460 gtatattgac gaagcttttg cttgtcatgc aggtactctc agagcgctca tagccattat 2520 aagacctaaa aaggcagtgc tctgcgggga tcccaaacag tgcggttttt ttaacatgat 2580 gtgcctgaaa gtgcatttta accacgagat ttgcacacaa gtcttccaca aaagcatctc 2640 tcgccgttgc actaaatctg tgacttcggt cgtctcaacc ttgttttacg acaaaaaaat 2700 gagaacgacg aatccgaaag agactaagat tgtgattgac actaccggca gtaccaaacc 2760 taagcaggac gatctcattc tcacttgttt cagagggtgg gtgaagcagt tgcaaataga 2820 ttacaaaggc aacgaaataa tgacggcagc tgcctctcaa gggctgaccc gtaaaggtgt 2880 gtatgccgtt cggtacaagg tgaatgaaaa tcctctgtac gcacccacct cagaacatgt 2940 gaacgtccta ctgacccgca cggaggaccg catcgtgtgg aaaacactag ccggcgaccc 3000 atggataaaa acactgactg ccaagtaccc tgggaatttc actgccacga tagaggagtg 3060 gcaagcagag catgatgcca tcatgaggca catcttggag agaccggacc ctaccgacgt 3120 cttccagaat aaggcaaacg tgtgttgggc caaggcttta gtgccggtgc tgaagaccgc 3180 tggcatagac atgaccactg aacaatggaa cactgtggat tattttgaaa cggacaaagc 3240 tcactcagca gagatagtat tgaaccaact atgcgtgagg ttctttggac tcgatctgga 3300 ctccggtcta ttttctgcac ccactgttcc gttatccatt aggaataatc actgggataa 3360 ctccccgtcg cctaacatgt acgggctgaa taaagaagtg gtccgtcagc tctctcgcag 3420 gtacccacaa ctgcctcggg cagttgccac tggaagagtc tatgacatga acactggtac 3480 actgcgcaat tatgatccgc gcataaacct agtacctgta aacagaagac tgcctcatgc 3540 tttagtcctc caccataatg aacacccaca gagtgacttt tcttcattcg tcagcaaatt 3600 gaagggcaga actgtcctgg tggtcgggga aaagttgtcc gtcccaggca aaatggttga 3660 ctggttgtca gaccggcctg aggctacctt cagagctcgg ctggatttag gcatcccagg 3720 tgatgtgccc aaatatgaca taatatttgt taatgtgagg accccatata aataccatca 3780 ctatcagcag tgtgaagacc atgccattaa gcttagcatg ttgaccaaga aagcttgtct 3840 gcatctgaat cccggcggaa cctgtgtcag cataggttat ggttacgctg acagggccag 3900 cgaaagcatc attggtgcta tagcgcggca gttcaagttt tcccgggtat gcaaaccgaa 3960 atcctcactt gaagagacgg aagttctgtt tgtattcatt gggtacgatc gcaaggcccg 4020 tacgcacaat ccttacaagc tttcatcaac cttgaccaac atttatacag gttccagact 4080 ccacgaagcc ggatgtgcac cctcatatca tgtggtgcga ggggatattg ccacggccac 4140 cgaaggagtg attataaatg ctgctaacag caaaggacaa cctggcggag gggtgtgcgg 4200 agcgctgtat aagaaattcc cggaaagctt cgatttacag ccgatcgaag taggaaaagc 4260 gcgactggtc aaaggtgcag ctaaacatat cattcatgcc gtaggaccaa acttcaacaa 4320 agtttcggag gttgaaggtg acaaacagtt ggcagaggct tatgagtcca tcgctaagat 4380 tgtcaacgat aacaattaca agtcagtagc gattccactg ttgtccaccg gcatcttttc 4440 cgggaacaaa gatcgactaa cccaatcatt gaaccatttg ctgacagctt tagacaccac 4500 tgatgcagat gtagccatat actgcaggga caagaaatgg gaaatgactc tcaaggaagc 4560 agtggctagg agagaagcag tggaggagat atgcatatcc gacgactctt cagtgacaga 4620 acctgatgca gagctggtga gggtgcatcc gaagagttct ttggctggaa ggaagggcta 4680 cagcacaagc gatggcaaaa ctttctcata tttggaaggg accaagtttc accaggcggc 4740 caaggatata gcagaaatta atgccatgtg gcccgttgca acggaggcca atgagcaggt 4800 atgcatgtat atcctcggag aaagcatgag cagtattagg tcgaaatgcc ccgtcgaaga 4860 gtcggaagcc tcctcaccac ctagcacgct gccttgcttg tgcatccatg ccatgactcc 4920 agaaagagta cagcgcctaa aagcctcacg tccagaacaa attactgtgt gctcatcctt 4980 tccattgccg aagtatagaa tcactggtgt gcagaagatc caatgctccc agcctatatt 5040 gttctcaccg aaagtgcctg cgtatattca tccaaggaag tatctcgtgg aaacaccacc 5100 ggtagacgag actccggagc catcggcaga gaaccaatcc acagagggga cacctgaaca 5160 accaccactt ataaccgagg atgagaccag gactagaacg cctgagccga tcatcatcga 5220 agaggaagaa gaggatagca taagtttgct gtcagatggc ccgacccacc aggtgctgca 5280 agtcgaggca gacattcacg ggccgccctc tgtatctagc tcatcctggt ccattcctca 5340 tgcatccgac tttgatgtgg acagtttatc catacttgac accctggagg gagctagcgt 5400 gaccagcggg gcaacgtcag ccgagactaa ctcttacttc gcaaagagta tggagtttct 5460 ggcgcgaccg gtgcctgcgc ctcgaacagt attcaggaac cctccacatc ccgctccgcg 5520 cacaagaaca ccgtcacttg cacccagcag ggcctgctcg agagggatca cgggagaaac 5580 cgtgggatac gcggttacac acaatagcga gggcttcttg ctatgcaaag ttactgacac 5640 agtaaaagga gaacgggtat cgttccctgt gtgcacgtac atcccggcca ccataaactc 5700 gagaaccagc ctggtctcca acccgccagg cgtaaatagg gtgattacaa gagaggagtt 5760 tgaggcgttc gtagcacaac aacaatgacg gtttgatgcg ggtgcataca tcttttcctc 5820 cgacaccggt caagggcatt tacaacaaaa atcagtaagg caaacggtgc tatccgaagt 5880 ggtgttggag aggaccgaat tggagatttc gtatgccccg cgcctcgacc aagaaaaaga 5940 agaattacta cgcaagaaat tacagttaaa tcccacacct gctaacagaa gcagatacca 6000 gtccaggaag gtggagaaca tgaaagccat aacagctaga cgtattctgc aaggcctagg 6060 gcattatttg aaggcagaag gaaaagtgga gtgctaccga accctgcatc ctgttccttt 6120 gtattcatct agtgtgaacc gtgccttttc aagccccaag gtcgcagtgg aagcctgtaa 6180 cgccatgttg aaagagaact ttccgactgt ggcttcttac tgtattattc cagagtacga 6240 tgcctatttg gacatggttg acggagcttc atgctgctta gacactgcca gtttttgccc 6300 tgcaaagctg cgcagctttc caaagaaaca ctcctatttg gaacccacaa tacgatcggc 6360 agtgccttca gcgatccaga acacgctcca gaacgtcctg gcagctgcca caaaaagaaa 6420 ttgcaatgtc acgcaaatga gagaattgcc cgtattggat tcggcggcct ttaatgtgga 6480 atgcttcaag aaatatgcgt gtaataatga atattgggaa acgtttaaag aaaaccccat 6540 caggcttact gaagaaaacg tggtaaatta cattaccaaa ttaaaaggac caaaagctgc 6600 tgctcttttt gcgaagacac ataatttgaa tatgttgcag gacataccaa tggacaggtt 6660 tgtaatggac ttaaagagag acgtgaaagt gactccagga acaaaacata ctgaagaacg 6720 gcccaaggta caggtgatcc aggctgccga tccgctagca acagcgtatc tgtgcggaat 6780 ccaccgagag ctggttagga gattaaatgc ggtcctgctt ccgaacattc atacactgtt 6840 tgatatgtcg gctgaagact ttgacgctat tatagccgag cacttccagc ctggggattg 6900 tgttctggaa actgacatcg cgtcgtttga taaaagtgag gacgacgcca tggctctgac 6960 cgcgttaatg attctggaag acttaggtgt ggacgcagag ctgttgacgc tgattgaggc 7020 ggctttcggc gaaatttcat caatacattt gcccactaaa actaaattta aattcggagc 7080 catgatgaaa tctggaatgt tcctcacact gtttgtgaac acagtcatta acattgtaat 7140 cgcaagcaga gtgttgagag aacggctaac cggatcacca tgtgcagcat tcattggaga 7200 tgacaatatc gtgaaaggag tcaaatcgga caaattaatg gcagacaggt gcgccacctg 7260 gttgaatatg gaagtcaaga ttatagatgc tgtggtgggc gagaaagcgc cttatttctg 7320 tggagggttt attttgtgtg actccgtgac cggcacagcg tgccgtgtgg cagaccccct 7380 aaaaaggctg tttaagcttg gcaaacctct ggcagcagac gatgaacatg atgatgacag 7440 gagaagggca ttgcatgaag agtcaacacg ctggaaccga gtgggtattc tttcagagct 7500 gtgcaaggca gtagaatcaa ggtatgaaac cgtaggaact tccatcatag ttatggccat 7560 gactactcta gctagcagtg ttaaatcatt cagctacctg agaggggccc ctataactct 7620 ctacggctaa cctgaatgga ctacgacata gtctagtcga cgccaccatg aggcctggcc 7680 tgccctccta cctgatcatc ctggccgtgt gcctgttcag ccacctgctg tccagcagat 7740 acggcgccga ggccgtgagc gagcccctgg acaaggcttt ccacctgctg ctgaacacct 7800 acggcagacc catccggttt ctgcgggaga acaccaccca gtgcacctac aacagcagcc 7860 tgcggaacag caccgtcgtg agagagaacg ccatcagctt caactttttc cagagctaca 7920 accagtacta cgtgttccac atgcccagat gcctgtttgc cggccctctg gccgagcagt 7980 tcctgaacca ggtggacctg accgagacac tggaaagata ccagcagcgg ctgaatacct 8040 acgccctggt gtccaaggac ctggccagct accggtcctt tagccagcag ctcaaggctc 8100 aggatagcct cggcgagcag cctaccaccg tgccccctcc catcgacctg agcatccccc 8160 acgtgtggat gcctccccag accacccctc acggctggac cgagagccac accacctccg 8220 gcctgcacag accccacttc aaccagacct gcatcctgtt cgacggccac gacctgctgt 8280 ttagcaccgt gaccccctgc ctgcaccagg gcttctacct gatcgacgag ctgagatacg 8340 tgaagatcac cctgaccgag gatttcttcg tggtcaccgt gtccatcgac gacgacaccc 8400 ccatgctgct gatcttcggc cacctgccca gagtgctgtt caaggccccc taccagcggg 8460 acaacttcat cctgcggcag accgagaagc acgagctgct ggtgctggtc aagaaggacc 8520 agctgaaccg gcactcctac ctgaaggacc ccgacttcct ggacgccgcc ctggacttca 8580 actacctgga cctgagcgcc ctgctgagaa acagcttcca cagatacgcc gtggacgtgc 8640 tgaagtccgg acggtgccag atgctcgatc ggcggaccgt ggagatggcc ttcgcctatg 8700 ccctcgccct gttcgccgct gccagacagg aagaggctgg cgcccaggtg tcagtgccca 8760 gagccctgga tagacaggcc gccctgctgc agatccagga attcatgatc acctgcctga 8820 gccagacccc ccctagaacc accctgctgc tgtaccccac agccgtggat ctggccaaga 8880 gggccctgtg gacccccaac cagatcaccg acatcacaag cctcgtgcgg ctcgtgtaca 8940 tcctgagcaa gcagaaccag cagcacctga tcccccagtg ggccctgaga cagatcgccg 9000 acttcgccct gaagctgcac aagacccatc tggccagctt tctgagcgcc ttcgccaggc 9060 aggaactgta cctgatgggc agcctggtcc acagcatgct ggtgcatacc accgagcggc 9120 gggagatctt catcgtggag acaggcctgt gtagcctggc cgagctgtcc cactttaccc 9180 agctgctggc ccaccctcac cacgagtacc tgagcgacct gtacaccccc tgcagcagca 9240 gcggcagacg ggaccacagc ctggaacggc tgaccagact gttccccgat gccaccgtgc 9300 ctgctacagt gcctgccgcc ctgtccatcc tgtccaccat gcagcccagc accctggaaa 9360 ccttccccga cctgttctgc ctgcccctgg gcgagagctt tagcgccctg accgtgtccg 9420 agcacgtgtc ctacatcgtg accaatcagt acctgatcaa gggcatcagc taccccgtgt 9480 ccaccacagt cgtgggccag agcctgatca tcacccagac cgacagccag accaagtgcg 9540 agctgacccg gaacatgcac accacacaca gcatcaccgt ggccctgaac atcagcctgg 9600 aaaactgcgc tttctgtcag tctgccctgc tggaatacga cgatacccag ggcgtgatca 9660 acatcatgta catgcacgac agcgacgacg tgctgttcgc cctggacccc tacaacgagg 9720 tggtggtgtc cagcccccgg acccactacc tgatgctgct gaagaacggc accgtgctgg 9780 aagtgaccga cgtggtggtg gacgccaccg acagcagact gctgatgatg agcgtgtacg 9840 ccctgagcgc catcatcggc atctacctgc tgtaccggat gctgaaaacc tgctgataat 9900 ctagacggcg cgcccaccca gcggccgcct ataactctct acggctaacc tgaatggact 9960 acgacatagt ctagtcgacg ccaccatgtg cagaaggccc gactgcggct tcagcttcag 10020 ccctggaccc gtgatcctgc tgtggtgctg cctgctgctg cctatcgtgt cctctgccgc 10080 cgtgtctgtg gcccctacag ccgccgagaa ggtgccagcc gagtgccccg agctgaccag 10140 aagatgcctg ctgggcgagg tgttcgaggg cgacaagtac gagagctggc tgcggcccct 10200 ggtcaacgtg accggcagag atggccccct gagccagctg atccggtaca gacccgtgac 10260 ccccgaggcc gccaatagcg tgctgctgga cgaggccttc ctggataccc tggccctgct 10320 gtacaacaac cccgaccagc tgagagccct gctgaccctg ctgtccagcg acaccgcccc 10380 cagatggatg accgtgatgc ggggctacag cgagtgtgga gatggcagcc ctgccgtgta 10440 cacctgcgtg gacgacctgt gcagaggcta cgacctgacc agactgagct acggccggtc 10500 catcttcaca gagcacgtgc tgggcttcga gctggtgccc cccagcctgt tcaacgtggt 10560 ggtggccatc cggaacgagg ccaccagaac caacagagcc gtgcggctgc ctgtgtctac 10620 agccgctgca cctgagggca tcacactgtt ctacggcctg tacaacgccg tgaaagagtt 10680 ctgcctccgg caccagctgg atccccccct gctgagacac ctggacaagt actacgccgg 10740 cctgccccca gagctgaagc agaccagagt gaacctgccc gcccacagca gatatggccc 10800 tcaggccgtg gacgccagat gataatctag acggcgcgcc cacccaatcg atgtacttcc 10860 gaggaactca cgtgcataat gcatcaggct ggtacattag atccccgctt accgcgggca 10920 atatagcaac actaaaaact cgatgtactt ccgaggaagc gcagtgcata atgctgcgca 10980 gtgttgccac ataaccacta tattaaccat ttatctagcg gacgccaaaa actcaatgta 11040 tttctgagga agcgtggtgc ataatgccac gcagcgtctg cataactttt attatttctt 11100 ttattaatca acaaaatttt gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa 11160 aaaaaaaaaa aaaagggtcg gcatggcatc tccacctcct cgcggtccga cctgggcatc 11220 cgaaggagga cgcacgtcca ctcggatggc taagggagag ccacgagctc ctgtttaaac 11280 cagctccaat tcgccctata gtgagtcgta ttacgcgcgc tcactggccg tcgttttaca 11340 acgtcgtgac tgggaaaacc ctggcgttac ccaacttaat cgccttgcag cacatccccc 11400 tttcgccagc tggcgtaata gcgaagaggc ccgcaccgat cgcccttccc aacagttgcg 11460 cagcctgaat ggcgaatggg acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt 11520 ggttacgcgc agcgtgaccg ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt 11580 cttcccttcc tttctcgcca cgttcgccgg ctttccccgt caagctctaa atcgggggct 11640 ccctttaggg ttccgattta gtgctttacg gcacctcgac cccaaaaaac ttgattaggg 11700 tgatggttca cgtagtgggc catcgccctg atagacggtt tttcgccctt tgacgttgga 11760 gtccacgttc tttaatagtg gactcttgtt ccaaactgga acaacactca accctatctc 11820 ggtctattct tttgatttat aagggatttt gccgatttcg gcctattggt taaaaaatga 11880 gctgatttaa caaaaattta acgcgaattt taacaaaata ttaacgctta caatttaggt 11940 ggcacttttc ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca 12000 aatatgtatc cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg 12060 aagagtatga gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc 12120 cttcctgttt ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg 12180 ggtgcacgag tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt 12240 cgccccgaag aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta 12300 ttatcccgta ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat 12360 gacttggttg agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga 12420 gaattatgca gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca 12480 acgatcggag gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact 12540 cgccttgatc gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc 12600 acgatgcctg tagcaatggc aacaacgttg cgcaaactat taactggcga actacttact 12660 ctagcttccc ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt 12720 ctgcgctcgg cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt 12780 gggtctcgcg gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt 12840 atctacacga cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata 12900 ggtgcctcac tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag 12960 attgatttaa aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat 13020 ctcatgacca aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa 13080 aagatcaaag gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca 13140 aaaaaaccac cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt 13200 ccgaaggtaa ctggcttcag cagagcgcag ataccaaata ctgttcttct agtgtagccg 13260 tagttaggcc accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc 13320 ctgttaccag tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga 13380 cgatagttac cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc 13440 agcttggagc gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc 13500 gccacgcttc ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca 13560 ggagagcgca cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg 13620 tttcgccacc tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta 13680 tggaaaaacg ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct 13740 cacatgttct ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag 13800 tgagctgata ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa 13860 gcggaagagc gcccaatacg caaaccgcct ctccccgcgc gttggccgat tcattaatgc 13920 agctggcacg acaggtttcc cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg 13980 agttagctca ctcattaggc accccaggct ttacacttta tgctcccggc tcgtatgttg 14040 tgtggaattg tgagcggata acaatttcac acaggaaaca gctatgacca tgattacgcc 14100 aagcgcgcaa ttaaccctca ctaaagggaa caaaagctgg gtaccggcgc ca 14152 <210> 54 <211> 15512 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 54 cgcgtcggct acaattaata cataacctta tgtatcatac acatacgatt taggtgacac 60 tatagatggg cggcgcatga gagaagccca gaccaattac ctacccaaaa tggagaaagt 120 tcacgttgac atcgaggaag acagcccatt cctcagagct ttgcagcgga gcttcccgca 180 gtttgaggta gaagccaagc aggtcactga taatgaccat gctaatgcca gagcgttttc 240 gcatctggct tcaaaactga tcgaaacgga ggtggaccca tccgacacga tccttgacat 300 tggaagtgcg cccgcccgca gaatgtattc taagcacaag tatcattgta tctgtccgat 360 gagatgtgcg gaagatccgg acagattgta taagtatgca actaagctga agaaaaactg 420 taaggaaata actgataagg aattggacaa gaaaatgaag gagctcgccg ccgtcatgag 480 cgaccctgac ctggaaactg agactatgtg cctccacgac gacgagtcgt gtcgctacga 540 agggcaagtc gctgtttacc aggatgtata cgcggttgac ggaccgacaa gtctctatca 600 ccaagccaat aagggagtta gagtcgccta ctggataggc tttgacacca ccccttttat 660 gtttaagaac ttggctggag catatccatc atactctacc aactgggccg acgaaaccgt 720 gttaacggct cgtaacatag gcctatgcag ctctgacgtt atggagcggt cacgtagagg 780 gatgtccatt cttagaaaga agtatttgaa accatccaac aatgttctat tctctgttgg 840 ctcgaccatc taccacgaga agagggactt actgaggagc tggcacctgc cgtctgtatt 900 tcacttacgt ggcaagcaaa attacacatg tcggtgtgag actatagtta gttgcgacgg 960 gtacgtcgtt aaaagaatag ctatcagtcc aggcctgtat gggaagcctt caggctatgc 1020 tgctacgatg caccgcgagg gattcttgtg ctgcaaagtg acagacacat tgaacgggga 1080 gagggtctct tttcccgtgt gcacgtatgt gccagctaca ttgtgtgacc aaatgactgg 1140 catactggca acagatgtca gtgcggacga cgcgcaaaaa ctgctggttg ggctcaacca 1200 gcgtatagtc gtcaacggtc gcacccagag aaacaccaat accatgaaaa attacctttt 1260 gcccgtagtg gcccaggcat ttgctaggtg ggcaaaggaa tataaggaag atcaagaaga 1320 tgaaaggcca ctaggactac gagatagaca gttagtcatg gggtgttgtt gggcttttag 1380 aaggcacaag ataacatcta tttataagcg cccggatacc caaaccatca tcaaagtgaa 1440 cagcgatttc cactcattcg tgctgcccag gataggcagt aacacattgg agatcgggct 1500 gagaacaaga atcaggaaaa tgttagagga gcacaaggag ccgtcacctc tcattaccgc 1560 cgaggacgta caagaagcta agtgcgcagc cgatgaggct aaggaggtgc gtgaagccga 1620 ggagttgcgc gcagctctac cacctttggc agctgatgtt gaggagccca ctctggaagc 1680 cgatgtagac ttgatgttac aagaggctgg ggccggctca gtggagacac ctcgtggctt 1740 gataaaggtt accagctacg ctggcgagga caagatcggc tcttacgctg tgctttctcc 1800 gcaggctgta ctcaagagtg aaaaattatc ttgcatccac cctctcgctg aacaagtcat 1860 agtgataaca cactctggcc gaaaagggcg ttatgccgtg gaaccatacc atggtaaagt 1920 agtggtgcca gagggacatg caatacccgt ccaggacttt caagctctga gtgaaagtgc 1980 caccattgtg tacaacgaac gtgagttcgt aaacaggtac ctgcaccata ttgccacaca 2040 tggaggagcg ctgaacactg atgaagaata ttacaaaact gtcaagccca gcgagcacga 2100 cggcgaatac ctgtacgaca tcgacaggaa acagtgcgtc aagaaagaac tagtcactgg 2160 gctagggctc acaggcgagc tggtggatcc tcccttccat gaattcgcct acgagagtct 2220 gagaacacga ccagccgctc cttaccaagt accaaccata ggggtgtatg gcgtgccagg 2280 atcaggcaag tctggcatca ttaaaagcgc agtcaccaaa aaagatctag tggtgagcgc 2340 caagaaagaa aactgtgcag aaattataag ggacgtcaag aaaatgaaag ggctggacgt 2400 caatgccaga actgtggact cagtgctctt gaatggatgc aaacaccccg tagagaccct 2460 gtatattgac gaagcttttg cttgtcatgc aggtactctc agagcgctca tagccattat 2520 aagacctaaa aaggcagtgc tctgcgggga tcccaaacag tgcggttttt ttaacatgat 2580 gtgcctgaaa gtgcatttta accacgagat ttgcacacaa gtcttccaca aaagcatctc 2640 tcgccgttgc actaaatctg tgacttcggt cgtctcaacc ttgttttacg acaaaaaaat 2700 gagaacgacg aatccgaaag agactaagat tgtgattgac actaccggca gtaccaaacc 2760 taagcaggac gatctcattc tcacttgttt cagagggtgg gtgaagcagt tgcaaataga 2820 ttacaaaggc aacgaaataa tgacggcagc tgcctctcaa gggctgaccc gtaaaggtgt 2880 gtatgccgtt cggtacaagg tgaatgaaaa tcctctgtac gcacccacct cagaacatgt 2940 gaacgtccta ctgacccgca cggaggaccg catcgtgtgg aaaacactag ccggcgaccc 3000 atggataaaa acactgactg ccaagtaccc tgggaatttc actgccacga tagaggagtg 3060 gcaagcagag catgatgcca tcatgaggca catcttggag agaccggacc ctaccgacgt 3120 cttccagaat aaggcaaacg tgtgttgggc caaggcttta gtgccggtgc tgaagaccgc 3180 tggcatagac atgaccactg aacaatggaa cactgtggat tattttgaaa cggacaaagc 3240 tcactcagca gagatagtat tgaaccaact atgcgtgagg ttctttggac tcgatctgga 3300 ctccggtcta ttttctgcac ccactgttcc gttatccatt aggaataatc actgggataa 3360 ctccccgtcg cctaacatgt acgggctgaa taaagaagtg gtccgtcagc tctctcgcag 3420 gtacccacaa ctgcctcggg cagttgccac tggaagagtc tatgacatga acactggtac 3480 actgcgcaat tatgatccgc gcataaacct agtacctgta aacagaagac tgcctcatgc 3540 tttagtcctc caccataatg aacacccaca gagtgacttt tcttcattcg tcagcaaatt 3600 gaagggcaga actgtcctgg tggtcgggga aaagttgtcc gtcccaggca aaatggttga 3660 ctggttgtca gaccggcctg aggctacctt cagagctcgg ctggatttag gcatcccagg 3720 tgatgtgccc aaatatgaca taatatttgt taatgtgagg accccatata aataccatca 3780 ctatcagcag tgtgaagacc atgccattaa gcttagcatg ttgaccaaga aagcttgtct 3840 gcatctgaat cccggcggaa cctgtgtcag cataggttat ggttacgctg acagggccag 3900 cgaaagcatc attggtgcta tagcgcggca gttcaagttt tcccgggtat gcaaaccgaa 3960 atcctcactt gaagagacgg aagttctgtt tgtattcatt gggtacgatc gcaaggcccg 4020 tacgcacaat ccttacaagc tttcatcaac cttgaccaac atttatacag gttccagact 4080 ccacgaagcc ggatgtgcac cctcatatca tgtggtgcga ggggatattg ccacggccac 4140 cgaaggagtg attataaatg ctgctaacag caaaggacaa cctggcggag gggtgtgcgg 4200 agcgctgtat aagaaattcc cggaaagctt cgatttacag ccgatcgaag taggaaaagc 4260 gcgactggtc aaaggtgcag ctaaacatat cattcatgcc gtaggaccaa acttcaacaa 4320 agtttcggag gttgaaggtg acaaacagtt ggcagaggct tatgagtcca tcgctaagat 4380 tgtcaacgat aacaattaca agtcagtagc gattccactg ttgtccaccg gcatcttttc 4440 cgggaacaaa gatcgactaa cccaatcatt gaaccatttg ctgacagctt tagacaccac 4500 tgatgcagat gtagccatat actgcaggga caagaaatgg gaaatgactc tcaaggaagc 4560 agtggctagg agagaagcag tggaggagat atgcatatcc gacgactctt cagtgacaga 4620 acctgatgca gagctggtga gggtgcatcc gaagagttct ttggctggaa ggaagggcta 4680 cagcacaagc gatggcaaaa ctttctcata tttggaaggg accaagtttc accaggcggc 4740 caaggatata gcagaaatta atgccatgtg gcccgttgca acggaggcca atgagcaggt 4800 atgcatgtat atcctcggag aaagcatgag cagtattagg tcgaaatgcc ccgtcgaaga 4860 gtcggaagcc tcctcaccac ctagcacgct gccttgcttg tgcatccatg ccatgactcc 4920 agaaagagta cagcgcctaa aagcctcacg tccagaacaa attactgtgt gctcatcctt 4980 tccattgccg aagtatagaa tcactggtgt gcagaagatc caatgctccc agcctatatt 5040 gttctcaccg aaagtgcctg cgtatattca tccaaggaag tatctcgtgg aaacaccacc 5100 ggtagacgag actccggagc catcggcaga gaaccaatcc acagagggga cacctgaaca 5160 accaccactt ataaccgagg atgagaccag gactagaacg cctgagccga tcatcatcga 5220 agaggaagaa gaggatagca taagtttgct gtcagatggc ccgacccacc aggtgctgca 5280 agtcgaggca gacattcacg ggccgccctc tgtatctagc tcatcctggt ccattcctca 5340 tgcatccgac tttgatgtgg acagtttatc catacttgac accctggagg gagctagcgt 5400 gaccagcggg gcaacgtcag ccgagactaa ctcttacttc gcaaagagta tggagtttct 5460 ggcgcgaccg gtgcctgcgc ctcgaacagt attcaggaac cctccacatc ccgctccgcg 5520 cacaagaaca ccgtcacttg cacccagcag ggcctgctcg agagggatca cgggagaaac 5580 cgtgggatac gcggttacac acaatagcga gggcttcttg ctatgcaaag ttactgacac 5640 agtaaaagga gaacgggtat cgttccctgt gtgcacgtac atcccggcca ccataaactc 5700 gagaaccagc ctggtctcca acccgccagg cgtaaatagg gtgattacaa gagaggagtt 5760 tgaggcgttc gtagcacaac aacaatgacg gtttgatgcg ggtgcataca tcttttcctc 5820 cgacaccggt caagggcatt tacaacaaaa atcagtaagg caaacggtgc tatccgaagt 5880 ggtgttggag aggaccgaat tggagatttc gtatgccccg cgcctcgacc aagaaaaaga 5940 agaattacta cgcaagaaat tacagttaaa tcccacacct gctaacagaa gcagatacca 6000 gtccaggaag gtggagaaca tgaaagccat aacagctaga cgtattctgc aaggcctagg 6060 gcattatttg aaggcagaag gaaaagtgga gtgctaccga accctgcatc ctgttccttt 6120 gtattcatct agtgtgaacc gtgccttttc aagccccaag gtcgcagtgg aagcctgtaa 6180 cgccatgttg aaagagaact ttccgactgt ggcttcttac tgtattattc cagagtacga 6240 tgcctatttg gacatggttg acggagcttc atgctgctta gacactgcca gtttttgccc 6300 tgcaaagctg cgcagctttc caaagaaaca ctcctatttg gaacccacaa tacgatcggc 6360 agtgccttca gcgatccaga acacgctcca gaacgtcctg gcagctgcca caaaaagaaa 6420 ttgcaatgtc acgcaaatga gagaattgcc cgtattggat tcggcggcct ttaatgtgga 6480 atgcttcaag aaatatgcgt gtaataatga atattgggaa acgtttaaag aaaaccccat 6540 caggcttact gaagaaaacg tggtaaatta cattaccaaa ttaaaaggac caaaagctgc 6600 tgctcttttt gcgaagacac ataatttgaa tatgttgcag gacataccaa tggacaggtt 6660 tgtaatggac ttaaagagag acgtgaaagt gactccagga acaaaacata ctgaagaacg 6720 gcccaaggta caggtgatcc aggctgccga tccgctagca acagcgtatc tgtgcggaat 6780 ccaccgagag ctggttagga gattaaatgc ggtcctgctt ccgaacattc atacactgtt 6840 tgatatgtcg gctgaagact ttgacgctat tatagccgag cacttccagc ctggggattg 6900 tgttctggaa actgacatcg cgtcgtttga taaaagtgag gacgacgcca tggctctgac 6960 cgcgttaatg attctggaag acttaggtgt ggacgcagag ctgttgacgc tgattgaggc 7020 ggctttcggc gaaatttcat caatacattt gcccactaaa actaaattta aattcggagc 7080 catgatgaaa tctggaatgt tcctcacact gtttgtgaac acagtcatta acattgtaat 7140 cgcaagcaga gtgttgagag aacggctaac cggatcacca tgtgcagcat tcattggaga 7200 tgacaatatc gtgaaaggag tcaaatcgga caaattaatg gcagacaggt gcgccacctg 7260 gttgaatatg gaagtcaaga ttatagatgc tgtggtgggc gagaaagcgc cttatttctg 7320 tggagggttt attttgtgtg actccgtgac cggcacagcg tgccgtgtgg cagaccccct 7380 aaaaaggctg tttaagcttg gcaaacctct ggcagcagac gatgaacatg atgatgacag 7440 gagaagggca ttgcatgaag agtcaacacg ctggaaccga gtgggtattc tttcagagct 7500 gtgcaaggca gtagaatcaa ggtatgaaac cgtaggaact tccatcatag ttatggccat 7560 gactactcta gctagcagtg ttaaatcatt cagctacctg agaggggccc ctataactct 7620 ctacggctaa cctgaatgga ctacgacata gtctagtcga cgccaccatg aggcctggcc 7680 tgccctccta cctgatcatc ctggccgtgt gcctgttcag ccacctgctg tccagcagat 7740 acggcgccga ggccgtgagc gagcccctgg acaaggcttt ccacctgctg ctgaacacct 7800 acggcagacc catccggttt ctgcgggaga acaccaccca gtgcacctac aacagcagcc 7860 tgcggaacag caccgtcgtg agagagaacg ccatcagctt caactttttc cagagctaca 7920 accagtacta cgtgttccac atgcccagat gcctgtttgc cggccctctg gccgagcagt 7980 tcctgaacca ggtggacctg accgagacac tggaaagata ccagcagcgg ctgaatacct 8040 acgccctggt gtccaaggac ctggccagct accggtcctt tagccagcag ctcaaggctc 8100 aggatagcct cggcgagcag cctaccaccg tgccccctcc catcgacctg agcatccccc 8160 acgtgtggat gcctccccag accacccctc acggctggac cgagagccac accacctccg 8220 gcctgcacag accccacttc aaccagacct gcatcctgtt cgacggccac gacctgctgt 8280 ttagcaccgt gaccccctgc ctgcaccagg gcttctacct gatcgacgag ctgagatacg 8340 tgaagatcac cctgaccgag gatttcttcg tggtcaccgt gtccatcgac gacgacaccc 8400 ccatgctgct gatcttcggc cacctgccca gagtgctgtt caaggccccc taccagcggg 8460 acaacttcat cctgcggcag accgagaagc acgagctgct ggtgctggtc aagaaggacc 8520 agctgaaccg gcactcctac ctgaaggacc ccgacttcct ggacgccgcc ctggacttca 8580 actacctgga cctgagcgcc ctgctgagaa acagcttcca cagatacgcc gtggacgtgc 8640 tgaagtccgg acggtgccag atgctcgatc ggcggaccgt ggagatggcc ttcgcctatg 8700 ccctcgccct gttcgccgct gccagacagg aagaggctgg cgcccaggtg tcagtgccca 8760 gagccctgga tagacaggcc gccctgctgc agatccagga attcatgatc acctgcctga 8820 gccagacccc ccctagaacc accctgctgc tgtaccccac agccgtggat ctggccaaga 8880 gggccctgtg gacccccaac cagatcaccg acatcacaag cctcgtgcgg ctcgtgtaca 8940 tcctgagcaa gcagaaccag cagcacctga tcccccagtg ggccctgaga cagatcgccg 9000 acttcgccct gaagctgcac aagacccatc tggccagctt tctgagcgcc ttcgccaggc 9060 aggaactgta cctgatgggc agcctggtcc acagcatgct ggtgcatacc accgagcggc 9120 gggagatctt catcgtggag acaggcctgt gtagcctggc cgagctgtcc cactttaccc 9180 agctgctggc ccaccctcac cacgagtacc tgagcgacct gtacaccccc tgcagcagca 9240 gcggcagacg ggaccacagc ctggaacggc tgaccagact gttccccgat gccaccgtgc 9300 ctgctacagt gcctgccgcc ctgtccatcc tgtccaccat gcagcccagc accctggaaa 9360 ccttccccga cctgttctgc ctgcccctgg gcgagagctt tagcgccctg accgtgtccg 9420 agcacgtgtc ctacatcgtg accaatcagt acctgatcaa gggcatcagc taccccgtgt 9480 ccaccacagt cgtgggccag agcctgatca tcacccagac cgacagccag accaagtgcg 9540 agctgacccg gaacatgcac accacacaca gcatcaccgt ggccctgaac atcagcctgg 9600 aaaactgcgc tttctgtcag tctgccctgc tggaatacga cgatacccag ggcgtgatca 9660 acatcatgta catgcacgac agcgacgacg tgctgttcgc cctggacccc tacaacgagg 9720 tggtggtgtc cagcccccgg acccactacc tgatgctgct gaagaacggc accgtgctgg 9780 aagtgaccga cgtggtggtg gacgccaccg actgataatc tagacggcgc gcccacccag 9840 cggccgccta taactctcta cggctaacct gaatggacta cgacatagtc tagtcgacgc 9900 caccatgtgc agaaggcccg actgcggctt cagcttcagc cctggacccg tgatcctgct 9960 gtggtgctgc ctgctgctgc ctatcgtgtc ctctgccgcc gtgtctgtgg cccctacagc 10020 cgccgagaag gtgccagccg agtgccccga gctgaccaga agatgcctgc tgggcgaggt 10080 gttcgagggc gacaagtacg agagctggct gcggcccctg gtcaacgtga ccggcagaga 10140 tggccccctg agccagctga tccggtacag acccgtgacc cccgaggccg ccaatagcgt 10200 gctgctggac gaggccttcc tggataccct ggccctgctg tacaacaacc ccgaccagct 10260 gagagccctg ctgaccctgc tgtccagcga caccgccccc agatggatga ccgtgatgcg 10320 gggctacagc gagtgtggag atggcagccc tgccgtgtac acctgcgtgg acgacctgtg 10380 cagaggctac gacctgacca gactgagcta cggccggtcc atcttcacag agcacgtgct 10440 gggcttcgag ctggtgcccc ccagcctgtt caacgtggtg gtggccatcc ggaacgaggc 10500 caccagaacc aacagagccg tgcggctgcc tgtgtctaca gccgctgcac ctgagggcat 10560 cacactgttc tacggcctgt acaacgccgt gaaagagttc tgcctccggc accagctgga 10620 tccccccctg ctgagacacc tggacaagta ctacgccggc ctgcccccag agctgaagca 10680 gaccagagtg aacctgcccg cccacagcag atatggccct caggccgtgg acgccagatg 10740 ataatctaga cggcgcgccc acccaatcga tctataactc tctacggcta acctgaatgg 10800 actacgacat agtctagtcg acgccaccat gggcaagaaa gaaatgatca tggtcaaggg 10860 catccccaag atcatgctgc tgattagcat cacctttctg ctgctgtccc tgatcaactg 10920 caacgtgctg gtcaacagcc ggggcaccag aagatcctgg ccctacaccg tgctgtccta 10980 ccggggcaaa gagatcctga agaagcagaa agaggacatc ctgaagcggc tgatgagcac 11040 cagcagcgac ggctaccggt tcctgatgta ccccagccag cagaaattcc acgccatcgt 11100 gatcagcatg gacaagttcc cccaggacta catcctggcc ggacccatcc ggaacgacag 11160 catcacccac atgtggttcg acttctacag cacccagctg cggaagcccg ccaaatacgt 11220 gtacagcgag tacaaccaca ccgcccacaa gatcaccctg aggcctcccc cttgtggcac 11280 cgtgcccagc atgaactgcc tgagcgagat gctgaacgtg tccaagcgga acgacaccgg 11340 cgagaagggc tgcggcaact tcaccacctt caaccccatg ttcttcaacg tgccccggtg 11400 gaacaccaag ctgtacatcg gcagcaacaa agtgaacgtg gacagccaga ccatctactt 11460 tctgggcctg accgccctgc tgctgagata cgcccagcgg aactgcaccc ggtccttcta 11520 cctggtcaac gccatgagcc ggaacctgtt ccgggtgccc aagtacatca acggcaccaa 11580 gctgaagaac accatgcgga agctgaagcg gaagcaggcc ctggtcaaag agcagcccca 11640 gaagaagaac aagaagtccc agagcaccac caccccctac ctgagctaca ccacctccac 11700 cgccttcaac gtgaccacca acgtgaccta cagcgccaca gccgccgtga ccagagtggc 11760 cacaagcacc accggctacc ggcccgacag caactttatg aagtccatca tggccaccca 11820 gctgagagat ctggccacct gggtgtacac caccctgcgg tacagaaacg agcccttctg 11880 caagcccgac cggaacagaa ccgccgtgag cgagttcatg aagaataccc acgtgctgat 11940 cagaaacgag acaccctaca ccatctacgg caccctggac atgagcagcc tgtactacaa 12000 cgagacaatg agcgtggaga acgagacagc cagcgacaac aacgaaacca cccccacctc 12060 ccccagcacc cggttccagc ggaccttcat cgaccccctg tgggactacc tggacagcct 12120 gctgttcctg gacaagatcc ggaacttcag cctgcagctg cccgcctacg gcaatctgac 12180 cccccctgag cacagaaggg ccgccaacct gagcaccctg aacagcctgt ggtggtggag 12240 ccagtgataa tctagacggc gcgcccaccc accgcgggca atatagcaac actaaaaact 12300 cgatgtactt ccgaggaagc gcagtgcata atgctgcgca gtgttgccac ataaccacta 12360 tattaaccat ttatctagcg gacgccaaaa actcaatgta tttctgagga agcgtggtgc 12420 ataatgccac gcagcgtctg cataactttt attatttctt ttattaatca acaaaatttt 12480 gtttttaaca tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaagggtcg 12540 gcatggcatc tccacctcct cgcggtccga cctgggcatc cgaaggagga cgcacgtcca 12600 ctcggatggc taagggagag ccacgagctc ctgtttaaac cagctccaat tcgccctata 12660 gtgagtcgta ttacgcgcgc tcactggccg tcgttttaca acgtcgtgac tgggaaaacc 12720 ctggcgttac ccaacttaat cgccttgcag cacatccccc tttcgccagc tggcgtaata 12780 gcgaagaggc ccgcaccgat cgcccttccc aacagttgcg cagcctgaat ggcgaatggg 12840 acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc agcgtgaccg 12900 ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc tttctcgcca 12960 cgttcgccgg ctttccccgt caagctctaa atcgggggct ccctttaggg ttccgattta 13020 gtgctttacg gcacctcgac cccaaaaaac ttgattaggg tgatggttca cgtagtgggc 13080 catcgccctg atagacggtt tttcgccctt tgacgttgga gtccacgttc tttaatagtg 13140 gactcttgtt ccaaactgga acaacactca accctatctc ggtctattct tttgatttat 13200 aagggatttt gccgatttcg gcctattggt taaaaaatga gctgatttaa caaaaattta 13260 acgcgaattt taacaaaata ttaacgctta caatttaggt ggcacttttc ggggaaatgt 13320 gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc cgctcatgag 13380 acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga gtattcaaca 13440 tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt ttgctcaccc 13500 agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag tgggttacat 13560 cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag aacgttttcc 13620 aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgta ttgacgccgg 13680 gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg agtactcacc 13740 agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca gtgctgccat 13800 aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag gaccgaagga 13860 gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc gttgggaacc 13920 ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg tagcaatggc 13980 aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc ggcaacaatt 14040 aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg cccttccggc 14100 tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg gtatcattgc 14160 agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga cggggagtca 14220 ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac tgattaagca 14280 ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa aacttcattt 14340 ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca aaatccctta 14400 acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag gatcttcttg 14460 agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac cgctaccagc 14520 ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag 14580 cagagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc accacttcaa 14640 gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag tggctgctgc 14700 cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac cggataaggc 14760 gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc gaacgaccta 14820 caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag 14880 aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca cgagggagct 14940 tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc tctgacttga 15000 gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc 15060 ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct ttcctgcgtt 15120 atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata ccgctcgccg 15180 cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc gcccaatacg 15240 caaaccgcct ctccccgcgc gttggccgat tcattaatgc agctggcacg acaggtttcc 15300 cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg agttagctca ctcattaggc 15360 accccaggct ttacacttta tgctcccggc tcgtatgttg tgtggaattg tgagcggata 15420 acaatttcac acaggaaaca gctatgacca tgattacgcc aagcgcgcaa ttaaccctca 15480 ctaaagggaa caaaagctgg gtaccggcgc ca 15512 <210> 55 <211> 15593 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 55 cgcgtcggct acaattaata cataacctta tgtatcatac acatacgatt taggtgacac 60 tatagatggg cggcgcatga gagaagccca gaccaattac ctacccaaaa tggagaaagt 120 tcacgttgac atcgaggaag acagcccatt cctcagagct ttgcagcgga gcttcccgca 180 gtttgaggta gaagccaagc aggtcactga taatgaccat gctaatgcca gagcgttttc 240 gcatctggct tcaaaactga tcgaaacgga ggtggaccca tccgacacga tccttgacat 300 tggaagtgcg cccgcccgca gaatgtattc taagcacaag tatcattgta tctgtccgat 360 gagatgtgcg gaagatccgg acagattgta taagtatgca actaagctga agaaaaactg 420 taaggaaata actgataagg aattggacaa gaaaatgaag gagctcgccg ccgtcatgag 480 cgaccctgac ctggaaactg agactatgtg cctccacgac gacgagtcgt gtcgctacga 540 agggcaagtc gctgtttacc aggatgtata cgcggttgac ggaccgacaa gtctctatca 600 ccaagccaat aagggagtta gagtcgccta ctggataggc tttgacacca ccccttttat 660 gtttaagaac ttggctggag catatccatc atactctacc aactgggccg acgaaaccgt 720 gttaacggct cgtaacatag gcctatgcag ctctgacgtt atggagcggt cacgtagagg 780 gatgtccatt cttagaaaga agtatttgaa accatccaac aatgttctat tctctgttgg 840 ctcgaccatc taccacgaga agagggactt actgaggagc tggcacctgc cgtctgtatt 900 tcacttacgt ggcaagcaaa attacacatg tcggtgtgag actatagtta gttgcgacgg 960 gtacgtcgtt aaaagaatag ctatcagtcc aggcctgtat gggaagcctt caggctatgc 1020 tgctacgatg caccgcgagg gattcttgtg ctgcaaagtg acagacacat tgaacgggga 1080 gagggtctct tttcccgtgt gcacgtatgt gccagctaca ttgtgtgacc aaatgactgg 1140 catactggca acagatgtca gtgcggacga cgcgcaaaaa ctgctggttg ggctcaacca 1200 gcgtatagtc gtcaacggtc gcacccagag aaacaccaat accatgaaaa attacctttt 1260 gcccgtagtg gcccaggcat ttgctaggtg ggcaaaggaa tataaggaag atcaagaaga 1320 tgaaaggcca ctaggactac gagatagaca gttagtcatg gggtgttgtt gggcttttag 1380 aaggcacaag ataacatcta tttataagcg cccggatacc caaaccatca tcaaagtgaa 1440 cagcgatttc cactcattcg tgctgcccag gataggcagt aacacattgg agatcgggct 1500 gagaacaaga atcaggaaaa tgttagagga gcacaaggag ccgtcacctc tcattaccgc 1560 cgaggacgta caagaagcta agtgcgcagc cgatgaggct aaggaggtgc gtgaagccga 1620 ggagttgcgc gcagctctac cacctttggc agctgatgtt gaggagccca ctctggaagc 1680 cgatgtagac ttgatgttac aagaggctgg ggccggctca gtggagacac ctcgtggctt 1740 gataaaggtt accagctacg ctggcgagga caagatcggc tcttacgctg tgctttctcc 1800 gcaggctgta ctcaagagtg aaaaattatc ttgcatccac cctctcgctg aacaagtcat 1860 agtgataaca cactctggcc gaaaagggcg ttatgccgtg gaaccatacc atggtaaagt 1920 agtggtgcca gagggacatg caatacccgt ccaggacttt caagctctga gtgaaagtgc 1980 caccattgtg tacaacgaac gtgagttcgt aaacaggtac ctgcaccata ttgccacaca 2040 tggaggagcg ctgaacactg atgaagaata ttacaaaact gtcaagccca gcgagcacga 2100 cggcgaatac ctgtacgaca tcgacaggaa acagtgcgtc aagaaagaac tagtcactgg 2160 gctagggctc acaggcgagc tggtggatcc tcccttccat gaattcgcct acgagagtct 2220 gagaacacga ccagccgctc cttaccaagt accaaccata ggggtgtatg gcgtgccagg 2280 atcaggcaag tctggcatca ttaaaagcgc agtcaccaaa aaagatctag tggtgagcgc 2340 caagaaagaa aactgtgcag aaattataag ggacgtcaag aaaatgaaag ggctggacgt 2400 caatgccaga actgtggact cagtgctctt gaatggatgc aaacaccccg tagagaccct 2460 gtatattgac gaagcttttg cttgtcatgc aggtactctc agagcgctca tagccattat 2520 aagacctaaa aaggcagtgc tctgcgggga tcccaaacag tgcggttttt ttaacatgat 2580 gtgcctgaaa gtgcatttta accacgagat ttgcacacaa gtcttccaca aaagcatctc 2640 tcgccgttgc actaaatctg tgacttcggt cgtctcaacc ttgttttacg acaaaaaaat 2700 gagaacgacg aatccgaaag agactaagat tgtgattgac actaccggca gtaccaaacc 2760 taagcaggac gatctcattc tcacttgttt cagagggtgg gtgaagcagt tgcaaataga 2820 ttacaaaggc aacgaaataa tgacggcagc tgcctctcaa gggctgaccc gtaaaggtgt 2880 gtatgccgtt cggtacaagg tgaatgaaaa tcctctgtac gcacccacct cagaacatgt 2940 gaacgtccta ctgacccgca cggaggaccg catcgtgtgg aaaacactag ccggcgaccc 3000 atggataaaa acactgactg ccaagtaccc tgggaatttc actgccacga tagaggagtg 3060 gcaagcagag catgatgcca tcatgaggca catcttggag agaccggacc ctaccgacgt 3120 cttccagaat aaggcaaacg tgtgttgggc caaggcttta gtgccggtgc tgaagaccgc 3180 tggcatagac atgaccactg aacaatggaa cactgtggat tattttgaaa cggacaaagc 3240 tcactcagca gagatagtat tgaaccaact atgcgtgagg ttctttggac tcgatctgga 3300 ctccggtcta ttttctgcac ccactgttcc gttatccatt aggaataatc actgggataa 3360 ctccccgtcg cctaacatgt acgggctgaa taaagaagtg gtccgtcagc tctctcgcag 3420 gtacccacaa ctgcctcggg cagttgccac tggaagagtc tatgacatga acactggtac 3480 actgcgcaat tatgatccgc gcataaacct agtacctgta aacagaagac tgcctcatgc 3540 tttagtcctc caccataatg aacacccaca gagtgacttt tcttcattcg tcagcaaatt 3600 gaagggcaga actgtcctgg tggtcgggga aaagttgtcc gtcccaggca aaatggttga 3660 ctggttgtca gaccggcctg aggctacctt cagagctcgg ctggatttag gcatcccagg 3720 tgatgtgccc aaatatgaca taatatttgt taatgtgagg accccatata aataccatca 3780 ctatcagcag tgtgaagacc atgccattaa gcttagcatg ttgaccaaga aagcttgtct 3840 gcatctgaat cccggcggaa cctgtgtcag cataggttat ggttacgctg acagggccag 3900 cgaaagcatc attggtgcta tagcgcggca gttcaagttt tcccgggtat gcaaaccgaa 3960 atcctcactt gaagagacgg aagttctgtt tgtattcatt gggtacgatc gcaaggcccg 4020 tacgcacaat ccttacaagc tttcatcaac cttgaccaac atttatacag gttccagact 4080 ccacgaagcc ggatgtgcac cctcatatca tgtggtgcga ggggatattg ccacggccac 4140 cgaaggagtg attataaatg ctgctaacag caaaggacaa cctggcggag gggtgtgcgg 4200 agcgctgtat aagaaattcc cggaaagctt cgatttacag ccgatcgaag taggaaaagc 4260 gcgactggtc aaaggtgcag ctaaacatat cattcatgcc gtaggaccaa acttcaacaa 4320 agtttcggag gttgaaggtg acaaacagtt ggcagaggct tatgagtcca tcgctaagat 4380 tgtcaacgat aacaattaca agtcagtagc gattccactg ttgtccaccg gcatcttttc 4440 cgggaacaaa gatcgactaa cccaatcatt gaaccatttg ctgacagctt tagacaccac 4500 tgatgcagat gtagccatat actgcaggga caagaaatgg gaaatgactc tcaaggaagc 4560 agtggctagg agagaagcag tggaggagat atgcatatcc gacgactctt cagtgacaga 4620 acctgatgca gagctggtga gggtgcatcc gaagagttct ttggctggaa ggaagggcta 4680 cagcacaagc gatggcaaaa ctttctcata tttggaaggg accaagtttc accaggcggc 4740 caaggatata gcagaaatta atgccatgtg gcccgttgca acggaggcca atgagcaggt 4800 atgcatgtat atcctcggag aaagcatgag cagtattagg tcgaaatgcc ccgtcgaaga 4860 gtcggaagcc tcctcaccac ctagcacgct gccttgcttg tgcatccatg ccatgactcc 4920 agaaagagta cagcgcctaa aagcctcacg tccagaacaa attactgtgt gctcatcctt 4980 tccattgccg aagtatagaa tcactggtgt gcagaagatc caatgctccc agcctatatt 5040 gttctcaccg aaagtgcctg cgtatattca tccaaggaag tatctcgtgg aaacaccacc 5100 ggtagacgag actccggagc catcggcaga gaaccaatcc acagagggga cacctgaaca 5160 accaccactt ataaccgagg atgagaccag gactagaacg cctgagccga tcatcatcga 5220 agaggaagaa gaggatagca taagtttgct gtcagatggc ccgacccacc aggtgctgca 5280 agtcgaggca gacattcacg ggccgccctc tgtatctagc tcatcctggt ccattcctca 5340 tgcatccgac tttgatgtgg acagtttatc catacttgac accctggagg gagctagcgt 5400 gaccagcggg gcaacgtcag ccgagactaa ctcttacttc gcaaagagta tggagtttct 5460 ggcgcgaccg gtgcctgcgc ctcgaacagt attcaggaac cctccacatc ccgctccgcg 5520 cacaagaaca ccgtcacttg cacccagcag ggcctgctcg agagggatca cgggagaaac 5580 cgtgggatac gcggttacac acaatagcga gggcttcttg ctatgcaaag ttactgacac 5640 agtaaaagga gaacgggtat cgttccctgt gtgcacgtac atcccggcca ccataaactc 5700 gagaaccagc ctggtctcca acccgccagg cgtaaatagg gtgattacaa gagaggagtt 5760 tgaggcgttc gtagcacaac aacaatgacg gtttgatgcg ggtgcataca tcttttcctc 5820 cgacaccggt caagggcatt tacaacaaaa atcagtaagg caaacggtgc tatccgaagt 5880 ggtgttggag aggaccgaat tggagatttc gtatgccccg cgcctcgacc aagaaaaaga 5940 agaattacta cgcaagaaat tacagttaaa tcccacacct gctaacagaa gcagatacca 6000 gtccaggaag gtggagaaca tgaaagccat aacagctaga cgtattctgc aaggcctagg 6060 gcattatttg aaggcagaag gaaaagtgga gtgctaccga accctgcatc ctgttccttt 6120 gtattcatct agtgtgaacc gtgccttttc aagccccaag gtcgcagtgg aagcctgtaa 6180 cgccatgttg aaagagaact ttccgactgt ggcttcttac tgtattattc cagagtacga 6240 tgcctatttg gacatggttg acggagcttc atgctgctta gacactgcca gtttttgccc 6300 tgcaaagctg cgcagctttc caaagaaaca ctcctatttg gaacccacaa tacgatcggc 6360 agtgccttca gcgatccaga acacgctcca gaacgtcctg gcagctgcca caaaaagaaa 6420 ttgcaatgtc acgcaaatga gagaattgcc cgtattggat tcggcggcct ttaatgtgga 6480 atgcttcaag aaatatgcgt gtaataatga atattgggaa acgtttaaag aaaaccccat 6540 caggcttact gaagaaaacg tggtaaatta cattaccaaa ttaaaaggac caaaagctgc 6600 tgctcttttt gcgaagacac ataatttgaa tatgttgcag gacataccaa tggacaggtt 6660 tgtaatggac ttaaagagag acgtgaaagt gactccagga acaaaacata ctgaagaacg 6720 gcccaaggta caggtgatcc aggctgccga tccgctagca acagcgtatc tgtgcggaat 6780 ccaccgagag ctggttagga gattaaatgc ggtcctgctt ccgaacattc atacactgtt 6840 tgatatgtcg gctgaagact ttgacgctat tatagccgag cacttccagc ctggggattg 6900 tgttctggaa actgacatcg cgtcgtttga taaaagtgag gacgacgcca tggctctgac 6960 cgcgttaatg attctggaag acttaggtgt ggacgcagag ctgttgacgc tgattgaggc 7020 ggctttcggc gaaatttcat caatacattt gcccactaaa actaaattta aattcggagc 7080 catgatgaaa tctggaatgt tcctcacact gtttgtgaac acagtcatta acattgtaat 7140 cgcaagcaga gtgttgagag aacggctaac cggatcacca tgtgcagcat tcattggaga 7200 tgacaatatc gtgaaaggag tcaaatcgga caaattaatg gcagacaggt gcgccacctg 7260 gttgaatatg gaagtcaaga ttatagatgc tgtggtgggc gagaaagcgc cttatttctg 7320 tggagggttt attttgtgtg actccgtgac cggcacagcg tgccgtgtgg cagaccccct 7380 aaaaaggctg tttaagcttg gcaaacctct ggcagcagac gatgaacatg atgatgacag 7440 gagaagggca ttgcatgaag agtcaacacg ctggaaccga gtgggtattc tttcagagct 7500 gtgcaaggca gtagaatcaa ggtatgaaac cgtaggaact tccatcatag ttatggccat 7560 gactactcta gctagcagtg ttaaatcatt cagctacctg agaggggccc ctataactct 7620 ctacggctaa cctgaatgga ctacgacata gtctagtcga cgccaccatg aggcctggcc 7680 tgccctccta cctgatcatc ctggccgtgt gcctgttcag ccacctgctg tccagcagat 7740 acggcgccga ggccgtgagc gagcccctgg acaaggcttt ccacctgctg ctgaacacct 7800 acggcagacc catccggttt ctgcgggaga acaccaccca gtgcacctac aacagcagcc 7860 tgcggaacag caccgtcgtg agagagaacg ccatcagctt caactttttc cagagctaca 7920 accagtacta cgtgttccac atgcccagat gcctgtttgc cggccctctg gccgagcagt 7980 tcctgaacca ggtggacctg accgagacac tggaaagata ccagcagcgg ctgaatacct 8040 acgccctggt gtccaaggac ctggccagct accggtcctt tagccagcag ctcaaggctc 8100 aggatagcct cggcgagcag cctaccaccg tgccccctcc catcgacctg agcatccccc 8160 acgtgtggat gcctccccag accacccctc acggctggac cgagagccac accacctccg 8220 gcctgcacag accccacttc aaccagacct gcatcctgtt cgacggccac gacctgctgt 8280 ttagcaccgt gaccccctgc ctgcaccagg gcttctacct gatcgacgag ctgagatacg 8340 tgaagatcac cctgaccgag gatttcttcg tggtcaccgt gtccatcgac gacgacaccc 8400 ccatgctgct gatcttcggc cacctgccca gagtgctgtt caaggccccc taccagcggg 8460 acaacttcat cctgcggcag accgagaagc acgagctgct ggtgctggtc aagaaggacc 8520 agctgaaccg gcactcctac ctgaaggacc ccgacttcct ggacgccgcc ctggacttca 8580 actacctgga cctgagcgcc ctgctgagaa acagcttcca cagatacgcc gtggacgtgc 8640 tgaagtccgg acggtgccag atgctcgatc ggcggaccgt ggagatggcc ttcgcctatg 8700 ccctcgccct gttcgccgct gccagacagg aagaggctgg cgcccaggtg tcagtgccca 8760 gagccctgga tagacaggcc gccctgctgc agatccagga attcatgatc acctgcctga 8820 gccagacccc ccctagaacc accctgctgc tgtaccccac agccgtggat ctggccaaga 8880 gggccctgtg gacccccaac cagatcaccg acatcacaag cctcgtgcgg ctcgtgtaca 8940 tcctgagcaa gcagaaccag cagcacctga tcccccagtg ggccctgaga cagatcgccg 9000 acttcgccct gaagctgcac aagacccatc tggccagctt tctgagcgcc ttcgccaggc 9060 aggaactgta cctgatgggc agcctggtcc acagcatgct ggtgcatacc accgagcggc 9120 gggagatctt catcgtggag acaggcctgt gtagcctggc cgagctgtcc cactttaccc 9180 agctgctggc ccaccctcac cacgagtacc tgagcgacct gtacaccccc tgcagcagca 9240 gcggcagacg ggaccacagc ctggaacggc tgaccagact gttccccgat gccaccgtgc 9300 ctgctacagt gcctgccgcc ctgtccatcc tgtccaccat gcagcccagc accctggaaa 9360 ccttccccga cctgttctgc ctgcccctgg gcgagagctt tagcgccctg accgtgtccg 9420 agcacgtgtc ctacatcgtg accaatcagt acctgatcaa gggcatcagc taccccgtgt 9480 ccaccacagt cgtgggccag agcctgatca tcacccagac cgacagccag accaagtgcg 9540 agctgacccg gaacatgcac accacacaca gcatcaccgt ggccctgaac atcagcctgg 9600 aaaactgcgc tttctgtcag tctgccctgc tggaatacga cgatacccag ggcgtgatca 9660 acatcatgta catgcacgac agcgacgacg tgctgttcgc cctggacccc tacaacgagg 9720 tggtggtgtc cagcccccgg acccactacc tgatgctgct gaagaacggc accgtgctgg 9780 aagtgaccga cgtggtggtg gacgccaccg acagcagact gctgatgatg agcgtgtacg 9840 ccctgagcgc catcatcggc atctacctgc tgtaccggat gctgaaaacc tgctgataat 9900 ctagacggcg cgcccaccca gcggccgcct ataactctct acggctaacc tgaatggact 9960 acgacatagt ctagtcgacg ccaccatgtg cagaaggccc gactgcggct tcagcttcag 10020 ccctggaccc gtgatcctgc tgtggtgctg cctgctgctg cctatcgtgt cctctgccgc 10080 cgtgtctgtg gcccctacag ccgccgagaa ggtgccagcc gagtgccccg agctgaccag 10140 aagatgcctg ctgggcgagg tgttcgaggg cgacaagtac gagagctggc tgcggcccct 10200 ggtcaacgtg accggcagag atggccccct gagccagctg atccggtaca gacccgtgac 10260 ccccgaggcc gccaatagcg tgctgctgga cgaggccttc ctggataccc tggccctgct 10320 gtacaacaac cccgaccagc tgagagccct gctgaccctg ctgtccagcg acaccgcccc 10380 cagatggatg accgtgatgc ggggctacag cgagtgtgga gatggcagcc ctgccgtgta 10440 cacctgcgtg gacgacctgt gcagaggcta cgacctgacc agactgagct acggccggtc 10500 catcttcaca gagcacgtgc tgggcttcga gctggtgccc cccagcctgt tcaacgtggt 10560 ggtggccatc cggaacgagg ccaccagaac caacagagcc gtgcggctgc ctgtgtctac 10620 agccgctgca cctgagggca tcacactgtt ctacggcctg tacaacgccg tgaaagagtt 10680 ctgcctccgg caccagctgg atccccccct gctgagacac ctggacaagt actacgccgg 10740 cctgccccca gagctgaagc agaccagagt gaacctgccc gcccacagca gatatggccc 10800 tcaggccgtg gacgccagat gataatctag acggcgcgcc cacccaatcg atctataact 10860 ctctacggct aacctgaatg gactacgaca tagtctagtc gacgccacca tgggcaagaa 10920 agaaatgatc atggtcaagg gcatccccaa gatcatgctg ctgattagca tcacctttct 10980 gctgctgtcc ctgatcaact gcaacgtgct ggtcaacagc cggggcacca gaagatcctg 11040 gccctacacc gtgctgtcct accggggcaa agagatcctg aagaagcaga aagaggacat 11100 cctgaagcgg ctgatgagca ccagcagcga cggctaccgg ttcctgatgt accccagcca 11160 gcagaaattc cacgccatcg tgatcagcat ggacaagttc ccccaggact acatcctggc 11220 cggacccatc cggaacgaca gcatcaccca catgtggttc gacttctaca gcacccagct 11280 gcggaagccc gccaaatacg tgtacagcga gtacaaccac accgcccaca agatcaccct 11340 gaggcctccc ccttgtggca ccgtgcccag catgaactgc ctgagcgaga tgctgaacgt 11400 gtccaagcgg aacgacaccg gcgagaaggg ctgcggcaac ttcaccacct tcaaccccat 11460 gttcttcaac gtgccccggt ggaacaccaa gctgtacatc ggcagcaaca aagtgaacgt 11520 ggacagccag accatctact ttctgggcct gaccgccctg ctgctgagat acgcccagcg 11580 gaactgcacc cggtccttct acctggtcaa cgccatgagc cggaacctgt tccgggtgcc 11640 caagtacatc aacggcacca agctgaagaa caccatgcgg aagctgaagc ggaagcaggc 11700 cctggtcaaa gagcagcccc agaagaagaa caagaagtcc cagagcacca ccacccccta 11760 cctgagctac accacctcca ccgccttcaa cgtgaccacc aacgtgacct acagcgccac 11820 agccgccgtg accagagtgg ccacaagcac caccggctac cggcccgaca gcaactttat 11880 gaagtccatc atggccaccc agctgagaga tctggccacc tgggtgtaca ccaccctgcg 11940 gtacagaaac gagcccttct gcaagcccga ccggaacaga accgccgtga gcgagttcat 12000 gaagaatacc cacgtgctga tcagaaacga gacaccctac accatctacg gcaccctgga 12060 catgagcagc ctgtactaca acgagacaat gagcgtggag aacgagacag ccagcgacaa 12120 caacgaaacc acccccacct cccccagcac ccggttccag cggaccttca tcgaccccct 12180 gtgggactac ctggacagcc tgctgttcct ggacaagatc cggaacttca gcctgcagct 12240 gcccgcctac ggcaatctga ccccccctga gcacagaagg gccgccaacc tgagcaccct 12300 gaacagcctg tggtggtgga gccagtgata atctagacgg cgcgcccacc caccgcgggc 12360 aatatagcaa cactaaaaac tcgatgtact tccgaggaag cgcagtgcat aatgctgcgc 12420 agtgttgcca cataaccact atattaacca tttatctagc ggacgccaaa aactcaatgt 12480 atttctgagg aagcgtggtg cataatgcca cgcagcgtct gcataacttt tattatttct 12540 tttattaatc aacaaaattt tgtttttaac atttcaaaaa aaaaaaaaaa aaaaaaaaaa 12600 aaaaaaaaaa aaaaagggtc ggcatggcat ctccacctcc tcgcggtccg acctgggcat 12660 ccgaaggagg acgcacgtcc actcggatgg ctaagggaga gccacgagct cctgtttaaa 12720 ccagctccaa ttcgccctat agtgagtcgt attacgcgcg ctcactggcc gtcgttttac 12780 aacgtcgtga ctgggaaaac cctggcgtta cccaacttaa tcgccttgca gcacatcccc 12840 ctttcgccag ctggcgtaat agcgaagagg cccgcaccga tcgcccttcc caacagttgc 12900 gcagcctgaa tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg 12960 tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt 13020 tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc 13080 tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg 13140 gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg 13200 agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct 13260 cggtctattc ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg 13320 agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgctt acaatttagg 13380 tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 13440 aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 13500 gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg 13560 ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 13620 gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 13680 tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 13740 attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 13800 tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 13860 agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 13920 aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 13980 tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 14040 cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac 14100 tctagcttcc cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact 14160 tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg 14220 tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt 14280 tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat 14340 aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta 14400 gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa 14460 tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga 14520 aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac 14580 aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt 14640 tccgaaggta actggcttca gcagagcgca gataccaaat actgttcttc tagtgtagcc 14700 gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat 14760 cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag 14820 acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc 14880 cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag 14940 cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac 15000 aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg 15060 gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct 15120 atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc 15180 tcacatgttc tttcctgcgt tatcccctga ttctgtggat aaccgtatta ccgcctttga 15240 gtgagctgat accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga 15300 agcggaagag cgcccaatac gcaaaccgcc tctccccgcg cgttggccga ttcattaatg 15360 cagctggcac gacaggtttc ccgactggaa agcgggcagt gagcgcaacg caattaatgt 15420 gagttagctc actcattagg caccccaggc tttacacttt atgctcccgg ctcgtatgtt 15480 gtgtggaatt gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc 15540 caagcgcgca attaaccctc actaaaggga acaaaagctg ggtaccggcg cca 15593 <210> 56 <211> 15271 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 56 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgacagca gactgctgat 9720 gatgagcgtg tacgccctga gcgccatcat cggcatctac ctgctgtacc ggatgctgaa 9780 aacctgctga taatctagag gcccctataa ctctctacgg ctaacctgaa tggactacga 9840 catagtctag tccgccaaga tgtgcagaag gcccgactgc ggcttcagct tcagccctgg 9900 acccgtgatc ctgctgtggt gctgcctgct gctgcctatc gtgtcctctg ccgccgtgtc 9960 tgtggcccct acagccgccg agaaggtgcc agccgagtgc cccgagctga ccagaagatg 10020 cctgctgggc gaggtgttcg agggcgacaa gtacgagagc tggctgcggc ccctggtcaa 10080 cgtgaccggc agagatggcc ccctgagcca gctgatccgg tacagacccg tgacccccga 10140 ggccgccaat agcgtgctgc tggacgaggc cttcctggat accctggccc tgctgtacaa 10200 caaccccgac cagctgagag ccctgctgac cctgctgtcc agcgacaccg cccccagatg 10260 gatgaccgtg atgcggggct acagcgagtg tggagatggc agccctgccg tgtacacctg 10320 cgtggacgac ctgtgcagag gctacgacct gaccagactg agctacggcc ggtccatctt 10380 cacagagcac gtgctgggct tcgagctggt gccccccagc ctgttcaacg tggtggtggc 10440 catccggaac gaggccacca gaaccaacag agccgtgcgg ctgcctgtgt ctacagccgc 10500 tgcacctgag ggcatcacac tgttctacgg cctgtacaac gccgtgaaag agttctgcct 10560 ccggcaccag ctggatcccc ccctgctgag acacctggac aagtactacg ccggcctgcc 10620 cccagagctg aagcagacca gagtgaacct gcccgcccac agcagatatg gccctcaggc 10680 cgtggacgcc agatgataac gccggcggcc cctataactc tctacggcta acctgaatgg 10740 actacgacat agtctagtcc gccaagatga gccccaagga cctgaccccc ttcctgacaa 10800 ccctgtggct gctcctgggc catagcagag tgcctagagt gcgggccgag gaatgctgcg 10860 agttcatcaa cgtgaaccac ccccccgagc ggtgctacga cttcaagatg tgcaaccggt 10920 tcaccgtggc cctgagatgc cccgacggcg aagtgtgcta cagccccgag aaaaccgccg 10980 agatccgggg catcgtgacc accatgaccc acagcctgac ccggcaggtg gtgcacaaca 11040 agctgaccag ctgcaactac aaccccctgt acctggaagc cgacggccgg atcagatgcg 11100 gcaaagtgaa cgacaaggcc cagtacctgc tgggagccgc cggaagcgtg ccctaccggt 11160 ggatcaacct ggaatacgac aagatcaccc ggatcgtggg cctggaccag tacctggaaa 11220 gcgtgaagaa gcacaagcgg ctggacgtgt gcagagccaa gatgggctac atgctgcagc 11280 tgttgaattt tgaccttctt aagcttgcgg gagacgtcga gtccaacccc gggcccatgc 11340 tgcggctgct gctgagacac cacttccact gcctgctgct gtgtgccgtg tgggccaccc 11400 cttgtctggc cagcccttgg agcaccctga ccgccaacca gaaccctagc cccccttggt 11460 ccaagctgac ctacagcaag ccccacgacg ccgccacctt ctactgcccc tttctgtacc 11520 ccagccctcc cagaagcccc ctgcagttca gcggcttcca gagagtgtcc accggccctg 11580 agtgccggaa cgagacactg tacctgctgt acaaccggga gggccagaca ctggtggagc 11640 ggagcagcac ctgggtgaaa aaagtgatct ggtatctgag cggccggaac cagaccatcc 11700 tgcagcggat gcccagaacc gccagcaagc ccagcgacgg caacgtgcag atcagcgtgg 11760 aggacgccaa aatcttcggc gcccacatgg tgcccaagca gaccaagctg ctgagattcg 11820 tggtcaacga cggcaccaga tatcagatgt gcgtgatgaa gctggaaagc tgggcccacg 11880 tgttccggga ctactccgtg agcttccagg tccggctgac cttcaccgag gccaacaacc 11940 agacctacac cttctgcacc caccccaacc tgatcgtgct gctgaacttc gacctgctga 12000 agctggccgg cgacgtggag agcaaccccg gcccccatat gcggctgtgc agagtgtggc 12060 tgtccgtgtg cctgtgtgcc gtggtgctgg gccagtgcca gagagagaca gccgagaaga 12120 acgactacta ccgggtgccc cactactggg atgcctgcag cagagccctg cccgaccaga 12180 cccggtacaa atacgtggag cagctcgtgg acctgaccct gaactaccac tacgacgcca 12240 gccacggcct ggacaacttc gacgtgctga agcggatcaa cgtgaccgag gtgtccctgc 12300 tgatcagcga cttccggcgg cagaacagaa gaggcggcac caacaagcgg accaccttca 12360 acgccgctgg ctctctggcc cctcacgcca gatccctgga attcagcgtg cggctgttcg 12420 ccaactgata acgttgcatc ctgcaggata cagcagcaat tggcaagctg cttacataga 12480 actcgcggcg attggcatgc cgccttaaaa tttttatttt atttttcttt tcttttccga 12540 atcggatttt gtttttaata tttcaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaag 12600 ggtcggcatg gcatctccac ctcctcgcgg tccgacctgg gcatccgaag gaggacgcac 12660 gtccactcgg atggctaagg gagagccacg tttaaacgct agagcaagac gtttcccgtt 12720 gaatatggct cataacaccc cttgtattac tgtttatgta agcagacagt tttattgttc 12780 atgatgatat atttttatct tgtgcaatgt aacatcagag attttgagac acaacgtggc 12840 tttgttgaat aaatcgaact tttgctgagt tgaaggatca gatcacgcat cttcccgaca 12900 acgcagaccg ttccgtggca aagcaaaagt tcaaaatcac caactggtcc acctacaaca 12960 aagctctcat caaccgtggc tccctcactt tctggctgga tgatggggcg attcaggcct 13020 ggtatgagtc agcaacacct tcttcacgag gcagacctca gcgctagcgg agtgtatact 13080 ggcttactat gttggcactg atgagggtgt cagtgaagtg cttcatgtgg caggagaaaa 13140 aaggctgcac cggtgcgtca gcagaatatg tgatacagga tatattccgc ttcctcgctc 13200 actgactcgc tacgctcggt cgttcgactg cggcgagcgg aaatggctta cgaacggggc 13260 ggagatttcc tggaagatgc caggaagata cttaacaggg aagtgagagg gccgcggcaa 13320 agccgttttt ccataggctc cgcccccctg acaagcatca cgaaatctga cgctcaaatc 13380 agtggtggcg aaacccgaca ggactataaa gataccaggc gtttcccctg gcggctccct 13440 cgtgcgctct cctgttcctg cctttcggtt taccggtgtc attccgctgt tatggccgcg 13500 tttgtctcat tccacgcctg acactcagtt ccgggtaggc agttcgctcc aagctggact 13560 gtatgcacga accccccgtt cagtccgacc gctgcgcctt atccggtaac tatcgtcttg 13620 agtccaaccc ggaaagacat gcaaaagcac cactggcagc agccactggt aattgattta 13680 gaggagttag tcttgaagtc atgcgccggt taaggctaaa ctgaaaggac aagttttggt 13740 gactgcgctc ctccaagcca gttacctcgg ttcaaagagt tggtagctca gagaaccttc 13800 gaaaaaccgc cctgcaaggc ggttttttcg ttttcagagc aagagattac gcgcagacca 13860 aaacgatctc aagaagatca tcttattaag gggtctgacg ctcagtggaa cgaaaactca 13920 cgttaaggga ttttggtcat gagattatca aaaaggatct tcacctagat ccttttaaat 13980 taaaaatgaa gttttaaatc aatctaaagt atatatgagt aaacttggtc tgacagttat 14040 tagaaaaatt catccagcag acgataaaac gcaatacgct ggctatccgg tgccgcaatg 14100 ccatacagca ccagaaaacg atccgcccat tcgccgccca gttcttccgc aatatcacgg 14160 gtggccagcg caatatcctg ataacgatcc gccacgccca gacggccgca atcaataaag 14220 ccgctaaaac ggccattttc caccataatg ttcggcaggc acgcatcacc atgggtcacc 14280 accagatctt cgccatccgg catgctcgct ttcagacgcg caaacagctc tgccggtgcc 14340 aggccctgat gttcttcatc cagatcatcc tgatccacca ggcccgcttc catacgggta 14400 cgcgcacgtt caatacgatg tttcgcctga tgatcaaacg gacaggtcgc cgggtccagg 14460 gtatgcagac gacgcatggc atccgccata atgctcactt tttctgccgg cgccagatgg 14520 ctagacagca gatcctgacc cggcacttcg cccagcagca gccaatcacg gcccgcttcg 14580 gtcaccacat ccagcaccgc cgcacacgga acaccggtgg tggccagcca gctcagacgc 14640 gccgcttcat cctgcagctc gttcagcgca ccgctcagat cggttttcac aaacagcacc 14700 ggacgaccct gcgcgctcag acgaaacacc gccgcatcag agcagccaat ggtctgctgc 14760 gcccaatcat agccaaacag acgttccacc cacgctgccg ggctacccgc atgcaggcca 14820 tcctgttcaa tcatactctt cctttttcaa tattattgaa gcatttatca gggttattgt 14880 ctcatgagcg gatacatatt tgaatgtatt tagaaaaata aacaaatagg ggttccgcgc 14940 acatttcccc gaaaagtgcc acctaaattg taagcgttaa tattttgtta aaattcgcgt 15000 taaatttttg ttaaatcagc tcatttttta accaataggc cgaaatcggc aaaatccctt 15060 ataaatcaaa agaatagacc gagatagggt tgagtggccg ctacagggcg ctcccattcg 15120 ccattcaggc tgcgcaactg ttgggaaggg cgtttcggtg cgggcctctt cgctattacg 15180 ccagctggcg aaagggggat gtgctgcaag gcgattaagt tgggtaacgc cagggttttc 15240 ccagtcacac gcgtaatacg actcactata g 15271 <210> 57 <211> 16405 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 57 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgacagca gactgctgat 9720 gatgagcgtg tacgccctga gcgccatcat cggcatctac ctgctgtacc ggatgctgaa 9780 aacctgctga taatctagag gcccctataa ctctctacgg ctaacctgaa tggactacga 9840 catagtctag tccgccaaga tgtgcagaag gcccgactgc ggcttcagct tcagccctgg 9900 acccgtgatc ctgctgtggt gctgcctgct gctgcctatc gtgtcctctg ccgccgtgtc 9960 tgtggcccct acagccgccg agaaggtgcc agccgagtgc cccgagctga ccagaagatg 10020 cctgctgggc gaggtgttcg agggcgacaa gtacgagagc tggctgcggc ccctggtcaa 10080 cgtgaccggc agagatggcc ccctgagcca gctgatccgg tacagacccg tgacccccga 10140 ggccgccaat agcgtgctgc tggacgaggc cttcctggat accctggccc tgctgtacaa 10200 caaccccgac cagctgagag ccctgctgac cctgctgtcc agcgacaccg cccccagatg 10260 gatgaccgtg atgcggggct acagcgagtg tggagatggc agccctgccg tgtacacctg 10320 cgtggacgac ctgtgcagag gctacgacct gaccagactg agctacggcc ggtccatctt 10380 cacagagcac gtgctgggct tcgagctggt gccccccagc ctgttcaacg tggtggtggc 10440 catccggaac gaggccacca gaaccaacag agccgtgcgg ctgcctgtgt ctacagccgc 10500 tgcacctgag ggcatcacac tgttctacgg cctgtacaac gccgtgaaag agttctgcct 10560 ccggcaccag ctggatcccc ccctgctgag acacctggac aagtactacg ccggcctgcc 10620 cccagagctg aagcagacca gagtgaacct gcccgcccac agcagatatg gccctcaggc 10680 cgtggacgcc agatgataac gccggcggcc cctataactc tctacggcta acctgaatgg 10740 actacgacat agtctagtcc gccaagatga gccccaagga cctgaccccc ttcctgacaa 10800 ccctgtggct gctcctgggc catagcagag tgcctagagt gcgggccgag gaatgctgcg 10860 agttcatcaa cgtgaaccac ccccccgagc ggtgctacga cttcaagatg tgcaaccggt 10920 tcaccgtggc cctgagatgc cccgacggcg aagtgtgcta cagccccgag aaaaccgccg 10980 agatccgggg catcgtgacc accatgaccc acagcctgac ccggcaggtg gtgcacaaca 11040 agctgaccag ctgcaactac aaccccctgt acctggaagc cgacggccgg atcagatgcg 11100 gcaaagtgaa cgacaaggcc cagtacctgc tgggagccgc cggaagcgtg ccctaccggt 11160 ggatcaacct ggaatacgac aagatcaccc ggatcgtggg cctggaccag tacctggaaa 11220 gcgtgaagaa gcacaagcgg ctggacgtgt gcagagccaa gatgggctac atgctgcagt 11280 gataaggcgc gccaacgtta ctggccgaag ccgcttggaa taaggccggt gtgcgtttgt 11340 ctatatgtta ttttccacca tattgccgtc ttttggcaat gtgagggccc ggaaacctgg 11400 ccctgtcttc ttgacgagca ttcctagggg tctttcccct ctcgccaaag gaatgcaagg 11460 tctgttgaat gtcgtgaagg aagcagttcc tctggaagct tcttgaagac aaacaacgtc 11520 tgtagcgacc ctttgcaggc agcggaaccc cccacctggc gacaggtgcc tctgcggcca 11580 aaagccacgt gtataagata cacctgcaaa ggcggcacaa ccccagtgcc acgttgtgag 11640 ttggatagtt gtggaaagag tcaaatggct ctcctcaagc gtattcaaca aggggctgaa 11700 ggatgcccag aaggtacccc attgtatggg atctgatctg gggcctcggt gcacatgctt 11760 tacatgtgtt tagtcgaggt taaaaaaacg tctaggcccc ccgaaccacg gggacgtggt 11820 tttcctttga aaaacacgat aatatgctgc ggctgctgct gagacaccac ttccactgcc 11880 tgctgctgtg tgccgtgtgg gccacccctt gtctggccag cccttggagc accctgaccg 11940 ccaaccagaa ccctagcccc ccttggtcca agctgaccta cagcaagccc cacgacgccg 12000 ccaccttcta ctgccccttt ctgtacccca gccctcccag aagccccctg cagttcagcg 12060 gcttccagag agtgtccacc ggccctgagt gccggaacga gacactgtac ctgctgtaca 12120 accgggaggg ccagacactg gtggagcgga gcagcacctg ggtgaaaaaa gtgatctggt 12180 atctgagcgg ccggaaccag accatcctgc agcggatgcc cagaaccgcc agcaagccca 12240 gcgacggcaa cgtgcagatc agcgtggagg acgccaaaat cttcggagcc cacatggtgc 12300 ccaagcagac caagctgctg agattcgtgg tcaacgacgg caccagatat cagatgtgcg 12360 tgatgaagct ggaaagctgg gcccacgtgt tccgggacta ctccgtgagc ttccaggtcc 12420 ggctgacctt caccgaggcc aacaaccaga cctacacctt ctgcacccac cccaacctga 12480 tcgtgtgata agtacctttg tacgcctgtt ttataccccc tccctgattt gcaacttaga 12540 agcaacgcaa accagatcaa tagtaggtgt gacataccag tcgcatcttg atcaagcact 12600 tctgtatccc cggaccgagt atcaatagac tgtgcacacg gttgaaggag aaaacgtccg 12660 ttacccggct aactacttcg agaagcctag taacgccatt gaagttgcag agtgtttcgc 12720 tcagcactcc ccccgtgtag atcaggtcga tgagtcaccg cattccccac gggcgaccgt 12780 ggcggtggct gcgttggcgg cctgcctatg gggtaaccca taggacgctc taatacggac 12840 atggcgtgaa gagtctattg agctagttag tagtcctccg gcccctgaat gcggctaatc 12900 ctaactgcgg agcacatacc cttaatccaa agggcagtgt gtcgtaacgg gcaactctgc 12960 agcggaaccg actactttgg gtgtccgtgt ttctttttat tcttgtattg gctgcttatg 13020 gtgacaatta aagaattgtt accatatagc tattggattg gccatccagt gtcaaacaga 13080 gctattgtat atctctttgt tggattcaca cctctcactc ttgaaacgtt acacaccctc 13140 aattacatta tactgctgaa cacgaagcgc atatgcggct gtgcagagtg tggctgtccg 13200 tgtgcctgtg tgccgtggtg ctgggccagt gccagagaga gacagccgag aagaacgact 13260 actaccgggt gccccactac tgggatgcct gcagcagagc cctgcccgac cagacccggt 13320 acaaatacgt ggagcagctc gtggacctga ccctgaacta ccactacgac gccagccacg 13380 gcctggacaa cttcgacgtg ctgaagcgga tcaacgtgac cgaggtgtcc ctgctgatca 13440 gcgacttccg gcggcagaac agaagaggcg gcaccaacaa gcggaccacc ttcaacgccg 13500 ctggctctct ggcccctcac gccagatccc tggaattcag cgtgcggctg ttcgccaact 13560 gataacgttg catcctgcag gatacagcag caattggcaa gctgcttaca tagaactcgc 13620 ggcgattggc atgccgcctt aaaattttta ttttattttt cttttctttt ccgaatcgga 13680 ttttgttttt aatatttcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaagggtcgg 13740 catggcatct ccacctcctc gcggtccgac ctgggcatcc gaaggaggac gcacgtccac 13800 tcggatggct aagggagagc cacgtttaaa cgctagagca agacgtttcc cgttgaatat 13860 ggctcataac accccttgta ttactgttta tgtaagcaga cagttttatt gttcatgatg 13920 atatattttt atcttgtgca atgtaacatc agagattttg agacacaacg tggctttgtt 13980 gaataaatcg aacttttgct gagttgaagg atcagatcac gcatcttccc gacaacgcag 14040 accgttccgt ggcaaagcaa aagttcaaaa tcaccaactg gtccacctac aacaaagctc 14100 tcatcaaccg tggctccctc actttctggc tggatgatgg ggcgattcag gcctggtatg 14160 agtcagcaac accttcttca cgaggcagac ctcagcgcta gcggagtgta tactggctta 14220 ctatgttggc actgatgagg gtgtcagtga agtgcttcat gtggcaggag aaaaaaggct 14280 gcaccggtgc gtcagcagaa tatgtgatac aggatatatt ccgcttcctc gctcactgac 14340 tcgctacgct cggtcgttcg actgcggcga gcggaaatgg cttacgaacg gggcggagat 14400 ttcctggaag atgccaggaa gatacttaac agggaagtga gagggccgcg gcaaagccgt 14460 ttttccatag gctccgcccc cctgacaagc atcacgaaat ctgacgctca aatcagtggt 14520 ggcgaaaccc gacaggacta taaagatacc aggcgtttcc cctggcggct ccctcgtgcg 14580 ctctcctgtt cctgcctttc ggtttaccgg tgtcattccg ctgttatggc cgcgtttgtc 14640 tcattccacg cctgacactc agttccgggt aggcagttcg ctccaagctg gactgtatgc 14700 acgaaccccc cgttcagtcc gaccgctgcg ccttatccgg taactatcgt cttgagtcca 14760 acccggaaag acatgcaaaa gcaccactgg cagcagccac tggtaattga tttagaggag 14820 ttagtcttga agtcatgcgc cggttaaggc taaactgaaa ggacaagttt tggtgactgc 14880 gctcctccaa gccagttacc tcggttcaaa gagttggtag ctcagagaac cttcgaaaaa 14940 ccgccctgca aggcggtttt ttcgttttca gagcaagaga ttacgcgcag accaaaacga 15000 tctcaagaag atcatcttat taaggggtct gacgctcagt ggaacgaaaa ctcacgttaa 15060 gggattttgg tcatgagatt atcaaaaagg atcttcacct agatcctttt aaattaaaaa 15120 tgaagtttta aatcaatcta aagtatatat gagtaaactt ggtctgacag ttattagaaa 15180 aattcatcca gcagacgata aaacgcaata cgctggctat ccggtgccgc aatgccatac 15240 agcaccagaa aacgatccgc ccattcgccg cccagttctt ccgcaatatc acgggtggcc 15300 agcgcaatat cctgataacg atccgccacg cccagacggc cgcaatcaat aaagccgcta 15360 aaacggccat tttccaccat aatgttcggc aggcacgcat caccatgggt caccaccaga 15420 tcttcgccat ccggcatgct cgctttcaga cgcgcaaaca gctctgccgg tgccaggccc 15480 tgatgttctt catccagatc atcctgatcc accaggcccg cttccatacg ggtacgcgca 15540 cgttcaatac gatgtttcgc ctgatgatca aacggacagg tcgccgggtc cagggtatgc 15600 agacgacgca tggcatccgc cataatgctc actttttctg ccggcgccag atggctagac 15660 agcagatcct gacccggcac ttcgcccagc agcagccaat cacggcccgc ttcggtcacc 15720 acatccagca ccgccgcaca cggaacaccg gtggtggcca gccagctcag acgcgccgct 15780 tcatcctgca gctcgttcag cgcaccgctc agatcggttt tcacaaacag caccggacga 15840 ccctgcgcgc tcagacgaaa caccgccgca tcagagcagc caatggtctg ctgcgcccaa 15900 tcatagccaa acagacgttc cacccacgct gccgggctac ccgcatgcag gccatcctgt 15960 tcaatcatac tcttcctttt tcaatattat tgaagcattt atcagggtta ttgtctcatg 16020 agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 16080 ccccgaaaag tgccacctaa attgtaagcg ttaatatttt gttaaaattc gcgttaaatt 16140 tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaaaatc ccttataaat 16200 caaaagaata gaccgagata gggttgagtg gccgctacag ggcgctccca ttcgccattc 16260 aggctgcgca actgttggga agggcgtttc ggtgcgggcc tcttcgctat tacgccagct 16320 ggcgaaaggg ggatgtgctg caaggcgatt aagttgggta acgccagggt tttcccagtc 16380 acacgcgtaa tacgactcac tatag 16405 <210> 58 <211> 13102 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 58 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgactgat aatctagagg 9720 cccctataac tctctacggc taacctgaat ggactacgac atagtctagt ccgccaagat 9780 gtgcagaagg cccgactgcg gcttcagctt cagccctgga cccgtgatcc tgctgtggtg 9840 ctgcctgctg ctgcctatcg tgtcctctgc cgccgtgtct gtggccccta cagccgccga 9900 gaaggtgcca gccgagtgcc ccgagctgac cagaagatgc ctgctgggcg aggtgttcga 9960 gggcgacaag tacgagagct ggctgcggcc cctggtcaac gtgaccggca gagatggccc 10020 cctgagccag ctgatccggt acagacccgt gacccccgag gccgccaata gcgtgctgct 10080 ggacgaggcc ttcctggata ccctggccct gctgtacaac aaccccgacc agctgagagc 10140 cctgctgacc ctgctgtcca gcgacaccgc ccccagatgg atgaccgtga tgcggggcta 10200 cagcgagtgt ggagatggca gccctgccgt gtacacctgc gtggacgacc tgtgcagagg 10260 ctacgacctg accagactga gctacggccg gtccatcttc acagagcacg tgctgggctt 10320 cgagctggtg ccccccagcc tgttcaacgt ggtggtggcc atccggaacg aggccaccag 10380 aaccaacaga gccgtgcggc tgcctgtgtc tacagccgct gcacctgagg gcatcacact 10440 gttctacggc ctgtacaacg ccgtgaaaga gttctgcctc cggcaccagc tggatccccc 10500 cctgctgaga cacctggaca agtactacgc cggcctgccc ccagagctga agcagaccag 10560 agtgaacctg cccgcccaca gcagatatgg ccctcaggcc gtggacgcca gatgataagc 10620 ggccgcatac agcagcaatt ggcaagctgc ttacatagaa ctcgcggcga ttggcatgcc 10680 gccttaaaat ttttatttta tttttctttt cttttccgaa tcggattttg tttttaatat 10740 ttcaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaagg gtcggcatgg catctccacc 10800 tcctcgcggt ccgacctggg catccgaagg aggacgcacg tccactcgga tggctaaggg 10860 agagccacgt ttaaacacgt gatatctggc ctcatgggcc ttcctttcac tgcccgcttt 10920 ccagtcggga aacctgtcgt gccagctgca ttaacatggt catagctgtt tccttgcgta 10980 ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc gggtaaagcc 11040 tggggtgcct aatgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 11100 ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 11160 cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 11220 ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 11280 tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 11340 gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 11400 tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 11460 gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 11520 tggtggccta actacggcta cactagaaga acagtatttg gtatctgcgc tctgctgaag 11580 ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 11640 agcggtggtt tttttgtttg caagcagcag attacgcgca gaaaaaaagg atctcaagaa 11700 gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 11760 attttggtca tgagattatc aaaaaggatc ttcacctaga tccttttaaa ttaaaaatga 11820 agttttaaat caatctaaag tatatatgag taaacttggt ctgacagtta ttagaaaaat 11880 tcatccagca gacgataaaa cgcaatacgc tggctatccg gtgccgcaat gccatacagc 11940 accagaaaac gatccgccca ttcgccgccc agttcttccg caatatcacg ggtggccagc 12000 gcaatatcct gataacgatc cgccacgccc agacggccgc aatcaataaa gccgctaaaa 12060 cggccatttt ccaccataat gttcggcagg cacgcatcac catgggtcac caccagatct 12120 tcgccatccg gcatgctcgc tttcagacgc gcaaacagct ctgccggtgc caggccctga 12180 tgttcttcat ccagatcatc ctgatccacc aggcccgctt ccatacgggt acgcgcacgt 12240 tcaatacgat gtttcgcctg atgatcaaac ggacaggtcg ccgggtccag ggtatgcaga 12300 cgacgcatgg catccgccat aatgctcact ttttctgccg gcgccagatg gctagacagc 12360 agatcctgac ccggcacttc gcccagcagc agccaatcac ggcccgcttc ggtcaccaca 12420 tccagcaccg ccgcacacgg aacaccggtg gtggccagcc agctcagacg cgccgcttca 12480 tcctgcagct cgttcagcgc accgctcaga tcggttttca caaacagcac cggacgaccc 12540 tgcgcgctca gacgaaacac cgccgcatca gagcagccaa tggtctgctg cgcccaatca 12600 tagccaaaca gacgttccac ccacgctgcc gggctacccg catgcaggcc atcctgttca 12660 atcatactct tcctttttca atattattga agcatttatc agggttattg tctcatgagc 12720 ggatacatat ttgaatgtat ttagaaaaat aaacaaatag gggttccgcg cacatttccc 12780 cgaaaagtgc cacctaaatt gtaagcgtta atattttgtt aaaattcgcg ttaaattttt 12840 gttaaatcag ctcatttttt aaccaatagg ccgaaatcgg caaaatccct tataaatcaa 12900 aagaatagac cgagataggg ttgagtggcc gctacagggc gctcccattc gccattcagg 12960 ctgcgcaact gttgggaagg gcgtttcggt gcgggcctct tcgctattac gccagctggc 13020 gaaaggggga tgtgctgcaa ggcgattaag ttgggtaacg ccagggtttt cccagtcaca 13080 cgcgtaatac gactcactat ag 13102 <210> 59 <211> 13087 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 59 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgacctgt tgaattttga 9720 ccttcttaag cttgcgggag acgtcgagtc caaccccggg cccatgtgca gaaggcccga 9780 ctgcggcttc agcttcagcc ctggacccgt gatcctgctg tggtgctgcc tgctgctgcc 9840 tatcgtgtcc tctgccgccg tgtctgtggc ccctacagcc gccgagaagg tgccagccga 9900 gtgccccgag ctgaccagaa gatgcctgct gggcgaggtg ttcgagggcg acaagtacga 9960 gagctggctg cggcccctgg tcaacgtgac cggcagagat ggccccctga gccagctgat 10020 ccggtacaga cccgtgaccc ccgaggccgc caatagcgtg ctgctggacg aggccttcct 10080 ggataccctg gccctgctgt acaacaaccc cgaccagctg agagccctgc tgaccctgct 10140 gtccagcgac accgccccca gatggatgac cgtgatgcgg ggctacagcg agtgtggaga 10200 tggcagccct gccgtgtaca cctgcgtgga cgacctgtgc agaggctacg acctgaccag 10260 actgagctac ggccggtcca tcttcacaga gcacgtgctg ggcttcgagc tggtgccccc 10320 cagcctgttc aacgtggtgg tggccatccg gaacgaggcc accagaacca acagagccgt 10380 gcggctgcct gtgtctacag ccgctgcacc tgagggcatc acactgttct acggcctgta 10440 caacgccgtg aaagagttct gcctccggca ccagctggat ccccccctgc tgagacacct 10500 ggacaagtac tacgccggcc tgcccccaga gctgaagcag accagagtga acctgcccgc 10560 ccacagcaga tatggccctc aggccgtgga cgccagatga taagcggccg catacagcag 10620 caattggcaa gctgcttaca tagaactcgc ggcgattggc atgccgcctt aaaattttta 10680 ttttattttt cttttctttt ccgaatcgga ttttgttttt aatatttcaa aaaaaaaaaa 10740 aaaaaaaaaa aaaaaaaaaa aaagggtcgg catggcatct ccacctcctc gcggtccgac 10800 ctgggcatcc gaaggaggac gcacgtccac tcggatggct aagggagagc cacgtttaaa 10860 cacgtgatat ctggcctcat gggccttcct ttcactgccc gctttccagt cgggaaacct 10920 gtcgtgccag ctgcattaac atggtcatag ctgtttcctt gcgtattggg cgctctccgc 10980 ttcctcgctc actgactcgc tgcgctcggt cgttcgggta aagcctgggg tgcctaatga 11040 gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg cgttgctggc gtttttccat 11100 aggctccgcc cccctgacga gcatcacaaa aatcgacgct caagtcagag gtggcgaaac 11160 ccgacaggac tataaagata ccaggcgttt ccccctggaa gctccctcgt gcgctctcct 11220 gttccgaccc tgccgcttac cggatacctg tccgcctttc tcccttcggg aagcgtggcg 11280 ctttctcata gctcacgctg taggtatctc agttcggtgt aggtcgttcg ctccaagctg 11340 ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg ccttatccgg taactatcgt 11400 cttgagtcca acccggtaag acacgactta tcgccactgg cagcagccac tggtaacagg 11460 attagcagag cgaggtatgt aggcggtgct acagagttct tgaagtggtg gcctaactac 11520 ggctacacta gaagaacagt atttggtatc tgcgctctgc tgaagccagt taccttcgga 11580 aaaagagttg gtagctcttg atccggcaaa caaaccaccg ctggtagcgg tggttttttt 11640 gtttgcaagc agcagattac gcgcagaaaa aaaggatctc aagaagatcc tttgatcttt 11700 tctacggggt ctgacgctca gtggaacgaa aactcacgtt aagggatttt ggtcatgaga 11760 ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa aatgaagttt taaatcaatc 11820 taaagtatat atgagtaaac ttggtctgac agttattaga aaaattcatc cagcagacga 11880 taaaacgcaa tacgctggct atccggtgcc gcaatgccat acagcaccag aaaacgatcc 11940 gcccattcgc cgcccagttc ttccgcaata tcacgggtgg ccagcgcaat atcctgataa 12000 cgatccgcca cgcccagacg gccgcaatca ataaagccgc taaaacggcc attttccacc 12060 ataatgttcg gcaggcacgc atcaccatgg gtcaccacca gatcttcgcc atccggcatg 12120 ctcgctttca gacgcgcaaa cagctctgcc ggtgccaggc cctgatgttc ttcatccaga 12180 tcatcctgat ccaccaggcc cgcttccata cgggtacgcg cacgttcaat acgatgtttc 12240 gcctgatgat caaacggaca ggtcgccggg tccagggtat gcagacgacg catggcatcc 12300 gccataatgc tcactttttc tgccggcgcc agatggctag acagcagatc ctgacccggc 12360 acttcgccca gcagcagcca atcacggccc gcttcggtca ccacatccag caccgccgca 12420 cacggaacac cggtggtggc cagccagctc agacgcgccg cttcatcctg cagctcgttc 12480 agcgcaccgc tcagatcggt tttcacaaac agcaccggac gaccctgcgc gctcagacga 12540 aacaccgccg catcagagca gccaatggtc tgctgcgccc aatcatagcc aaacagacgt 12600 tccacccacg ctgccgggct acccgcatgc aggccatcct gttcaatcat actcttcctt 12660 tttcaatatt attgaagcat ttatcagggt tattgtctca tgagcggata catatttgaa 12720 tgtatttaga aaaataaaca aataggggtt ccgcgcacat ttccccgaaa agtgccacct 12780 aaattgtaag cgttaatatt ttgttaaaat tcgcgttaaa tttttgttaa atcagctcat 12840 tttttaacca ataggccgaa atcggcaaaa tcccttataa atcaaaagaa tagaccgaga 12900 tagggttgag tggccgctac agggcgctcc cattcgccat tcaggctgcg caactgttgg 12960 gaagggcgtt tcggtgcggg cctcttcgct attacgccag ctggcgaaag ggggatgtgc 13020 tgcaaggcga ttaagttggg taacgccagg gttttcccag tcacacgcgt aatacgactc 13080 actatag 13087 <210> 60 <211> 13788 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 60 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgactgat aatctagatt 9720 aaaacagctg tgggttgttc ccacccacag ggcccactgg gcgctagcac tctgatttta 9780 cgaaatcctt gtgcgcctgt tttatatccc ttccctaatt cgaaacgtag aagcaatgcg 9840 caccactgat caatagtagg cgtaacgcgc cagttacgtc atgatcaagc atatctgttc 9900 ccccggactg agtatcaata gactgcttac gcggttgaag gagaaaacgt tcgttatccg 9960 gctaactact tcgagaagcc cagtaacacc atggaagctg cagggtgttt cgctcagcac 10020 ttcccccgtg tagatcaggt cgatgagcca ctgcaatccc cacaggtgac tgtggcagtg 10080 gctgcgttgg cggcctgcct atggggagac ccataggacg ctctaatgtg gacatggtgc 10140 gaagagccta ttgagctagt tagtagtcct ccggcccctg aatgcggcta atcctaactg 10200 cggagcacat gccttcaacc cagagggtag tgtgtcgtaa tgggcaactc tgcagcggaa 10260 ccgactactt tgggtgtccg tgtttctttt tattcttata ttggctgctt atggtgacaa 10320 ttacagaatt gttaccatat agctattgga ttggccatcc ggtgtgtaat agagctgtta 10380 tatacctatt tgttggcttt gtaccactaa ctttaaaatc tataactacc ctcaacttta 10440 tattaaccct caatacagtt gaacatgtgc agaaggcccg actgcggctt cagcttcagc 10500 cctggacccg tgatcctgct gtggtgctgc ctgctgctgc ctatcgtgtc ctctgccgcc 10560 gtgtctgtgg cccctacagc cgccgagaag gtgccagccg agtgccccga gctgaccaga 10620 agatgcctgc tgggcgaggt gttcgagggc gacaagtacg agagctggct gcggcccctg 10680 gtcaacgtga ccggcagaga tggccccctg agccagctga tccggtacag acccgtgacc 10740 cccgaggccg ccaatagcgt gctgctggac gaggccttcc tggataccct ggccctgctg 10800 tacaacaacc ccgaccagct gagagccctg ctgaccctgc tgtccagcga caccgccccc 10860 agatggatga ccgtgatgcg gggctacagc gagtgtggag atggcagccc tgccgtgtac 10920 acctgcgtgg acgacctgtg cagaggctac gacctgacca gactgagcta cggccggtcc 10980 atcttcacag agcacgtgct gggcttcgag ctggtgcccc ccagcctgtt caacgtggtg 11040 gtggccatcc ggaacgaggc caccagaacc aacagagccg tgcggctgcc tgtgtctaca 11100 gccgctgcac ctgagggcat cacactgttc tacggcctgt acaacgccgt gaaagagttc 11160 tgcctccggc accagctgga tccccccctg ctgagacacc tggacaagta ctacgccggc 11220 ctgcccccag agctgaagca gaccagagtg aacctgcccg cccacagcag atatggccct 11280 caggccgtgg acgccagatg ataagcggcc gcatacagca gcaattggca agctgcttac 11340 atagaactcg cggcgattgg catgccgcct taaaattttt attttatttt tcttttcttt 11400 tccgaatcgg attttgtttt taatatttca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11460 aaaagggtcg gcatggcatc tccacctcct cgcggtccga cctgggcatc cgaaggagga 11520 cgcacgtcca ctcggatggc taagggagag ccacgtttaa acacgtgata tctggcctca 11580 tgggccttcc tttcactgcc cgctttccag tcgggaaacc tgtcgtgcca gctgcattaa 11640 catggtcata gctgtttcct tgcgtattgg gcgctctccg cttcctcgct cactgactcg 11700 ctgcgctcgg tcgttcgggt aaagcctggg gtgcctaatg agcaaaaggc cagcaaaagg 11760 ccaggaaccg taaaaaggcc gcgttgctgg cgtttttcca taggctccgc ccccctgacg 11820 agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat 11880 accaggcgtt tccccctgga agctccctcg tgcgctctcc tgttccgacc ctgccgctta 11940 ccggatacct gtccgccttt ctcccttcgg gaagcgtggc gctttctcat agctcacgct 12000 gtaggtatct cagttcggtg taggtcgttc gctccaagct gggctgtgtg cacgaacccc 12060 ccgttcagcc cgaccgctgc gccttatccg gtaactatcg tcttgagtcc aacccggtaa 12120 gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatg 12180 taggcggtgc tacagagttc ttgaagtggt ggcctaacta cggctacact agaagaacag 12240 tatttggtat ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt 12300 gatccggcaa acaaaccacc gctggtagcg gtggtttttt tgtttgcaag cagcagatta 12360 cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgctc 12420 agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca 12480 cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa 12540 cttggtctga cagttattag aaaaattcat ccagcagacg ataaaacgca atacgctggc 12600 tatccggtgc cgcaatgcca tacagcacca gaaaacgatc cgcccattcg ccgcccagtt 12660 cttccgcaat atcacgggtg gccagcgcaa tatcctgata acgatccgcc acgcccagac 12720 ggccgcaatc aataaagccg ctaaaacggc cattttccac cataatgttc ggcaggcacg 12780 catcaccatg ggtcaccacc agatcttcgc catccggcat gctcgctttc agacgcgcaa 12840 acagctctgc cggtgccagg ccctgatgtt cttcatccag atcatcctga tccaccaggc 12900 ccgcttccat acgggtacgc gcacgttcaa tacgatgttt cgcctgatga tcaaacggac 12960 aggtcgccgg gtccagggta tgcagacgac gcatggcatc cgccataatg ctcacttttt 13020 ctgccggcgc cagatggcta gacagcagat cctgacccgg cacttcgccc agcagcagcc 13080 aatcacggcc cgcttcggtc accacatcca gcaccgccgc acacggaaca ccggtggtgg 13140 ccagccagct cagacgcgcc gcttcatcct gcagctcgtt cagcgcaccg ctcagatcgg 13200 ttttcacaaa cagcaccgga cgaccctgcg cgctcagacg aaacaccgcc gcatcagagc 13260 agccaatggt ctgctgcgcc caatcatagc caaacagacg ttccacccac gctgccgggc 13320 tacccgcatg caggccatcc tgttcaatca tactcttcct ttttcaatat tattgaagca 13380 tttatcaggg ttattgtctc atgagcggat acatatttga atgtatttag aaaaataaac 13440 aaataggggt tccgcgcaca tttccccgaa aagtgccacc taaattgtaa gcgttaatat 13500 tttgttaaaa ttcgcgttaa atttttgtta aatcagctca ttttttaacc aataggccga 13560 aatcggcaaa atcccttata aatcaaaaga atagaccgag atagggttga gtggccgcta 13620 cagggcgctc ccattcgcca ttcaggctgc gcaactgttg ggaagggcgt ttcggtgcgg 13680 gcctcttcgc tattacgcca gctggcgaaa gggggatgtg ctgcaaggcg attaagttgg 13740 gtaacgccag ggttttccca gtcacacgcg taatacgact cactatag 13788 <210> 61 <211> 13788 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 61 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgtgcaga aggcccgact gcggcttcag cttcagccct ggacccgtga tcctgctgtg 7620 gtgctgcctg ctgctgccta tcgtgtcctc tgccgccgtg tctgtggccc ctacagccgc 7680 cgagaaggtg ccagccgagt gccccgagct gaccagaaga tgcctgctgg gcgaggtgtt 7740 cgagggcgac aagtacgaga gctggctgcg gcccctggtc aacgtgaccg gcagagatgg 7800 ccccctgagc cagctgatcc ggtacagacc cgtgaccccc gaggccgcca atagcgtgct 7860 gctggacgag gccttcctgg ataccctggc cctgctgtac aacaaccccg accagctgag 7920 agccctgctg accctgctgt ccagcgacac cgcccccaga tggatgaccg tgatgcgggg 7980 ctacagcgag tgtggagatg gcagccctgc cgtgtacacc tgcgtggacg acctgtgcag 8040 aggctacgac ctgaccagac tgagctacgg ccggtccatc ttcacagagc acgtgctggg 8100 cttcgagctg gtgcccccca gcctgttcaa cgtggtggtg gccatccgga acgaggccac 8160 cagaaccaac agagccgtgc ggctgcctgt gtctacagcc gctgcacctg agggcatcac 8220 actgttctac ggcctgtaca acgccgtgaa agagttctgc ctccggcacc agctggatcc 8280 ccccctgctg agacacctgg acaagtacta cgccggcctg cccccagagc tgaagcagac 8340 cagagtgaac ctgcccgccc acagcagata tggccctcag gccgtggacg ccagatgata 8400 atctagatta aaacagctgt gggttgttcc cacccacagg gcccactggg cgctagcact 8460 ctgattttac gaaatccttg tgcgcctgtt ttatatccct tccctaattc gaaacgtaga 8520 agcaatgcgc accactgatc aatagtaggc gtaacgcgcc agttacgtca tgatcaagca 8580 tatctgttcc cccggactga gtatcaatag actgcttacg cggttgaagg agaaaacgtt 8640 cgttatccgg ctaactactt cgagaagccc agtaacacca tggaagctgc agggtgtttc 8700 gctcagcact tcccccgtgt agatcaggtc gatgagccac tgcaatcccc acaggtgact 8760 gtggcagtgg ctgcgttggc ggcctgccta tggggagacc cataggacgc tctaatgtgg 8820 acatggtgcg aagagcctat tgagctagtt agtagtcctc cggcccctga atgcggctaa 8880 tcctaactgc ggagcacatg ccttcaaccc agagggtagt gtgtcgtaat gggcaactct 8940 gcagcggaac cgactacttt gggtgtccgt gtttcttttt attcttatat tggctgctta 9000 tggtgacaat tacagaattg ttaccatata gctattggat tggccatccg gtgtgtaata 9060 gagctgttat atacctattt gttggctttg taccactaac tttaaaatct ataactaccc 9120 tcaactttat attaaccctc aatacagttg aacatgaggc ctggcctgcc ctcctacctg 9180 atcatcctgg ccgtgtgcct gttcagccac ctgctgtcca gcagatacgg cgccgaggcc 9240 gtgagcgagc ccctggacaa ggctttccac ctgctgctga acacctacgg cagacccatc 9300 cggtttctgc gggagaacac cacccagtgc acctacaaca gcagcctgcg gaacagcacc 9360 gtcgtgagag agaacgccat cagcttcaac tttttccaga gctacaacca gtactacgtg 9420 ttccacatgc ccagatgcct gtttgccggc cctctggccg agcagttcct gaaccaggtg 9480 gacctgaccg agacactgga aagataccag cagcggctga atacctacgc cctggtgtcc 9540 aaggacctgg ccagctaccg gtcctttagc cagcagctca aggctcagga tagcctcggc 9600 gagcagccta ccaccgtgcc ccctcccatc gacctgagca tcccccacgt gtggatgcct 9660 ccccagacca cccctcacgg ctggaccgag agccacacca cctccggcct gcacagaccc 9720 cacttcaacc agacctgcat cctgttcgac ggccacgacc tgctgtttag caccgtgacc 9780 ccctgcctgc accagggctt ctacctgatc gacgagctga gatacgtgaa gatcaccctg 9840 accgaggatt tcttcgtggt caccgtgtcc atcgacgacg acacccccat gctgctgatc 9900 ttcggccacc tgcccagagt gctgttcaag gccccctacc agcgggacaa cttcatcctg 9960 cggcagaccg agaagcacga gctgctggtg ctggtcaaga aggaccagct gaaccggcac 10020 tcctacctga aggaccccga cttcctggac gccgccctgg acttcaacta cctggacctg 10080 agcgccctgc tgagaaacag cttccacaga tacgccgtgg acgtgctgaa gtccggacgg 10140 tgccagatgc tcgatcggcg gaccgtggag atggccttcg cctatgccct cgccctgttc 10200 gccgctgcca gacaggaaga ggctggcgcc caggtgtcag tgcccagagc cctggataga 10260 caggccgccc tgctgcagat ccaggaattc atgatcacct gcctgagcca gaccccccct 10320 agaaccaccc tgctgctgta ccccacagcc gtggatctgg ccaagagggc cctgtggacc 10380 cccaaccaga tcaccgacat cacaagcctc gtgcggctcg tgtacatcct gagcaagcag 10440 aaccagcagc acctgatccc ccagtgggcc ctgagacaga tcgccgactt cgccctgaag 10500 ctgcacaaga cccatctggc cagctttctg agcgccttcg ccaggcagga actgtacctg 10560 atgggcagcc tggtccacag catgctggtg cataccaccg agcggcggga gatcttcatc 10620 gtggagacag gcctgtgtag cctggccgag ctgtcccact ttacccagct gctggcccac 10680 cctcaccacg agtacctgag cgacctgtac accccctgca gcagcagcgg cagacgggac 10740 cacagcctgg aacggctgac cagactgttc cccgatgcca ccgtgcctgc tacagtgcct 10800 gccgccctgt ccatcctgtc caccatgcag cccagcaccc tggaaacctt ccccgacctg 10860 ttctgcctgc ccctgggcga gagctttagc gccctgaccg tgtccgagca cgtgtcctac 10920 atcgtgacca atcagtacct gatcaagggc atcagctacc ccgtgtccac cacagtcgtg 10980 ggccagagcc tgatcatcac ccagaccgac agccagacca agtgcgagct gacccggaac 11040 atgcacacca cacacagcat caccgtggcc ctgaacatca gcctggaaaa ctgcgctttc 11100 tgtcagtctg ccctgctgga atacgacgat acccagggcg tgatcaacat catgtacatg 11160 cacgacagcg acgacgtgct gttcgccctg gacccctaca acgaggtggt ggtgtccagc 11220 ccccggaccc actacctgat gctgctgaag aacggcaccg tgctggaagt gaccgacgtg 11280 gtggtggacg ccaccgactg ataagcggcc gcatacagca gcaattggca agctgcttac 11340 atagaactcg cggcgattgg catgccgcct taaaattttt attttatttt tcttttcttt 11400 tccgaatcgg attttgtttt taatatttca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 11460 aaaagggtcg gcatggcatc tccacctcct cgcggtccga cctgggcatc cgaaggagga 11520 cgcacgtcca ctcggatggc taagggagag ccacgtttaa acacgtgata tctggcctca 11580 tgggccttcc tttcactgcc cgctttccag tcgggaaacc tgtcgtgcca gctgcattaa 11640 catggtcata gctgtttcct tgcgtattgg gcgctctccg cttcctcgct cactgactcg 11700 ctgcgctcgg tcgttcgggt aaagcctggg gtgcctaatg agcaaaaggc cagcaaaagg 11760 ccaggaaccg taaaaaggcc gcgttgctgg cgtttttcca taggctccgc ccccctgacg 11820 agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat 11880 accaggcgtt tccccctgga agctccctcg tgcgctctcc tgttccgacc ctgccgctta 11940 ccggatacct gtccgccttt ctcccttcgg gaagcgtggc gctttctcat agctcacgct 12000 gtaggtatct cagttcggtg taggtcgttc gctccaagct gggctgtgtg cacgaacccc 12060 ccgttcagcc cgaccgctgc gccttatccg gtaactatcg tcttgagtcc aacccggtaa 12120 gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatg 12180 taggcggtgc tacagagttc ttgaagtggt ggcctaacta cggctacact agaagaacag 12240 tatttggtat ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt 12300 gatccggcaa acaaaccacc gctggtagcg gtggtttttt tgtttgcaag cagcagatta 12360 cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgctc 12420 agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca 12480 cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa 12540 cttggtctga cagttattag aaaaattcat ccagcagacg ataaaacgca atacgctggc 12600 tatccggtgc cgcaatgcca tacagcacca gaaaacgatc cgcccattcg ccgcccagtt 12660 cttccgcaat atcacgggtg gccagcgcaa tatcctgata acgatccgcc acgcccagac 12720 ggccgcaatc aataaagccg ctaaaacggc cattttccac cataatgttc ggcaggcacg 12780 catcaccatg ggtcaccacc agatcttcgc catccggcat gctcgctttc agacgcgcaa 12840 acagctctgc cggtgccagg ccctgatgtt cttcatccag atcatcctga tccaccaggc 12900 ccgcttccat acgggtacgc gcacgttcaa tacgatgttt cgcctgatga tcaaacggac 12960 aggtcgccgg gtccagggta tgcagacgac gcatggcatc cgccataatg ctcacttttt 13020 ctgccggcgc cagatggcta gacagcagat cctgacccgg cacttcgccc agcagcagcc 13080 aatcacggcc cgcttcggtc accacatcca gcaccgccgc acacggaaca ccggtggtgg 13140 ccagccagct cagacgcgcc gcttcatcct gcagctcgtt cagcgcaccg ctcagatcgg 13200 ttttcacaaa cagcaccgga cgaccctgcg cgctcagacg aaacaccgcc gcatcagagc 13260 agccaatggt ctgctgcgcc caatcatagc caaacagacg ttccacccac gctgccgggc 13320 tacccgcatg caggccatcc tgttcaatca tactcttcct ttttcaatat tattgaagca 13380 tttatcaggg ttattgtctc atgagcggat acatatttga atgtatttag aaaaataaac 13440 aaataggggt tccgcgcaca tttccccgaa aagtgccacc taaattgtaa gcgttaatat 13500 tttgttaaaa ttcgcgttaa atttttgtta aatcagctca ttttttaacc aataggccga 13560 aatcggcaaa atcccttata aatcaaaaga atagaccgag atagggttga gtggccgcta 13620 cagggcgctc ccattcgcca ttcaggctgc gcaactgttg ggaagggcgt ttcggtgcgg 13680 gcctcttcgc tattacgcca gctggcgaaa gggggatgtg ctgcaaggcg attaagttgg 13740 gtaacgccag ggttttccca gtcacacgcg taatacgact cactatag 13788 <210> 62 <211> 14202 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 62 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gctattccag aagtagtgag gaggcttttt tggaggccta ggcttttgca aaaagcttgt 7620 atatccattt tcggatctga tcaagagaca ggatgaggat cgtttcgcat gattgaataa 7680 gatggattgc acgtaggttc tccggccgct tgggtggaga ggctattcgg ctatgactgg 7740 gcacaactga caatcggctg ctctgatgcc gccgtgatcc ggttgtcagc gcaggggcgc 7800 ccggttcttt ttgtcaagac cgacctgtcc ggtgccctga atgaactgaa ggacgaggca 7860 gcgcggctat cgtggctggc cacgacgggc gttccttgcg cagtctagac tggcgcgcca 7920 aacctgcagg ttaaaacagc tgtgggttgt tcccacccac agggcccact gggcgctagc 7980 actctgattt tacgaaatcc ttgtgcgcct gttttatatc ccttccctaa ttcgaaacgt 8040 agaagcaatg cgcaccactg atcaatagta ggcgtaacgc gccagttacg tcatgatcaa 8100 gcatatctgt tcccccggac tgagtatcaa tagactgctt acgcggttga aggagaaaac 8160 gttcgttatc cggctaacta cttcgagaag cccagtaaca ccatggaagc tgcagggtgt 8220 ttcgctcagc acttcccccg tgtagatcag gtcgatgagc cactgcaatc cccacaggtg 8280 actgtggcag tggctgcgtt ggcggcctgc ctatggggag acccatagga cgctctaatg 8340 tggacatggt gcgaagagcc tattgagcta gttagtagtc ctccggcccc tgaatgcggc 8400 taatcctaac tgcggagcac atgccttcaa cccagagggt agtgtgtcgt aatgggcaac 8460 tctgcagcgg aaccgactac tttgggtgtc cgtgtttctt tttattctta tattggctgc 8520 ttatggtgac aattacagaa ttgttaccat atagctattg gattggccat ccggtgtgta 8580 atagagctgt tatataccta tttgttggct ttgtaccact aactttaaaa tctataacta 8640 ccctcaactt tatattaacc ctcaatacag ttgaacatga ggcctggcct gccctcctac 8700 ctgatcatcc tggccgtgtg cctgttcagc cacctgctgt ccagcagata cggcgccgag 8760 gccgtgagcg agcccctgga caaggctttc cacctgctgc tgaacaccta cggcagaccc 8820 atccggtttc tgcgggagaa caccacccag tgcacctaca acagcagcct gcggaacagc 8880 accgtcgtga gagagaacgc catcagcttc aactttttcc agagctacaa ccagtactac 8940 gtgttccaca tgcccagatg cctgtttgcc ggccctctgg ccgagcagtt cctgaaccag 9000 gtggacctga ccgagacact ggaaagatac cagcagcggc tgaataccta cgccctggtg 9060 tccaaggacc tggccagcta ccggtccttt agccagcagc tcaaggctca ggatagcctc 9120 ggcgagcagc ctaccaccgt gccccctccc atcgacctga gcatccccca cgtgtggatg 9180 cctccccaga ccacccctca cggctggacc gagagccaca ccacctccgg cctgcacaga 9240 ccccacttca accagacctg catcctgttc gacggccacg acctgctgtt tagcaccgtg 9300 accccctgcc tgcaccaggg cttctacctg atcgacgagc tgagatacgt gaagatcacc 9360 ctgaccgagg atttcttcgt ggtcaccgtg tccatcgacg acgacacccc catgctgctg 9420 atcttcggcc acctgcccag agtgctgttc aaggccccct accagcggga caacttcatc 9480 ctgcggcaga ccgagaagca cgagctgctg gtgctggtca agaaggacca gctgaaccgg 9540 cactcctacc tgaaggaccc cgacttcctg gacgccgccc tggacttcaa ctacctggac 9600 ctgagcgccc tgctgagaaa cagcttccac agatacgccg tggacgtgct gaagtccgga 9660 cggtgccaga tgctcgatcg gcggaccgtg gagatggcct tcgcctatgc cctcgccctg 9720 ttcgccgctg ccagacagga agaggctggc gcccaggtgt cagtgcccag agccctggat 9780 agacaggccg ccctgctgca gatccaggaa ttcatgatca cctgcctgag ccagaccccc 9840 cctagaacca ccctgctgct gtaccccaca gccgtggatc tggccaagag ggccctgtgg 9900 acccccaacc agatcaccga catcacaagc ctcgtgcggc tcgtgtacat cctgagcaag 9960 cagaaccagc agcacctgat cccccagtgg gccctgagac agatcgccga cttcgccctg 10020 aagctgcaca agacccatct ggccagcttt ctgagcgcct tcgccaggca ggaactgtac 10080 ctgatgggca gcctggtcca cagcatgctg gtgcatacca ccgagcggcg ggagatcttc 10140 atcgtggaga caggcctgtg tagcctggcc gagctgtccc actttaccca gctgctggcc 10200 caccctcacc acgagtacct gagcgacctg tacaccccct gcagcagcag cggcagacgg 10260 gaccacagcc tggaacggct gaccagactg ttccccgatg ccaccgtgcc tgctacagtg 10320 cctgccgccc tgtccatcct gtccaccatg cagcccagca ccctggaaac cttccccgac 10380 ctgttctgcc tgcccctggg cgagagcttt agcgccctga ccgtgtccga gcacgtgtcc 10440 tacatcgtga ccaatcagta cctgatcaag ggcatcagct accccgtgtc caccacagtc 10500 gtgggccaga gcctgatcat cacccagacc gacagccaga ccaagtgcga gctgacccgg 10560 aacatgcaca ccacacacag catcaccgtg gccctgaaca tcagcctgga aaactgcgct 10620 ttctgtcagt ctgccctgct ggaatacgac gatacccagg gcgtgatcaa catcatgtac 10680 atgcacgaca gcgacgacgt gctgttcgcc ctggacccct acaacgaggt ggtggtgtcc 10740 agcccccgga cccactacct gatgctgctg aagaacggca ccgtgctgga agtgaccgac 10800 gtggtggtgg acgccaccga cctgttgaat tttgaccttc ttaagcttgc gggagacgtc 10860 gagtccaacc ccgggcccat gtgcagaagg cccgactgcg gcttcagctt cagccctgga 10920 cccgtgatcc tgctgtggtg ctgcctgctg ctgcctatcg tgtcctctgc cgccgtgtct 10980 gtggccccta cagccgccga gaaggtgcca gccgagtgcc ccgagctgac cagaagatgc 11040 ctgctgggcg aggtgttcga gggcgacaag tacgagagct ggctgcggcc cctggtcaac 11100 gtgaccggca gagatggccc cctgagccag ctgatccggt acagacccgt gacccccgag 11160 gccgccaata gcgtgctgct ggacgaggcc ttcctggata ccctggccct gctgtacaac 11220 aaccccgacc agctgagagc cctgctgacc ctgctgtcca gcgacaccgc ccccagatgg 11280 atgaccgtga tgcggggcta cagcgagtgt ggagatggca gccctgccgt gtacacctgc 11340 gtggacgacc tgtgcagagg ctacgacctg accagactga gctacggccg gtccatcttc 11400 acagagcacg tgctgggctt cgagctggtg ccccccagcc tgttcaacgt ggtggtggcc 11460 atccggaacg aggccaccag aaccaacaga gccgtgcggc tgcctgtgtc tacagccgct 11520 gcacctgagg gcatcacact gttctacggc ctgtacaacg ccgtgaaaga gttctgcctc 11580 cggcaccagc tggatccccc cctgctgaga cacctggaca agtactacgc cggcctgccc 11640 ccagagctga agcagaccag agtgaacctg cccgcccaca gcagatatgg ccctcaggcc 11700 gtggacgcca gatgataagc ggccgcatac agcagcaatt ggcaagctgc ttacatagaa 11760 ctcgcggcga ttggcatgcc gccttaaaat ttttatttta tttttctttt cttttccgaa 11820 tcggattttg tttttaatat ttcaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaagg 11880 gtcggcatgg catctccacc tcctcgcggt ccgacctggg catccgaagg aggacgcacg 11940 tccactcgga tggctaaggg agagccacgt ttaaacacgt gatatctggc ctcatgggcc 12000 ttcctttcac tgcccgcttt ccagtcggga aacctgtcgt gccagctgca ttaacatggt 12060 catagctgtt tccttgcgta ttgggcgctc tccgcttcct cgctcactga ctcgctgcgc 12120 tcggtcgttc gggtaaagcc tggggtgcct aatgagcaaa aggccagcaa aaggccagga 12180 accgtaaaaa ggccgcgttg ctggcgtttt tccataggct ccgcccccct gacgagcatc 12240 acaaaaatcg acgctcaagt cagaggtggc gaaacccgac aggactataa agataccagg 12300 cgtttccccc tggaagctcc ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat 12360 acctgtccgc ctttctccct tcgggaagcg tggcgctttc tcatagctca cgctgtaggt 12420 atctcagttc ggtgtaggtc gttcgctcca agctgggctg tgtgcacgaa ccccccgttc 12480 agcccgaccg ctgcgcctta tccggtaact atcgtcttga gtccaacccg gtaagacacg 12540 acttatcgcc actggcagca gccactggta acaggattag cagagcgagg tatgtaggcg 12600 gtgctacaga gttcttgaag tggtggccta actacggcta cactagaaga acagtatttg 12660 gtatctgcgc tctgctgaag ccagttacct tcggaaaaag agttggtagc tcttgatccg 12720 gcaaacaaac caccgctggt agcggtggtt tttttgtttg caagcagcag attacgcgca 12780 gaaaaaaagg atctcaagaa gatcctttga tcttttctac ggggtctgac gctcagtgga 12840 acgaaaactc acgttaaggg attttggtca tgagattatc aaaaaggatc ttcacctaga 12900 tccttttaaa ttaaaaatga agttttaaat caatctaaag tatatatgag taaacttggt 12960 ctgacagtta ttagaaaaat tcatccagca gacgataaaa cgcaatacgc tggctatccg 13020 gtgccgcaat gccatacagc accagaaaac gatccgccca ttcgccgccc agttcttccg 13080 caatatcacg ggtggccagc gcaatatcct gataacgatc cgccacgccc agacggccgc 13140 aatcaataaa gccgctaaaa cggccatttt ccaccataat gttcggcagg cacgcatcac 13200 catgggtcac caccagatct tcgccatccg gcatgctcgc tttcagacgc gcaaacagct 13260 ctgccggtgc caggccctga tgttcttcat ccagatcatc ctgatccacc aggcccgctt 13320 ccatacgggt acgcgcacgt tcaatacgat gtttcgcctg atgatcaaac ggacaggtcg 13380 ccgggtccag ggtatgcaga cgacgcatgg catccgccat aatgctcact ttttctgccg 13440 gcgccagatg gctagacagc agatcctgac ccggcacttc gcccagcagc agccaatcac 13500 ggcccgcttc ggtcaccaca tccagcaccg ccgcacacgg aacaccggtg gtggccagcc 13560 agctcagacg cgccgcttca tcctgcagct cgttcagcgc accgctcaga tcggttttca 13620 caaacagcac cggacgaccc tgcgcgctca gacgaaacac cgccgcatca gagcagccaa 13680 tggtctgctg cgcccaatca tagccaaaca gacgttccac ccacgctgcc gggctacccg 13740 catgcaggcc atcctgttca atcatactct tcctttttca atattattga agcatttatc 13800 agggttattg tctcatgagc ggatacatat ttgaatgtat ttagaaaaat aaacaaatag 13860 gggttccgcg cacatttccc cgaaaagtgc cacctaaatt gtaagcgtta atattttgtt 13920 aaaattcgcg ttaaattttt gttaaatcag ctcatttttt aaccaatagg ccgaaatcgg 13980 caaaatccct tataaatcaa aagaatagac cgagataggg ttgagtggcc gctacagggc 14040 gctcccattc gccattcagg ctgcgcaact gttgggaagg gcgtttcggt gcgggcctct 14100 tcgctattac gccagctggc gaaaggggga tgtgctgcaa ggcgattaag ttgggtaacg 14160 ccagggtttt cccagtcaca cgcgtaatac gactcactat ag 14202 <210> 63 <211> 14721 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 63 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gctattccag aagtagtgag gaggcttttt tggaggccta ggcttttgca aaaagcttgt 7620 atatccattt tcggatctga tcaagagaca ggatgaggat cgtttcgcat gattgaataa 7680 gatggattgc acgtaggttc tccggccgct tgggtggaga ggctattcgg ctatgactgg 7740 gcacaactga caatcggctg ctctgatgcc gccgtgatcc ggttgtcagc gcaggggcgc 7800 ccggttcttt ttgtcaagac cgacctgtcc ggtgccctga atgaactgaa ggacgaggca 7860 gcgcggctat cgtggctggc cacgacgggc gttccttgcg cagtctagac tggcgcgcca 7920 aacctgcagg ttaaaacagc tgtgggttgt tcccacccac agggcccact gggcgctagc 7980 actctgattt tacgaaatcc ttgtgcgcct gttttatatc ccttccctaa ttcgaaacgt 8040 agaagcaatg cgcaccactg atcaatagta ggcgtaacgc gccagttacg tcatgatcaa 8100 gcatatctgt tcccccggac tgagtatcaa tagactgctt acgcggttga aggagaaaac 8160 gttcgttatc cggctaacta cttcgagaag cccagtaaca ccatggaagc tgcagggtgt 8220 ttcgctcagc acttcccccg tgtagatcag gtcgatgagc cactgcaatc cccacaggtg 8280 actgtggcag tggctgcgtt ggcggcctgc ctatggggag acccatagga cgctctaatg 8340 tggacatggt gcgaagagcc tattgagcta gttagtagtc ctccggcccc tgaatgcggc 8400 taatcctaac tgcggagcac atgccttcaa cccagagggt agtgtgtcgt aatgggcaac 8460 tctgcagcgg aaccgactac tttgggtgtc cgtgtttctt tttattctta tattggctgc 8520 ttatggtgac aattacagaa ttgttaccat atagctattg gattggccat ccggtgtgta 8580 atagagctgt tatataccta tttgttggct ttgtaccact aactttaaaa tctataacta 8640 ccctcaactt tatattaacc ctcaatacag ttgaacatga ggcctggcct gccctcctac 8700 ctgatcatcc tggccgtgtg cctgttcagc cacctgctgt ccagcagata cggcgccgag 8760 gccgtgagcg agcccctgga caaggctttc cacctgctgc tgaacaccta cggcagaccc 8820 atccggtttc tgcgggagaa caccacccag tgcacctaca acagcagcct gcggaacagc 8880 accgtcgtga gagagaacgc catcagcttc aactttttcc agagctacaa ccagtactac 8940 gtgttccaca tgcccagatg cctgtttgcc ggccctctgg ccgagcagtt cctgaaccag 9000 gtggacctga ccgagacact ggaaagatac cagcagcggc tgaataccta cgccctggtg 9060 tccaaggacc tggccagcta ccggtccttt agccagcagc tcaaggctca ggatagcctc 9120 ggcgagcagc ctaccaccgt gccccctccc atcgacctga gcatccccca cgtgtggatg 9180 cctccccaga ccacccctca cggctggacc gagagccaca ccacctccgg cctgcacaga 9240 ccccacttca accagacctg catcctgttc gacggccacg acctgctgtt tagcaccgtg 9300 accccctgcc tgcaccaggg cttctacctg atcgacgagc tgagatacgt gaagatcacc 9360 ctgaccgagg atttcttcgt ggtcaccgtg tccatcgacg acgacacccc catgctgctg 9420 atcttcggcc acctgcccag agtgctgttc aaggccccct accagcggga caacttcatc 9480 ctgcggcaga ccgagaagca cgagctgctg gtgctggtca agaaggacca gctgaaccgg 9540 cactcctacc tgaaggaccc cgacttcctg gacgccgccc tggacttcaa ctacctggac 9600 ctgagcgccc tgctgagaaa cagcttccac agatacgccg tggacgtgct gaagtccgga 9660 cggtgccaga tgctcgatcg gcggaccgtg gagatggcct tcgcctatgc cctcgccctg 9720 ttcgccgctg ccagacagga agaggctggc gcccaggtgt cagtgcccag agccctggat 9780 agacaggccg ccctgctgca gatccaggaa ttcatgatca cctgcctgag ccagaccccc 9840 cctagaacca ccctgctgct gtaccccaca gccgtggatc tggccaagag ggccctgtgg 9900 acccccaacc agatcaccga catcacaagc ctcgtgcggc tcgtgtacat cctgagcaag 9960 cagaaccagc agcacctgat cccccagtgg gccctgagac agatcgccga cttcgccctg 10020 aagctgcaca agacccatct ggccagcttt ctgagcgcct tcgccaggca ggaactgtac 10080 ctgatgggca gcctggtcca cagcatgctg gtgcatacca ccgagcggcg ggagatcttc 10140 atcgtggaga caggcctgtg tagcctggcc gagctgtccc actttaccca gctgctggcc 10200 caccctcacc acgagtacct gagcgacctg tacaccccct gcagcagcag cggcagacgg 10260 gaccacagcc tggaacggct gaccagactg ttccccgatg ccaccgtgcc tgctacagtg 10320 cctgccgccc tgtccatcct gtccaccatg cagcccagca ccctggaaac cttccccgac 10380 ctgttctgcc tgcccctggg cgagagcttt agcgccctga ccgtgtccga gcacgtgtcc 10440 tacatcgtga ccaatcagta cctgatcaag ggcatcagct accccgtgtc caccacagtc 10500 gtgggccaga gcctgatcat cacccagacc gacagccaga ccaagtgcga gctgacccgg 10560 aacatgcaca ccacacacag catcaccgtg gccctgaaca tcagcctgga aaactgcgct 10620 ttctgtcagt ctgccctgct ggaatacgac gatacccagg gcgtgatcaa catcatgtac 10680 atgcacgaca gcgacgacgt gctgttcgcc ctggacccct acaacgaggt ggtggtgtcc 10740 agcccccgga cccactacct gatgctgctg aagaacggca ccgtgctgga agtgaccgac 10800 gtggtggtgg acgccaccga ctgataacgc cggcgccccc ccctaacgtt actggccgaa 10860 gccgcttgga ataaggccgg tgtgcgtttg tctatatgtt attttccacc atattgccgt 10920 cttttggcaa tgtgagggcc cggaaacctg gccctgtctt cttgacgagc attcctaggg 10980 gtctttcccc tctcgccaaa ggaatgcaag gtctgttgaa tgtcgtgaag gaagcagttc 11040 ctctggaagc ttcttgaaga caaacaacgt ctgtagcgac cctttgcagg cagcggaacc 11100 ccccacctgg cgacaggtgc ctctgcggcc aaaagccacg tgtataagat acacctgcaa 11160 aggcggcaca accccagtgc cacgttgtga gttggatagt tgtggaaaga gtcaaatggc 11220 tctcctcaag cgtattcaac aaggggctga aggatgccca gaaggtaccc cattgtatgg 11280 gatctgatct ggggcctcgg tgcacatgct ttacatgtgt ttagtcgagg ttaaaaaaac 11340 gtctaggccc cccgaaccac ggggacgtgg ttttcctttg aaaaacacga taataatatg 11400 tgcagaaggc ccgactgcgg cttcagcttc agccctggac ccgtgatcct gctgtggtgc 11460 tgcctgctgc tgcctatcgt gtcctctgcc gccgtgtctg tggcccctac agccgccgag 11520 aaggtgccag ccgagtgccc cgagctgacc agaagatgcc tgctgggcga ggtgttcgag 11580 ggcgacaagt acgagagctg gctgcggccc ctggtcaacg tgaccggcag agatggcccc 11640 ctgagccagc tgatccggta cagacccgtg acccccgagg ccgccaatag cgtgctgctg 11700 gacgaggcct tcctggatac cctggccctg ctgtacaaca accccgacca gctgagagcc 11760 ctgctgaccc tgctgtccag cgacaccgcc cccagatgga tgaccgtgat gcggggctac 11820 agcgagtgtg gagatggcag ccctgccgtg tacacctgcg tggacgacct gtgcagaggc 11880 tacgacctga ccagactgag ctacggccgg tccatcttca cagagcacgt gctgggcttc 11940 gagctggtgc cccccagcct gttcaacgtg gtggtggcca tccggaacga ggccaccaga 12000 accaacagag ccgtgcggct gcctgtgtct acagccgctg cacctgaggg catcacactg 12060 ttctacggcc tgtacaacgc cgtgaaagag ttctgcctcc ggcaccagct ggatcccccc 12120 ctgctgagac acctggacaa gtactacgcc ggcctgcccc cagagctgaa gcagaccaga 12180 gtgaacctgc ccgcccacag cagatatggc cctcaggccg tggacgccag atgataagcg 12240 gccgcataca gcagcaattg gcaagctgct tacatagaac tcgcggcgat tggcatgccg 12300 ccttaaaatt tttattttat ttttcttttc ttttccgaat cggattttgt ttttaatatt 12360 tcaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaggg tcggcatggc atctccacct 12420 cctcgcggtc cgacctgggc atccgaagga ggacgcacgt ccactcggat ggctaaggga 12480 gagccacgtt taaacacgtg atatctggcc tcatgggcct tcctttcact gcccgctttc 12540 cagtcgggaa acctgtcgtg ccagctgcat taacatggtc atagctgttt ccttgcgtat 12600 tgggcgctct ccgcttcctc gctcactgac tcgctgcgct cggtcgttcg ggtaaagcct 12660 ggggtgccta atgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag gccgcgttgc 12720 tggcgttttt ccataggctc cgcccccctg acgagcatca caaaaatcga cgctcaagtc 12780 agaggtggcg aaacccgaca ggactataaa gataccaggc gtttccccct ggaagctccc 12840 tcgtgcgctc tcctgttccg accctgccgc ttaccggata cctgtccgcc tttctccctt 12900 cgggaagcgt ggcgctttct catagctcac gctgtaggta tctcagttcg gtgtaggtcg 12960 ttcgctccaa gctgggctgt gtgcacgaac cccccgttca gcccgaccgc tgcgccttat 13020 ccggtaacta tcgtcttgag tccaacccgg taagacacga cttatcgcca ctggcagcag 13080 ccactggtaa caggattagc agagcgaggt atgtaggcgg tgctacagag ttcttgaagt 13140 ggtggcctaa ctacggctac actagaagaa cagtatttgg tatctgcgct ctgctgaagc 13200 cagttacctt cggaaaaaga gttggtagct cttgatccgg caaacaaacc accgctggta 13260 gcggtggttt ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga tctcaagaag 13320 atcctttgat cttttctacg gggtctgacg ctcagtggaa cgaaaactca cgttaaggga 13380 ttttggtcat gagattatca aaaaggatct tcacctagat ccttttaaat taaaaatgaa 13440 gttttaaatc aatctaaagt atatatgagt aaacttggtc tgacagttat tagaaaaatt 13500 catccagcag acgataaaac gcaatacgct ggctatccgg tgccgcaatg ccatacagca 13560 ccagaaaacg atccgcccat tcgccgccca gttcttccgc aatatcacgg gtggccagcg 13620 caatatcctg ataacgatcc gccacgccca gacggccgca atcaataaag ccgctaaaac 13680 ggccattttc caccataatg ttcggcaggc acgcatcacc atgggtcacc accagatctt 13740 cgccatccgg catgctcgct ttcagacgcg caaacagctc tgccggtgcc aggccctgat 13800 gttcttcatc cagatcatcc tgatccacca ggcccgcttc catacgggta cgcgcacgtt 13860 caatacgatg tttcgcctga tgatcaaacg gacaggtcgc cgggtccagg gtatgcagac 13920 gacgcatggc atccgccata atgctcactt tttctgccgg cgccagatgg ctagacagca 13980 gatcctgacc cggcacttcg cccagcagca gccaatcacg gcccgcttcg gtcaccacat 14040 ccagcaccgc cgcacacgga acaccggtgg tggccagcca gctcagacgc gccgcttcat 14100 cctgcagctc gttcagcgca ccgctcagat cggttttcac aaacagcacc ggacgaccct 14160 gcgcgctcag acgaaacacc gccgcatcag agcagccaat ggtctgctgc gcccaatcat 14220 agccaaacag acgttccacc cacgctgccg ggctacccgc atgcaggcca tcctgttcaa 14280 tcatactctt cctttttcaa tattattgaa gcatttatca gggttattgt ctcatgagcg 14340 gatacatatt tgaatgtatt tagaaaaata aacaaatagg ggttccgcgc acatttcccc 14400 gaaaagtgcc acctaaattg taagcgttaa tattttgtta aaattcgcgt taaatttttg 14460 ttaaatcagc tcatttttta accaataggc cgaaatcggc aaaatccctt ataaatcaaa 14520 agaatagacc gagatagggt tgagtggccg ctacagggcg ctcccattcg ccattcaggc 14580 tgcgcaactg ttgggaaggg cgtttcggtg cgggcctctt cgctattacg ccagctggcg 14640 aaagggggat gtgctgcaag gcgattaagt tgggtaacgc cagggttttc ccagtcacac 14700 gcgtaatacg actcactata g 14721 <210> 64 <211> 14721 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 64 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tcgacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gctattccag aagtagtgag gaggcttttt tggaggccta ggcttttgca aaaagcttgt 7620 atatccattt tcggatctga tcaagagaca ggatgaggat cgtttcgcat gattgaataa 7680 gatggattgc acgtaggttc tccggccgct tgggtggaga ggctattcgg ctatgactgg 7740 gcacaactga caatcggctg ctctgatgcc gccgtgatcc ggttgtcagc gcaggggcgc 7800 ccggttcttt ttgtcaagac cgacctgtcc ggtgccctga atgaactgaa ggacgaggca 7860 gcgcggctat cgtggctggc cacgacgggc gttccttgcg cagtctagac tggcgcgcca 7920 aacctgcagg ttaaaacagc tgtgggttgt tcccacccac agggcccact gggcgctagc 7980 actctgattt tacgaaatcc ttgtgcgcct gttttatatc ccttccctaa ttcgaaacgt 8040 agaagcaatg cgcaccactg atcaatagta ggcgtaacgc gccagttacg tcatgatcaa 8100 gcatatctgt tcccccggac tgagtatcaa tagactgctt acgcggttga aggagaaaac 8160 gttcgttatc cggctaacta cttcgagaag cccagtaaca ccatggaagc tgcagggtgt 8220 ttcgctcagc acttcccccg tgtagatcag gtcgatgagc cactgcaatc cccacaggtg 8280 actgtggcag tggctgcgtt ggcggcctgc ctatggggag acccatagga cgctctaatg 8340 tggacatggt gcgaagagcc tattgagcta gttagtagtc ctccggcccc tgaatgcggc 8400 taatcctaac tgcggagcac atgccttcaa cccagagggt agtgtgtcgt aatgggcaac 8460 tctgcagcgg aaccgactac tttgggtgtc cgtgtttctt tttattctta tattggctgc 8520 ttatggtgac aattacagaa ttgttaccat atagctattg gattggccat ccggtgtgta 8580 atagagctgt tatataccta tttgttggct ttgtaccact aactttaaaa tctataacta 8640 ccctcaactt tatattaacc ctcaatacag ttgaacatgt gcagaaggcc cgactgcggc 8700 ttcagcttca gccctggacc cgtgatcctg ctgtggtgct gcctgctgct gcctatcgtg 8760 tcctctgccg ccgtgtctgt ggcccctaca gccgccgaga aggtgccagc cgagtgcccc 8820 gagctgacca gaagatgcct gctgggcgag gtgttcgagg gcgacaagta cgagagctgg 8880 ctgcggcccc tggtcaacgt gaccggcaga gatggccccc tgagccagct gatccggtac 8940 agacccgtga cccccgaggc cgccaatagc gtgctgctgg acgaggcctt cctggatacc 9000 ctggccctgc tgtacaacaa ccccgaccag ctgagagccc tgctgaccct gctgtccagc 9060 gacaccgccc ccagatggat gaccgtgatg cggggctaca gcgagtgtgg agatggcagc 9120 cctgccgtgt acacctgcgt ggacgacctg tgcagaggct acgacctgac cagactgagc 9180 tacggccggt ccatcttcac agagcacgtg ctgggcttcg agctggtgcc ccccagcctg 9240 ttcaacgtgg tggtggccat ccggaacgag gccaccagaa ccaacagagc cgtgcggctg 9300 cctgtgtcta cagccgctgc acctgagggc atcacactgt tctacggcct gtacaacgcc 9360 gtgaaagagt tctgcctccg gcaccagctg gatccccccc tgctgagaca cctggacaag 9420 tactacgccg gcctgccccc agagctgaag cagaccagag tgaacctgcc cgcccacagc 9480 agatatggcc ctcaggccgt ggacgccaga tgataacgcc ggcgcccccc cctaacgtta 9540 ctggccgaag ccgcttggaa taaggccggt gtgcgtttgt ctatatgtta ttttccacca 9600 tattgccgtc ttttggcaat gtgagggccc ggaaacctgg ccctgtcttc ttgacgagca 9660 ttcctagggg tctttcccct ctcgccaaag gaatgcaagg tctgttgaat gtcgtgaagg 9720 aagcagttcc tctggaagct tcttgaagac aaacaacgtc tgtagcgacc ctttgcaggc 9780 agcggaaccc cccacctggc gacaggtgcc tctgcggcca aaagccacgt gtataagata 9840 cacctgcaaa ggcggcacaa ccccagtgcc acgttgtgag ttggatagtt gtggaaagag 9900 tcaaatggct ctcctcaagc gtattcaaca aggggctgaa ggatgcccag aaggtacccc 9960 attgtatggg atctgatctg gggcctcggt gcacatgctt tacatgtgtt tagtcgaggt 10020 taaaaaaacg tctaggcccc ccgaaccacg gggacgtggt tttcctttga aaaacacgat 10080 aataatatga ggcctggcct gccctcctac ctgatcatcc tggccgtgtg cctgttcagc 10140 cacctgctgt ccagcagata cggcgccgag gccgtgagcg agcccctgga caaggctttc 10200 cacctgctgc tgaacaccta cggcagaccc atccggtttc tgcgggagaa caccacccag 10260 tgcacctaca acagcagcct gcggaacagc accgtcgtga gagagaacgc catcagcttc 10320 aactttttcc agagctacaa ccagtactac gtgttccaca tgcccagatg cctgtttgcc 10380 ggccctctgg ccgagcagtt cctgaaccag gtggacctga ccgagacact ggaaagatac 10440 cagcagcggc tgaataccta cgccctggtg tccaaggacc tggccagcta ccggtccttt 10500 agccagcagc tcaaggctca ggatagcctc ggcgagcagc ctaccaccgt gccccctccc 10560 atcgacctga gcatccccca cgtgtggatg cctccccaga ccacccctca cggctggacc 10620 gagagccaca ccacctccgg cctgcacaga ccccacttca accagacctg catcctgttc 10680 gacggccacg acctgctgtt tagcaccgtg accccctgcc tgcaccaggg cttctacctg 10740 atcgacgagc tgagatacgt gaagatcacc ctgaccgagg atttcttcgt ggtcaccgtg 10800 tccatcgacg acgacacccc catgctgctg atcttcggcc acctgcccag agtgctgttc 10860 aaggccccct accagcggga caacttcatc ctgcggcaga ccgagaagca cgagctgctg 10920 gtgctggtca agaaggacca gctgaaccgg cactcctacc tgaaggaccc cgacttcctg 10980 gacgccgccc tggacttcaa ctacctggac ctgagcgccc tgctgagaaa cagcttccac 11040 agatacgccg tggacgtgct gaagtccgga cggtgccaga tgctcgatcg gcggaccgtg 11100 gagatggcct tcgcctatgc cctcgccctg ttcgccgctg ccagacagga agaggctggc 11160 gcccaggtgt cagtgcccag agccctggat agacaggccg ccctgctgca gatccaggaa 11220 ttcatgatca cctgcctgag ccagaccccc cctagaacca ccctgctgct gtaccccaca 11280 gccgtggatc tggccaagag ggccctgtgg acccccaacc agatcaccga catcacaagc 11340 ctcgtgcggc tcgtgtacat cctgagcaag cagaaccagc agcacctgat cccccagtgg 11400 gccctgagac agatcgccga cttcgccctg aagctgcaca agacccatct ggccagcttt 11460 ctgagcgcct tcgccaggca ggaactgtac ctgatgggca gcctggtcca cagcatgctg 11520 gtgcatacca ccgagcggcg ggagatcttc atcgtggaga caggcctgtg tagcctggcc 11580 gagctgtccc actttaccca gctgctggcc caccctcacc acgagtacct gagcgacctg 11640 tacaccccct gcagcagcag cggcagacgg gaccacagcc tggaacggct gaccagactg 11700 ttccccgatg ccaccgtgcc tgctacagtg cctgccgccc tgtccatcct gtccaccatg 11760 cagcccagca ccctggaaac cttccccgac ctgttctgcc tgcccctggg cgagagcttt 11820 agcgccctga ccgtgtccga gcacgtgtcc tacatcgtga ccaatcagta cctgatcaag 11880 ggcatcagct accccgtgtc caccacagtc gtgggccaga gcctgatcat cacccagacc 11940 gacagccaga ccaagtgcga gctgacccgg aacatgcaca ccacacacag catcaccgtg 12000 gccctgaaca tcagcctgga aaactgcgct ttctgtcagt ctgccctgct ggaatacgac 12060 gatacccagg gcgtgatcaa catcatgtac atgcacgaca gcgacgacgt gctgttcgcc 12120 ctggacccct acaacgaggt ggtggtgtcc agcccccgga cccactacct gatgctgctg 12180 aagaacggca ccgtgctgga agtgaccgac gtggtggtgg acgccaccga ctgataagcg 12240 gccgcataca gcagcaattg gcaagctgct tacatagaac tcgcggcgat tggcatgccg 12300 ccttaaaatt tttattttat ttttcttttc ttttccgaat cggattttgt ttttaatatt 12360 tcaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaggg tcggcatggc atctccacct 12420 cctcgcggtc cgacctgggc atccgaagga ggacgcacgt ccactcggat ggctaaggga 12480 gagccacgtt taaacacgtg atatctggcc tcatgggcct tcctttcact gcccgctttc 12540 cagtcgggaa acctgtcgtg ccagctgcat taacatggtc atagctgttt ccttgcgtat 12600 tgggcgctct ccgcttcctc gctcactgac tcgctgcgct cggtcgttcg ggtaaagcct 12660 ggggtgccta atgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag gccgcgttgc 12720 tggcgttttt ccataggctc cgcccccctg acgagcatca caaaaatcga cgctcaagtc 12780 agaggtggcg aaacccgaca ggactataaa gataccaggc gtttccccct ggaagctccc 12840 tcgtgcgctc tcctgttccg accctgccgc ttaccggata cctgtccgcc tttctccctt 12900 cgggaagcgt ggcgctttct catagctcac gctgtaggta tctcagttcg gtgtaggtcg 12960 ttcgctccaa gctgggctgt gtgcacgaac cccccgttca gcccgaccgc tgcgccttat 13020 ccggtaacta tcgtcttgag tccaacccgg taagacacga cttatcgcca ctggcagcag 13080 ccactggtaa caggattagc agagcgaggt atgtaggcgg tgctacagag ttcttgaagt 13140 ggtggcctaa ctacggctac actagaagaa cagtatttgg tatctgcgct ctgctgaagc 13200 cagttacctt cggaaaaaga gttggtagct cttgatccgg caaacaaacc accgctggta 13260 gcggtggttt ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga tctcaagaag 13320 atcctttgat cttttctacg gggtctgacg ctcagtggaa cgaaaactca cgttaaggga 13380 ttttggtcat gagattatca aaaaggatct tcacctagat ccttttaaat taaaaatgaa 13440 gttttaaatc aatctaaagt atatatgagt aaacttggtc tgacagttat tagaaaaatt 13500 catccagcag acgataaaac gcaatacgct ggctatccgg tgccgcaatg ccatacagca 13560 ccagaaaacg atccgcccat tcgccgccca gttcttccgc aatatcacgg gtggccagcg 13620 caatatcctg ataacgatcc gccacgccca gacggccgca atcaataaag ccgctaaaac 13680 ggccattttc caccataatg ttcggcaggc acgcatcacc atgggtcacc accagatctt 13740 cgccatccgg catgctcgct ttcagacgcg caaacagctc tgccggtgcc aggccctgat 13800 gttcttcatc cagatcatcc tgatccacca ggcccgcttc catacgggta cgcgcacgtt 13860 caatacgatg tttcgcctga tgatcaaacg gacaggtcgc cgggtccagg gtatgcagac 13920 gacgcatggc atccgccata atgctcactt tttctgccgg cgccagatgg ctagacagca 13980 gatcctgacc cggcacttcg cccagcagca gccaatcacg gcccgcttcg gtcaccacat 14040 ccagcaccgc cgcacacgga acaccggtgg tggccagcca gctcagacgc gccgcttcat 14100 cctgcagctc gttcagcgca ccgctcagat cggttttcac aaacagcacc ggacgaccct 14160 gcgcgctcag acgaaacacc gccgcatcag agcagccaat ggtctgctgc gcccaatcat 14220 agccaaacag acgttccacc cacgctgccg ggctacccgc atgcaggcca tcctgttcaa 14280 tcatactctt cctttttcaa tattattgaa gcatttatca gggttattgt ctcatgagcg 14340 gatacatatt tgaatgtatt tagaaaaata aacaaatagg ggttccgcgc acatttcccc 14400 gaaaagtgcc acctaaattg taagcgttaa tattttgtta aaattcgcgt taaatttttg 14460 ttaaatcagc tcatttttta accaataggc cgaaatcggc aaaatccctt ataaatcaaa 14520 agaatagacc gagatagggt tgagtggccg ctacagggcg ctcccattcg ccattcaggc 14580 tgcgcaactg ttgggaaggg cgtttcggtg cgggcctctt cgctattacg ccagctggcg 14640 aaagggggat gtgctgcaag gcgattaagt tgggtaacgc cagggttttc ccagtcacac 14700 gcgtaatacg actcactata g 14721 <210> 65 <211> 15300 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 65 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgacagca gactgctgat 9720 gatgagcgtg tacgccctga gcgccatcat cggcatctac ctgctgtacc ggatgctgaa 9780 aacctgctga taatctagag gcccctataa ctctctacgg ctaacctgaa tggactacga 9840 catagtctag tccgccaaga tgtgcagaag gcccgactgc ggcttcagct tcagccctgg 9900 acccgtgatc ctgctgtggt gctgcctgct gctgcctatc gtgtcctctg ccgccgtgtc 9960 tgtggcccct acagccgccg agaaggtgcc agccgagtgc cccgagctga ccagaagatg 10020 cctgctgggc gaggtgttcg agggcgacaa gtacgagagc tggctgcggc ccctggtcaa 10080 cgtgaccggc agagatggcc ccctgagcca gctgatccgg tacagacccg tgacccccga 10140 ggccgccaat agcgtgctgc tggacgaggc cttcctggat accctggccc tgctgtacaa 10200 caaccccgac cagctgagag ccctgctgac cctgctgtcc agcgacaccg cccccagatg 10260 gatgaccgtg atgcggggct acagcgagtg tggagatggc agccctgccg tgtacacctg 10320 cgtggacgac ctgtgcagag gctacgacct gaccagactg agctacggcc ggtccatctt 10380 cacagagcac gtgctgggct tcgagctggt gccccccagc ctgttcaacg tggtggtggc 10440 catccggaac gaggccacca gaaccaacag agccgtgcgg ctgcctgtgt ctacagccgc 10500 tgcacctgag ggcatcacac tgttctacgg cctgtacaac gccgtgaaag agttctgcct 10560 ccggcaccag ctggatcccc ccctgctgag acacctggac aagtactacg ccggcctgcc 10620 cccagagctg aagcagacca gagtgaacct gcccgcccac agcagatatg gccctcaggc 10680 cgtggacgcc agatgataac gccggcggcc cctataactc tctacggcta acctgaatgg 10740 actacgacat agtctagtcc gccaagatga gccccaagga cctgaccccc ttcctgacaa 10800 ccctgtggct gctcctgggc catagcagag tgcctagagt gcgggccgag gaatgctgcg 10860 agttcatcaa cgtgaaccac ccccccgagc ggtgctacga cttcaagatg tgcaaccggt 10920 tcaccgtggc cctgagatgc cccgacggcg aagtgtgcta cagccccgag aaaaccgccg 10980 agatccgggg catcgtgacc accatgaccc acagcctgac ccggcaggtg gtgcacaaca 11040 agctgaccag ctgcaactac aaccccctgt acctggaagc cgacggccgg atcagatgcg 11100 gcaaagtgaa cgacaaggcc cagtacctgc tgggagccgc cggaagcgtg ccctaccggt 11160 ggatcaacct ggaatacgac aagatcaccc ggatcgtggg cctggaccag tacctggaaa 11220 gcgtgaagaa gcacaagcgg ctggacgtgt gcagagccaa gatgggctac atgctgcagt 11280 gataaggcgc gccgccccta taactctcta cggctaacct gaatggacta cgacatagtc 11340 tagtccgcca agatgctgcg gctgctgctg agacaccact tccactgcct gctgctgtgt 11400 gccgtgtggg ccaccccttg tctggccagc ccttggagca ccctgaccgc caaccagaac 11460 cctagccccc cttggtccaa gctgacctac agcaagcccc acgacgccgc caccttctac 11520 tgcccctttc tgtaccccag ccctcccaga agccccctgc agttcagcgg cttccagaga 11580 gtgtccaccg gccctgagtg ccggaacgag acactgtacc tgctgtacaa ccgggagggc 11640 cagacactgg tggagcggag cagcacctgg gtgaaaaaag tgatctggta tctgagcggc 11700 cggaaccaga ccatcctgca gcggatgccc agaaccgcca gcaagcccag cgacggcaac 11760 gtgcagatca gcgtggagga cgccaaaatc ttcggagccc acatggtgcc caagcagacc 11820 aagctgctga gattcgtggt caacgacggc accagatatc agatgtgcgt gatgaagctg 11880 gaaagctggg cccacgtgtt ccgggactac tccgtgagct tccaggtccg gctgaccttc 11940 accgaggcca acaaccagac ctacaccttc tgcacccacc ccaacctgat cgtgtgataa 12000 gcggccgcgc ccctataact ctctacggct aacctgaatg gactacgaca tagtctagtc 12060 cgccaagatg cggctgtgca gagtgtggct gtccgtgtgc ctgtgtgccg tggtgctggg 12120 ccagtgccag agagagacag ccgagaagaa cgactactac cgggtgcccc actactggga 12180 tgcctgcagc agagccctgc ccgaccagac ccggtacaaa tacgtggagc agctcgtgga 12240 cctgaccctg aactaccact acgacgccag ccacggcctg gacaacttcg acgtgctgaa 12300 gcggatcaac gtgaccgagg tgtccctgct gatcagcgac ttccggcggc agaacagaag 12360 aggcggcacc aacaagcgga ccaccttcaa cgccgctggc tctctggccc ctcacgccag 12420 atccctggaa ttcagcgtgc ggctgttcgc caactgataa cgttgcatcc tgcaggatac 12480 agcagcaatt ggcaagctgc ttacatagaa ctcgcggcga ttggcatgcc gccttaaaat 12540 ttttatttta tttttctttt cttttccgaa tcggattttg tttttaatat ttcaaaaaaa 12600 aaaaaaaaaa aaaaaaaaaa aaaaaaaagg gtcggcatgg catctccacc tcctcgcggt 12660 ccgacctggg catccgaagg aggacgcacg tccactcgga tggctaaggg agagccacgt 12720 ttaaacgcta gagcaagacg tttcccgttg aatatggctc ataacacccc ttgtattact 12780 gtttatgtaa gcagacagtt ttattgttca tgatgatata tttttatctt gtgcaatgta 12840 acatcagaga ttttgagaca caacgtggct ttgttgaata aatcgaactt ttgctgagtt 12900 gaaggatcag atcacgcatc ttcccgacaa cgcagaccgt tccgtggcaa agcaaaagtt 12960 caaaatcacc aactggtcca cctacaacaa agctctcatc aaccgtggct ccctcacttt 13020 ctggctggat gatggggcga ttcaggcctg gtatgagtca gcaacacctt cttcacgagg 13080 cagacctcag cgctagcgga gtgtatactg gcttactatg ttggcactga tgagggtgtc 13140 agtgaagtgc ttcatgtggc aggagaaaaa aggctgcacc ggtgcgtcag cagaatatgt 13200 gatacaggat atattccgct tcctcgctca ctgactcgct acgctcggtc gttcgactgc 13260 ggcgagcgga aatggcttac gaacggggcg gagatttcct ggaagatgcc aggaagatac 13320 ttaacaggga agtgagaggg ccgcggcaaa gccgtttttc cataggctcc gcccccctga 13380 caagcatcac gaaatctgac gctcaaatca gtggtggcga aacccgacag gactataaag 13440 ataccaggcg tttcccctgg cggctccctc gtgcgctctc ctgttcctgc ctttcggttt 13500 accggtgtca ttccgctgtt atggccgcgt ttgtctcatt ccacgcctga cactcagttc 13560 cgggtaggca gttcgctcca agctggactg tatgcacgaa ccccccgttc agtccgaccg 13620 ctgcgcctta tccggtaact atcgtcttga gtccaacccg gaaagacatg caaaagcacc 13680 actggcagca gccactggta attgatttag aggagttagt cttgaagtca tgcgccggtt 13740 aaggctaaac tgaaaggaca agttttggtg actgcgctcc tccaagccag ttacctcggt 13800 tcaaagagtt ggtagctcag agaaccttcg aaaaaccgcc ctgcaaggcg gttttttcgt 13860 tttcagagca agagattacg cgcagaccaa aacgatctca agaagatcat cttattaagg 13920 ggtctgacgc tcagtggaac gaaaactcac gttaagggat tttggtcatg agattatcaa 13980 aaaggatctt cacctagatc cttttaaatt aaaaatgaag ttttaaatca atctaaagta 14040 tatatgagta aacttggtct gacagttatt agaaaaattc atccagcaga cgataaaacg 14100 caatacgctg gctatccggt gccgcaatgc catacagcac cagaaaacga tccgcccatt 14160 cgccgcccag ttcttccgca atatcacggg tggccagcgc aatatcctga taacgatccg 14220 ccacgcccag acggccgcaa tcaataaagc cgctaaaacg gccattttcc accataatgt 14280 tcggcaggca cgcatcacca tgggtcacca ccagatcttc gccatccggc atgctcgctt 14340 tcagacgcgc aaacagctct gccggtgcca ggccctgatg ttcttcatcc agatcatcct 14400 gatccaccag gcccgcttcc atacgggtac gcgcacgttc aatacgatgt ttcgcctgat 14460 gatcaaacgg acaggtcgcc gggtccaggg tatgcagacg acgcatggca tccgccataa 14520 tgctcacttt ttctgccggc gccagatggc tagacagcag atcctgaccc ggcacttcgc 14580 ccagcagcag ccaatcacgg cccgcttcgg tcaccacatc cagcaccgcc gcacacggaa 14640 caccggtggt ggccagccag ctcagacgcg ccgcttcatc ctgcagctcg ttcagcgcac 14700 cgctcagatc ggttttcaca aacagcaccg gacgaccctg cgcgctcaga cgaaacaccg 14760 ccgcatcaga gcagccaatg gtctgctgcg cccaatcata gccaaacaga cgttccaccc 14820 acgctgccgg gctacccgca tgcaggccat cctgttcaat catactcttc ctttttcaat 14880 attattgaag catttatcag ggttattgtc tcatgagcgg atacatattt gaatgtattt 14940 agaaaaataa acaaataggg gttccgcgca catttccccg aaaagtgcca cctaaattgt 15000 aagcgttaat attttgttaa aattcgcgtt aaatttttgt taaatcagct cattttttaa 15060 ccaataggcc gaaatcggca aaatccctta taaatcaaaa gaatagaccg agatagggtt 15120 gagtggccgc tacagggcgc tcccattcgc cattcaggct gcgcaactgt tgggaagggc 15180 gtttcggtgc gggcctcttc gctattacgc cagctggcga aagggggatg tgctgcaagg 15240 cgattaagtt gggtaacgcc agggttttcc cagtcacacg cgtaatacga ctcactatag 15300 <210> 66 <211> 16324 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 66 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgactgat aatctagagg 9720 cccctataac tctctacggc taacctgaat ggactacgac atagtctagt ccgccaagat 9780 gtgcagaagg cccgactgcg gcttcagctt cagccctgga cccgtgatcc tgctgtggtg 9840 ctgcctgctg ctgcctatcg tgtcctctgc cgccgtgtct gtggccccta cagccgccga 9900 gaaggtgcca gccgagtgcc ccgagctgac cagaagatgc ctgctgggcg aggtgttcga 9960 gggcgacaag tacgagagct ggctgcggcc cctggtcaac gtgaccggca gagatggccc 10020 cctgagccag ctgatccggt acagacccgt gacccccgag gccgccaata gcgtgctgct 10080 ggacgaggcc ttcctggata ccctggccct gctgtacaac aaccccgacc agctgagagc 10140 cctgctgacc ctgctgtcca gcgacaccgc ccccagatgg atgaccgtga tgcggggcta 10200 cagcgagtgt ggagatggca gccctgccgt gtacacctgc gtggacgacc tgtgcagagg 10260 ctacgacctg accagactga gctacggccg gtccatcttc acagagcacg tgctgggctt 10320 cgagctggtg ccccccagcc tgttcaacgt ggtggtggcc atccggaacg aggccaccag 10380 aaccaacaga gccgtgcggc tgcctgtgtc tacagccgct gcacctgagg gcatcacact 10440 gttctacggc ctgtacaacg ccgtgaaaga gttctgcctc cggcaccagc tggatccccc 10500 cctgctgaga cacctggaca agtactacgc cggcctgccc ccagagctga agcagaccag 10560 agtgaacctg cccgcccaca gcagatatgg ccctcaggcc gtggacgcca gatgataacg 10620 ccggcggccc ctataactct ctacggctaa cctgaatgga ctacgacata gtctagtccg 10680 ccaagatgag ccccaaggac ctgaccccct tcctgacaac cctgtggctg ctcctgggcc 10740 atagcagagt gcctagagtg cgggccgagg aatgctgcga gttcatcaac gtgaaccacc 10800 cccccgagcg gtgctacgac ttcaagatgt gcaaccggtt caccgtggcc ctgagatgcc 10860 ccgacggcga agtgtgctac agccccgaga aaaccgccga gatccggggc atcgtgacca 10920 ccatgaccca cagcctgacc cggcaggtgg tgcacaacaa gctgaccagc tgcaactaca 10980 accccctgta cctggaagcc gacggccgga tcagatgcgg caaagtgaac gacaaggccc 11040 agtacctgct gggagccgcc ggaagcgtgc cctaccggtg gatcaacctg gaatacgaca 11100 agatcacccg gatcgtgggc ctggaccagt acctggaaag cgtgaagaag cacaagcggc 11160 tggacgtgtg cagagccaag atgggctaca tgctgcagtg ataaggcgcg ccaacgttac 11220 tggccgaagc cgcttggaat aaggccggtg tgcgtttgtc tatatgttat tttccaccat 11280 attgccgtct tttggcaatg tgagggcccg gaaacctggc cctgtcttct tgacgagcat 11340 tcctaggggt ctttcccctc tcgccaaagg aatgcaaggt ctgttgaatg tcgtgaagga 11400 agcagttcct ctggaagctt cttgaagaca aacaacgtct gtagcgaccc tttgcaggca 11460 gcggaacccc ccacctggcg acaggtgcct ctgcggccaa aagccacgtg tataagatac 11520 acctgcaaag gcggcacaac cccagtgcca cgttgtgagt tggatagttg tggaaagagt 11580 caaatggctc tcctcaagcg tattcaacaa ggggctgaag gatgcccaga aggtacccca 11640 ttgtatggga tctgatctgg ggcctcggtg cacatgcttt acatgtgttt agtcgaggtt 11700 aaaaaaacgt ctaggccccc cgaaccacgg ggacgtggtt ttcctttgaa aaacacgata 11760 atatgctgcg gctgctgctg agacaccact tccactgcct gctgctgtgt gccgtgtggg 11820 ccaccccttg tctggccagc ccttggagca ccctgaccgc caaccagaac cctagccccc 11880 cttggtccaa gctgacctac agcaagcccc acgacgccgc caccttctac tgcccctttc 11940 tgtaccccag ccctcccaga agccccctgc agttcagcgg cttccagaga gtgtccaccg 12000 gccctgagtg ccggaacgag acactgtacc tgctgtacaa ccgggagggc cagacactgg 12060 tggagcggag cagcacctgg gtgaaaaaag tgatctggta tctgagcggc cggaaccaga 12120 ccatcctgca gcggatgccc agaaccgcca gcaagcccag cgacggcaac gtgcagatca 12180 gcgtggagga cgccaaaatc ttcggagccc acatggtgcc caagcagacc aagctgctga 12240 gattcgtggt caacgacggc accagatatc agatgtgcgt gatgaagctg gaaagctggg 12300 cccacgtgtt ccgggactac tccgtgagct tccaggtccg gctgaccttc accgaggcca 12360 acaaccagac ctacaccttc tgcacccacc ccaacctgat cgtgtgataa gtacctttgt 12420 acgcctgttt tataccccct ccctgatttg caacttagaa gcaacgcaaa ccagatcaat 12480 agtaggtgtg acataccagt cgcatcttga tcaagcactt ctgtatcccc ggaccgagta 12540 tcaatagact gtgcacacgg ttgaaggaga aaacgtccgt tacccggcta actacttcga 12600 gaagcctagt aacgccattg aagttgcaga gtgtttcgct cagcactccc cccgtgtaga 12660 tcaggtcgat gagtcaccgc attccccacg ggcgaccgtg gcggtggctg cgttggcggc 12720 ctgcctatgg ggtaacccat aggacgctct aatacggaca tggcgtgaag agtctattga 12780 gctagttagt agtcctccgg cccctgaatg cggctaatcc taactgcgga gcacataccc 12840 ttaatccaaa gggcagtgtg tcgtaacggg caactctgca gcggaaccga ctactttggg 12900 tgtccgtgtt tctttttatt cttgtattgg ctgcttatgg tgacaattaa agaattgtta 12960 ccatatagct attggattgg ccatccagtg tcaaacagag ctattgtata tctctttgtt 13020 ggattcacac ctctcactct tgaaacgtta cacaccctca attacattat actgctgaac 13080 acgaagcgca tatgcggctg tgcagagtgt ggctgtccgt gtgcctgtgt gccgtggtgc 13140 tgggccagtg ccagagagag acagccgaga agaacgacta ctaccgggtg ccccactact 13200 gggatgcctg cagcagagcc ctgcccgacc agacccggta caaatacgtg gagcagctcg 13260 tggacctgac cctgaactac cactacgacg ccagccacgg cctggacaac ttcgacgtgc 13320 tgaagcggat caacgtgacc gaggtgtccc tgctgatcag cgacttccgg cggcagaaca 13380 gaagaggcgg caccaacaag cggaccacct tcaacgccgc tggctctctg gcccctcacg 13440 ccagatccct ggaattcagc gtgcggctgt tcgccaactg ataacgttgc atcctgcagg 13500 atacagcagc aattggcaag ctgcttacat agaactcgcg gcgattggca tgccgcctta 13560 aaatttttat tttatttttc ttttcttttc cgaatcggat tttgttttta atatttcaaa 13620 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aagggtcggc atggcatctc cacctcctcg 13680 cggtccgacc tgggcatccg aaggaggacg cacgtccact cggatggcta agggagagcc 13740 acgtttaaac gctagagcaa gacgtttccc gttgaatatg gctcataaca ccccttgtat 13800 tactgtttat gtaagcagac agttttattg ttcatgatga tatattttta tcttgtgcaa 13860 tgtaacatca gagattttga gacacaacgt ggctttgttg aataaatcga acttttgctg 13920 agttgaagga tcagatcacg catcttcccg acaacgcaga ccgttccgtg gcaaagcaaa 13980 agttcaaaat caccaactgg tccacctaca acaaagctct catcaaccgt ggctccctca 14040 ctttctggct ggatgatggg gcgattcagg cctggtatga gtcagcaaca ccttcttcac 14100 gaggcagacc tcagcgctag cggagtgtat actggcttac tatgttggca ctgatgaggg 14160 tgtcagtgaa gtgcttcatg tggcaggaga aaaaaggctg caccggtgcg tcagcagaat 14220 atgtgataca ggatatattc cgcttcctcg ctcactgact cgctacgctc ggtcgttcga 14280 ctgcggcgag cggaaatggc ttacgaacgg ggcggagatt tcctggaaga tgccaggaag 14340 atacttaaca gggaagtgag agggccgcgg caaagccgtt tttccatagg ctccgccccc 14400 ctgacaagca tcacgaaatc tgacgctcaa atcagtggtg gcgaaacccg acaggactat 14460 aaagatacca ggcgtttccc ctggcggctc cctcgtgcgc tctcctgttc ctgcctttcg 14520 gtttaccggt gtcattccgc tgttatggcc gcgtttgtct cattccacgc ctgacactca 14580 gttccgggta ggcagttcgc tccaagctgg actgtatgca cgaacccccc gttcagtccg 14640 accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggaaaga catgcaaaag 14700 caccactggc agcagccact ggtaattgat ttagaggagt tagtcttgaa gtcatgcgcc 14760 ggttaaggct aaactgaaag gacaagtttt ggtgactgcg ctcctccaag ccagttacct 14820 cggttcaaag agttggtagc tcagagaacc ttcgaaaaac cgccctgcaa ggcggttttt 14880 tcgttttcag agcaagagat tacgcgcaga ccaaaacgat ctcaagaaga tcatcttatt 14940 aaggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgagatta 15000 tcaaaaagga tcttcaccta gatcctttta aattaaaaat gaagttttaa atcaatctaa 15060 agtatatatg agtaaacttg gtctgacagt tattagaaaa attcatccag cagacgataa 15120 aacgcaatac gctggctatc cggtgccgca atgccataca gcaccagaaa acgatccgcc 15180 cattcgccgc ccagttcttc cgcaatatca cgggtggcca gcgcaatatc ctgataacga 15240 tccgccacgc ccagacggcc gcaatcaata aagccgctaa aacggccatt ttccaccata 15300 atgttcggca ggcacgcatc accatgggtc accaccagat cttcgccatc cggcatgctc 15360 gctttcagac gcgcaaacag ctctgccggt gccaggccct gatgttcttc atccagatca 15420 tcctgatcca ccaggcccgc ttccatacgg gtacgcgcac gttcaatacg atgtttcgcc 15480 tgatgatcaa acggacaggt cgccgggtcc agggtatgca gacgacgcat ggcatccgcc 15540 ataatgctca ctttttctgc cggcgccaga tggctagaca gcagatcctg acccggcact 15600 tcgcccagca gcagccaatc acggcccgct tcggtcacca catccagcac cgccgcacac 15660 ggaacaccgg tggtggccag ccagctcaga cgcgccgctt catcctgcag ctcgttcagc 15720 gcaccgctca gatcggtttt cacaaacagc accggacgac cctgcgcgct cagacgaaac 15780 accgccgcat cagagcagcc aatggtctgc tgcgcccaat catagccaaa cagacgttcc 15840 acccacgctg ccgggctacc cgcatgcagg ccatcctgtt caatcatact cttccttttt 15900 caatattatt gaagcattta tcagggttat tgtctcatga gcggatacat atttgaatgt 15960 atttagaaaa ataaacaaat aggggttccg cgcacatttc cccgaaaagt gccacctaaa 16020 ttgtaagcgt taatattttg ttaaaattcg cgttaaattt ttgttaaatc agctcatttt 16080 ttaaccaata ggccgaaatc ggcaaaatcc cttataaatc aaaagaatag accgagatag 16140 ggttgagtgg ccgctacagg gcgctcccat tcgccattca ggctgcgcaa ctgttgggaa 16200 gggcgtttcg gtgcgggcct cttcgctatt acgccagctg gcgaaagggg gatgtgctgc 16260 aaggcgatta agttgggtaa cgccagggtt ttcccagtca cacgcgtaat acgactcact 16320 atag 16324 <210> 67 <211> 16360 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 67 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtccgccaa 7560 gatgaggcct ggcctgccct cctacctgat catcctggcc gtgtgcctgt tcagccacct 7620 gctgtccagc agatacggcg ccgaggccgt gagcgagccc ctggacaagg ctttccacct 7680 gctgctgaac acctacggca gacccatccg gtttctgcgg gagaacacca cccagtgcac 7740 ctacaacagc agcctgcgga acagcaccgt cgtgagagag aacgccatca gcttcaactt 7800 tttccagagc tacaaccagt actacgtgtt ccacatgccc agatgcctgt ttgccggccc 7860 tctggccgag cagttcctga accaggtgga cctgaccgag acactggaaa gataccagca 7920 gcggctgaat acctacgccc tggtgtccaa ggacctggcc agctaccggt cctttagcca 7980 gcagctcaag gctcaggata gcctcggcga gcagcctacc accgtgcccc ctcccatcga 8040 cctgagcatc ccccacgtgt ggatgcctcc ccagaccacc cctcacggct ggaccgagag 8100 ccacaccacc tccggcctgc acagacccca cttcaaccag acctgcatcc tgttcgacgg 8160 ccacgacctg ctgtttagca ccgtgacccc ctgcctgcac cagggcttct acctgatcga 8220 cgagctgaga tacgtgaaga tcaccctgac cgaggatttc ttcgtggtca ccgtgtccat 8280 cgacgacgac acccccatgc tgctgatctt cggccacctg cccagagtgc tgttcaaggc 8340 cccctaccag cgggacaact tcatcctgcg gcagaccgag aagcacgagc tgctggtgct 8400 ggtcaagaag gaccagctga accggcactc ctacctgaag gaccccgact tcctggacgc 8460 cgccctggac ttcaactacc tggacctgag cgccctgctg agaaacagct tccacagata 8520 cgccgtggac gtgctgaagt ccggacggtg ccagatgctc gatcggcgga ccgtggagat 8580 ggccttcgcc tatgccctcg ccctgttcgc cgctgccaga caggaagagg ctggcgccca 8640 ggtgtcagtg cccagagccc tggatagaca ggccgccctg ctgcagatcc aggaattcat 8700 gatcacctgc ctgagccaga ccccccctag aaccaccctg ctgctgtacc ccacagccgt 8760 ggatctggcc aagagggccc tgtggacccc caaccagatc accgacatca caagcctcgt 8820 gcggctcgtg tacatcctga gcaagcagaa ccagcagcac ctgatccccc agtgggccct 8880 gagacagatc gccgacttcg ccctgaagct gcacaagacc catctggcca gctttctgag 8940 cgccttcgcc aggcaggaac tgtacctgat gggcagcctg gtccacagca tgctggtgca 9000 taccaccgag cggcgggaga tcttcatcgt ggagacaggc ctgtgtagcc tggccgagct 9060 gtcccacttt acccagctgc tggcccaccc tcaccacgag tacctgagcg acctgtacac 9120 cccctgcagc agcagcggca gacgggacca cagcctggaa cggctgacca gactgttccc 9180 cgatgccacc gtgcctgcta cagtgcctgc cgccctgtcc atcctgtcca ccatgcagcc 9240 cagcaccctg gaaaccttcc ccgacctgtt ctgcctgccc ctgggcgaga gctttagcgc 9300 cctgaccgtg tccgagcacg tgtcctacat cgtgaccaat cagtacctga tcaagggcat 9360 cagctacccc gtgtccacca cagtcgtggg ccagagcctg atcatcaccc agaccgacag 9420 ccagaccaag tgcgagctga cccggaacat gcacaccaca cacagcatca ccgtggccct 9480 gaacatcagc ctggaaaact gcgctttctg tcagtctgcc ctgctggaat acgacgatac 9540 ccagggcgtg atcaacatca tgtacatgca cgacagcgac gacgtgctgt tcgccctgga 9600 cccctacaac gaggtggtgg tgtccagccc ccggacccac tacctgatgc tgctgaagaa 9660 cggcaccgtg ctggaagtga ccgacgtggt ggtggacgcc accgacggca gcggatctgg 9720 gtcccaccat caccatcacc attgataatc tagaggcccc tataactctc tacggctaac 9780 ctgaatggac tacgacatag tctagtccgc caagatgtgc agaaggcccg actgcggctt 9840 cagcttcagc cctggacccg tgatcctgct gtggtgctgc ctgctgctgc ctatcgtgtc 9900 ctctgccgcc gtgtctgtgg cccctacagc cgccgagaag gtgccagccg agtgccccga 9960 gctgaccaga agatgcctgc tgggcgaggt gttcgagggc gacaagtacg agagctggct 10020 gcggcccctg gtcaacgtga ccggcagaga tggccccctg agccagctga tccggtacag 10080 acccgtgacc cccgaggccg ccaatagcgt gctgctggac gaggccttcc tggataccct 10140 ggccctgctg tacaacaacc ccgaccagct gagagccctg ctgaccctgc tgtccagcga 10200 caccgccccc agatggatga ccgtgatgcg gggctacagc gagtgtggag atggcagccc 10260 tgccgtgtac acctgcgtgg acgacctgtg cagaggctac gacctgacca gactgagcta 10320 cggccggtcc atcttcacag agcacgtgct gggcttcgag ctggtgcccc ccagcctgtt 10380 caacgtggtg gtggccatcc ggaacgaggc caccagaacc aacagagccg tgcggctgcc 10440 tgtgtctaca gccgctgcac ctgagggcat cacactgttc tacggcctgt acaacgccgt 10500 gaaagagttc tgcctccggc accagctgga tccccccctg ctgagacacc tggacaagta 10560 ctacgccggc ctgcccccag agctgaagca gaccagagtg aacctgcccg cccacagcag 10620 atatggccct caggccgtgg acgccagatg ataacgccgg cggcccctat aactctctac 10680 ggctaacctg aatggactac gacatagtct agtccgccaa gatgagcccc aaggacctga 10740 cccccttcct gacaaccctg tggctgctcc tgggccatag cagagtgcct agagtgcggg 10800 ccgaggaatg ctgcgagttc atcaacgtga accacccccc cgagcggtgc tacgacttca 10860 agatgtgcaa ccggttcacc gtggccctga gatgccccga cggcgaagtg tgctacagcc 10920 ccgagaaaac cgccgagatc cggggcatcg tgaccaccat gacccacagc ctgacccggc 10980 aggtggtgca caacaagctg accagctgca actacaaccc cctgtacctg gaagccgacg 11040 gccggatcag atgcggcaaa gtgaacgaca aggcccagta cctgctggga gccgccggaa 11100 gcgtgcccta ccggtggatc aacctggaat acgacaagat cacccggatc gtgggcctgg 11160 accagtacct ggaaagcgtg aagaagcaca agcggctgga cgtgtgcaga gccaagatgg 11220 gctacatgct gcagtgataa ggcgcgccaa cgttactggc cgaagccgct tggaataagg 11280 ccggtgtgcg tttgtctata tgttattttc caccatattg ccgtcttttg gcaatgtgag 11340 ggcccggaaa cctggccctg tcttcttgac gagcattcct aggggtcttt cccctctcgc 11400 caaaggaatg caaggtctgt tgaatgtcgt gaaggaagca gttcctctgg aagcttcttg 11460 aagacaaaca acgtctgtag cgaccctttg caggcagcgg aaccccccac ctggcgacag 11520 gtgcctctgc ggccaaaagc cacgtgtata agatacacct gcaaaggcgg cacaacccca 11580 gtgccacgtt gtgagttgga tagttgtgga aagagtcaaa tggctctcct caagcgtatt 11640 caacaagggg ctgaaggatg cccagaaggt accccattgt atgggatctg atctggggcc 11700 tcggtgcaca tgctttacat gtgtttagtc gaggttaaaa aaacgtctag gccccccgaa 11760 ccacggggac gtggttttcc tttgaaaaac acgataatat gctgcggctg ctgctgagac 11820 accacttcca ctgcctgctg ctgtgtgccg tgtgggccac cccttgtctg gccagccctt 11880 ggagcaccct gaccgccaac cagaacccta gccccccttg gtccaagctg acctacagca 11940 agccccacga cgccgccacc ttctactgcc cctttctgta ccccagccct cccagaagcc 12000 ccctgcagtt cagcggcttc cagagagtgt ccaccggccc tgagtgccgg aacgagacac 12060 tgtacctgct gtacaaccgg gagggccaga cactggtgga gcggagcagc acctgggtga 12120 aaaaagtgat ctggtatctg agcggccgga accagaccat cctgcagcgg atgcccagaa 12180 ccgccagcaa gcccagcgac ggcaacgtgc agatcagcgt ggaggacgcc aaaatcttcg 12240 gagcccacat ggtgcccaag cagaccaagc tgctgagatt cgtggtcaac gacggcacca 12300 gatatcagat gtgcgtgatg aagctggaaa gctgggccca cgtgttccgg gactactccg 12360 tgagcttcca ggtccggctg accttcaccg aggccaacaa ccagacctac accttctgca 12420 cccaccccaa cctgatcgtg tgataagtac ctttgtacgc ctgttttata ccccctccct 12480 gatttgcaac ttagaagcaa cgcaaaccag atcaatagta ggtgtgacat accagtcgca 12540 tcttgatcaa gcacttctgt atccccggac cgagtatcaa tagactgtgc acacggttga 12600 aggagaaaac gtccgttacc cggctaacta cttcgagaag cctagtaacg ccattgaagt 12660 tgcagagtgt ttcgctcagc actccccccg tgtagatcag gtcgatgagt caccgcattc 12720 cccacgggcg accgtggcgg tggctgcgtt ggcggcctgc ctatggggta acccatagga 12780 cgctctaata cggacatggc gtgaagagtc tattgagcta gttagtagtc ctccggcccc 12840 tgaatgcggc taatcctaac tgcggagcac atacccttaa tccaaagggc agtgtgtcgt 12900 aacgggcaac tctgcagcgg aaccgactac tttgggtgtc cgtgtttctt tttattcttg 12960 tattggctgc ttatggtgac aattaaagaa ttgttaccat atagctattg gattggccat 13020 ccagtgtcaa acagagctat tgtatatctc tttgttggat tcacacctct cactcttgaa 13080 acgttacaca ccctcaatta cattatactg ctgaacacga agcgcatatg cggctgtgca 13140 gagtgtggct gtccgtgtgc ctgtgtgccg tggtgctggg ccagtgccag agagagacag 13200 ccgagaagaa cgactactac cgggtgcccc actactggga tgcctgcagc agagccctgc 13260 ccgaccagac ccggtacaaa tacgtggagc agctcgtgga cctgaccctg aactaccact 13320 acgacgccag ccacggcctg gacaacttcg acgtgctgaa gcggatcaac gtgaccgagg 13380 tgtccctgct gatcagcgac ttccggcggc agaacagaag aggcggcacc aacaagcgga 13440 ccaccttcaa cgccgctggc tctctggccc ctcacgccag atccctggaa ttcagcgtgc 13500 ggctgttcgc caactgataa cgttgcatcc tgcaggatac agcagcaatt ggcaagctgc 13560 ttacatagaa ctcgcggcga ttggcatgcc gccttaaaat ttttatttta tttttctttt 13620 cttttccgaa tcggattttg tttttaatat ttcaaaaaaa aaaaaaaaaa aaaaaaaaaa 13680 aaaaaaaagg gtcggcatgg catctccacc tcctcgcggt ccgacctggg catccgaagg 13740 aggacgcacg tccactcgga tggctaaggg agagccacgt ttaaacgcta gagcaagacg 13800 tttcccgttg aatatggctc ataacacccc ttgtattact gtttatgtaa gcagacagtt 13860 ttattgttca tgatgatata tttttatctt gtgcaatgta acatcagaga ttttgagaca 13920 caacgtggct ttgttgaata aatcgaactt ttgctgagtt gaaggatcag atcacgcatc 13980 ttcccgacaa cgcagaccgt tccgtggcaa agcaaaagtt caaaatcacc aactggtcca 14040 cctacaacaa agctctcatc aaccgtggct ccctcacttt ctggctggat gatggggcga 14100 ttcaggcctg gtatgagtca gcaacacctt cttcacgagg cagacctcag cgctagcgga 14160 gtgtatactg gcttactatg ttggcactga tgagggtgtc agtgaagtgc ttcatgtggc 14220 aggagaaaaa aggctgcacc ggtgcgtcag cagaatatgt gatacaggat atattccgct 14280 tcctcgctca ctgactcgct acgctcggtc gttcgactgc ggcgagcgga aatggcttac 14340 gaacggggcg gagatttcct ggaagatgcc aggaagatac ttaacaggga agtgagaggg 14400 ccgcggcaaa gccgtttttc cataggctcc gcccccctga caagcatcac gaaatctgac 14460 gctcaaatca gtggtggcga aacccgacag gactataaag ataccaggcg tttcccctgg 14520 cggctccctc gtgcgctctc ctgttcctgc ctttcggttt accggtgtca ttccgctgtt 14580 atggccgcgt ttgtctcatt ccacgcctga cactcagttc cgggtaggca gttcgctcca 14640 agctggactg tatgcacgaa ccccccgttc agtccgaccg ctgcgcctta tccggtaact 14700 atcgtcttga gtccaacccg gaaagacatg caaaagcacc actggcagca gccactggta 14760 attgatttag aggagttagt cttgaagtca tgcgccggtt aaggctaaac tgaaaggaca 14820 agttttggtg actgcgctcc tccaagccag ttacctcggt tcaaagagtt ggtagctcag 14880 agaaccttcg aaaaaccgcc ctgcaaggcg gttttttcgt tttcagagca agagattacg 14940 cgcagaccaa aacgatctca agaagatcat cttattaagg ggtctgacgc tcagtggaac 15000 gaaaactcac gttaagggat tttggtcatg agattatcaa aaaggatctt cacctagatc 15060 cttttaaatt aaaaatgaag ttttaaatca atctaaagta tatatgagta aacttggtct 15120 gacagttatt agaaaaattc atccagcaga cgataaaacg caatacgctg gctatccggt 15180 gccgcaatgc catacagcac cagaaaacga tccgcccatt cgccgcccag ttcttccgca 15240 atatcacggg tggccagcgc aatatcctga taacgatccg ccacgcccag acggccgcaa 15300 tcaataaagc cgctaaaacg gccattttcc accataatgt tcggcaggca cgcatcacca 15360 tgggtcacca ccagatcttc gccatccggc atgctcgctt tcagacgcgc aaacagctct 15420 gccggtgcca ggccctgatg ttcttcatcc agatcatcct gatccaccag gcccgcttcc 15480 atacgggtac gcgcacgttc aatacgatgt ttcgcctgat gatcaaacgg acaggtcgcc 15540 gggtccaggg tatgcagacg acgcatggca tccgccataa tgctcacttt ttctgccggc 15600 gccagatggc tagacagcag atcctgaccc ggcacttcgc ccagcagcag ccaatcacgg 15660 cccgcttcgg tcaccacatc cagcaccgcc gcacacggaa caccggtggt ggccagccag 15720 ctcagacgcg ccgcttcatc ctgcagctcg ttcagcgcac cgctcagatc ggttttcaca 15780 aacagcaccg gacgaccctg cgcgctcaga cgaaacaccg ccgcatcaga gcagccaatg 15840 gtctgctgcg cccaatcata gccaaacaga cgttccaccc acgctgccgg gctacccgca 15900 tgcaggccat cctgttcaat catactcttc ctttttcaat attattgaag catttatcag 15960 ggttattgtc tcatgagcgg atacatattt gaatgtattt agaaaaataa acaaataggg 16020 gttccgcgca catttccccg aaaagtgcca cctaaattgt aagcgttaat attttgttaa 16080 aattcgcgtt aaatttttgt taaatcagct cattttttaa ccaataggcc gaaatcggca 16140 aaatccctta taaatcaaaa gaatagaccg agatagggtt gagtggccgc tacagggcgc 16200 tcccattcgc cattcaggct gcgcaactgt tgggaagggc gtttcggtgc gggcctcttc 16260 gctattacgc cagctggcga aagggggatg tgctgcaagg cgattaagtt gggtaacgcc 16320 agggttttcc cagtcacacg cgtaatacga ctcactatag 16360 <210> 68 <211> 868 <212> PRT <213> Varicella zoster virus <400> 68 Met Phe Val Thr Ala Val Val Ser Val Ser Pro Ser Ser Phe Tyr Glu 1 5 10 15 Ser Leu Gln Val Glu Pro Thr Gln Ser Glu Asp Ile Thr Arg Ser Ala 20 25 30 His Leu Gly Asp Gly Asp Glu Ile Arg Glu Ala Ile His Lys Ser Gln 35 40 45 Asp Ala Glu Thr Lys Pro Thr Phe Tyr Val Cys Pro Pro Pro Thr Gly 50 55 60 Ser Thr Ile Val Arg Leu Glu Pro Pro Arg Thr Cys Pro Asp Tyr His 65 70 75 80 Leu Gly Lys Asn Phe Thr Glu Gly Ile Ala Val Val Tyr Lys Glu Asn 85 90 95 Ile Ala Ala Tyr Lys Phe Lys Ala Thr Val Tyr Tyr Lys Asp Val Ile 100 105 110 Val Ser Thr Ala Trp Ala Gly Ser Ser Tyr Thr Gln Ile Thr Asn Arg 115 120 125 Tyr Ala Asp Arg Val Pro Ile Pro Val Ser Glu Ile Thr Asp Thr Ile 130 135 140 Asp Lys Phe Gly Lys Cys Ser Ser Lys Ala Thr Tyr Val Arg Asn Asn 145 150 155 160 His Lys Val Glu Ala Phe Asn Glu Asp Lys Asn Pro Gln Asp Met Pro 165 170 175 Leu Ile Ala Ser Lys Tyr Asn Ser Val Gly Ser Lys Ala Trp His Thr 180 185 190 Thr Asn Asp Thr Tyr Met Val Ala Gly Thr Pro Gly Thr Tyr Arg Thr 195 200 205 Gly Thr Ser Val Asn Cys Ile Ile Glu Glu Val Glu Ala Arg Ser Ile 210 215 220 Phe Pro Tyr Asp Ser Phe Gly Leu Ser Thr Gly Asp Ile Ile Tyr Met 225 230 235 240 Ser Pro Phe Phe Gly Leu Arg Asp Gly Ala Tyr Arg Glu His Ser Asn 245 250 255 Tyr Ala Met Asp Arg Phe His Gln Phe Glu Gly Tyr Arg Gln Arg Asp 260 265 270 Leu Asp Thr Arg Ala Leu Leu Glu Pro Ala Ala Arg Asn Phe Leu Val 275 280 285 Thr Pro His Leu Thr Val Gly Trp Asn Trp Lys Pro Lys Arg Thr Glu 290 295 300 Val Cys Ser Leu Val Lys Trp Arg Glu Val Glu Asp Val Val Arg Asp 305 310 315 320 Glu Tyr Ala His Asn Phe Arg Phe Thr Met Lys Thr Leu Ser Thr Thr 325 330 335 Phe Ile Ser Glu Thr Asn Glu Phe Asn Leu Asn Gln Ile His Leu Ser 340 345 350 Gln Cys Val Lys Glu Glu Ala Arg Ala Ile Ile Asn Arg Ile Tyr Thr 355 360 365 Thr Arg Tyr Asn Ser Ser His Val Arg Thr Gly Asp Ile Gln Thr Tyr 370 375 380 Leu Ala Arg Gly Gly Phe Val Val Val Phe Gln Pro Leu Leu Ser Asn 385 390 395 400 Ser Leu Ala Arg Leu Tyr Leu Gln Glu Leu Val Arg Glu Asn Thr Asn 405 410 415 His Ser Pro Gln Lys His Pro Thr Arg Asn Thr Arg Ser Arg Arg Ser 420 425 430 Val Pro Val Glu Leu Arg Ala Asn Arg Thr Ile Thr Thr Thr Ser Ser 435 440 445 Val Glu Phe Ala Met Leu Gln Phe Thr Tyr Asp His Ile Gln Glu His 450 455 460 Val Asn Glu Met Leu Ala Arg Ile Ser Ser Ser Trp Cys Gln Leu Gln 465 470 475 480 Asn Arg Glu Arg Ala Leu Trp Ser Gly Leu Phe Pro Ile Asn Pro Ser 485 490 495 Ala Leu Ala Ser Thr Ile Leu Asp Gln Arg Val Lys Ala Arg Ile Leu 500 505 510 Gly Asp Val Ile Ser Val Ser Asn Cys Pro Glu Leu Gly Ser Asp Thr 515 520 525 Arg Ile Ile Leu Gln Asn Ser Met Arg Val Ser Gly Ser Thr Thr Arg 530 535 540 Cys Tyr Ser Arg Pro Leu Ile Ser Ile Val Ser Leu Asn Gly Ser Gly 545 550 555 560 Thr Val Glu Gly Gln Leu Gly Thr Asp Asn Glu Leu Ile Met Ser Arg 565 570 575 Asp Leu Leu Glu Pro Cys Val Ala Asn His Lys Arg Tyr Phe Leu Phe 580 585 590 Gly His His Tyr Val Tyr Tyr Glu Asp Tyr Arg Tyr Val Arg Glu Ile 595 600 605 Ala Val His Asp Val Gly Met Ile Ser Thr Tyr Val Asp Leu Asn Leu 610 615 620 Thr Leu Leu Lys Asp Arg Glu Phe Met Pro Leu Gln Val Tyr Thr Arg 625 630 635 640 Asp Glu Leu Arg Asp Thr Gly Leu Leu Asp Tyr Ser Glu Ile Gln Arg 645 650 655 Arg Asn Gln Met His Ser Leu Arg Phe Tyr Asp Ile Asp Lys Val Val 660 665 670 Gln Tyr Asp Ser Gly Thr Ala Ile Met Gln Gly Met Ala Gln Phe Phe 675 680 685 Gln Gly Leu Gly Thr Ala Gly Gln Ala Val Gly His Val Val Leu Gly 690 695 700 Ala Thr Gly Ala Leu Leu Ser Thr Val His Gly Phe Thr Thr Phe Leu 705 710 715 720 Ser Asn Pro Phe Gly Ala Leu Ala Val Gly Leu Leu Val Leu Ala Gly 725 730 735 Leu Val Ala Ala Phe Phe Ala Tyr Arg Tyr Val Leu Lys Leu Lys Thr 740 745 750 Ser Pro Met Lys Ala Leu Tyr Pro Leu Thr Thr Lys Gly Leu Lys Gln 755 760 765 Leu Pro Glu Gly Met Asp Pro Phe Ala Glu Lys Pro Asn Ala Thr Asp 770 775 780 Thr Pro Ile Glu Glu Ile Gly Asp Ser Gln Asn Thr Glu Pro Ser Val 785 790 795 800 Asn Ser Gly Phe Asp Pro Asp Lys Phe Arg Glu Ala Gln Glu Met Ile 805 810 815 Lys Tyr Met Thr Leu Val Ser Ala Ala Glu Arg Gln Glu Ser Lys Ala 820 825 830 Arg Lys Lys Asn Lys Thr Ser Ala Leu Leu Thr Ser Arg Leu Thr Gly 835 840 845 Leu Ala Leu Arg Asn Arg Arg Gly Tyr Ser Arg Val Arg Thr Glu Asn 850 855 860 Val Thr Gly Val 865 <210> 69 <211> 841 <212> PRT <213> Varicella zoster virus <400> 69 Met Phe Ala Leu Val Leu Ala Val Val Ile Leu Pro Leu Trp Thr Thr 1 5 10 15 Ala Asn Lys Ser Tyr Val Thr Pro Thr Pro Ala Thr Arg Ser Ile Gly 20 25 30 His Met Ser Ala Leu Leu Arg Glu Tyr Ser Asp Arg Asn Met Ser Leu 35 40 45 Lys Leu Glu Ala Phe Tyr Pro Thr Gly Phe Asp Glu Glu Leu Ile Lys 50 55 60 Ser Leu His Trp Gly Asn Asp Arg Lys His Val Phe Leu Val Ile Val 65 70 75 80 Lys Val Asn Pro Thr Thr His Glu Gly Asp Val Gly Leu Val Ile Phe 85 90 95 Pro Lys Tyr Leu Leu Ser Pro Tyr His Phe Lys Ala Glu His Arg Ala 100 105 110 Pro Phe Pro Ala Gly Arg Phe Gly Phe Leu Ser His Pro Val Thr Pro 115 120 125 Asp Val Ser Phe Phe Asp Ser Ser Phe Ala Pro Tyr Leu Thr Thr Gln 130 135 140 His Leu Val Ala Phe Thr Thr Phe Pro Pro Asn Pro Leu Val Trp His 145 150 155 160 Leu Glu Arg Ala Glu Thr Ala Ala Thr Ala Glu Arg Pro Phe Gly Val 165 170 175 Ser Leu Leu Pro Ala Arg Pro Thr Val Pro Lys Asn Thr Ile Leu Glu 180 185 190 His Lys Ala His Phe Ala Thr Trp Asp Ala Leu Ala Arg His Thr Phe 195 200 205 Phe Ser Ala Glu Ala Ile Ile Thr Asn Ser Thr Leu Arg Ile His Val 210 215 220 Pro Leu Phe Gly Ser Val Trp Pro Ile Arg Tyr Trp Ala Thr Gly Ser 225 230 235 240 Val Leu Leu Thr Ser Asp Ser Gly Arg Val Glu Val Asn Ile Gly Val 245 250 255 Gly Phe Met Ser Ser Leu Ile Ser Leu Ser Ser Gly Leu Pro Ile Glu 260 265 270 Leu Ile Val Val Pro His Thr Val Lys Leu Asn Ala Val Thr Ser Asp 275 280 285 Thr Thr Trp Phe Gln Leu Asn Pro Pro Gly Pro Asp Pro Gly Pro Ser 290 295 300 Tyr Arg Val Tyr Leu Leu Gly Arg Gly Leu Asp Met Asn Phe Ser Lys 305 310 315 320 His Ala Thr Val Asp Ile Cys Ala Tyr Pro Glu Glu Ser Leu Asp Tyr 325 330 335 Arg Tyr His Leu Ser Met Ala His Thr Glu Ala Leu Arg Met Thr Thr 340 345 350 Lys Ala Asp Gln His Asp Ile Asn Glu Glu Ser Tyr Tyr His Ile Ala 355 360 365 Ala Arg Ile Ala Thr Ser Ile Phe Ala Leu Ser Glu Met Gly Arg Thr 370 375 380 Thr Glu Tyr Phe Leu Leu Asp Glu Ile Val Asp Val Gln Tyr Gln Leu 385 390 395 400 Lys Phe Leu Asn Tyr Ile Leu Met Arg Ile Gly Ala Gly Ala His Pro 405 410 415 Asn Thr Ile Ser Gly Thr Ser Asp Leu Ile Phe Ala Asp Pro Ser Gln 420 425 430 Leu His Asp Glu Leu Ser Leu Leu Phe Gly Gln Val Lys Pro Ala Asn 435 440 445 Val Asp Tyr Phe Ile Ser Tyr Asp Glu Ala Arg Asp Gln Leu Lys Thr 450 455 460 Ala Tyr Ala Leu Ser Arg Gly Gln Asp His Val Asn Ala Leu Ser Leu 465 470 475 480 Ala Arg Arg Val Ile Met Ser Ile Tyr Lys Gly Leu Leu Val Lys Gln 485 490 495 Asn Leu Asn Ala Thr Glu Arg Gln Ala Leu Phe Phe Ala Ser Met Ile 500 505 510 Leu Leu Asn Phe Arg Glu Gly Leu Glu Asn Ser Ser Arg Val Leu Asp 515 520 525 Gly Arg Thr Thr Leu Leu Leu Met Thr Ser Met Cys Thr Ala Ala His 530 535 540 Ala Thr Gln Ala Ala Leu Asn Ile Gln Glu Gly Leu Ala Tyr Leu Asn 545 550 555 560 Pro Ser Lys His Met Phe Thr Ile Pro Asn Val Tyr Ser Pro Cys Met 565 570 575 Gly Ser Leu Arg Thr Asp Leu Thr Glu Glu Ile His Val Met Asn Leu 580 585 590 Leu Ser Ala Ile Pro Thr Arg Pro Gly Leu Asn Glu Val Leu His Thr 595 600 605 Gln Leu Asp Glu Ser Glu Ile Phe Asp Ala Ala Phe Lys Thr Met Met 610 615 620 Ile Phe Thr Thr Trp Thr Ala Lys Asp Leu His Ile Leu His Thr His 625 630 635 640 Val Pro Glu Val Phe Thr Cys Gln Asp Ala Ala Ala Arg Asn Gly Glu 645 650 655 Tyr Val Leu Ile Leu Pro Ala Val Gln Gly His Ser Tyr Val Ile Thr 660 665 670 Arg Asn Lys Pro Gln Arg Gly Leu Val Tyr Ser Leu Ala Asp Val Asp 675 680 685 Val Tyr Asn Pro Ile Ser Val Val Tyr Leu Ser Lys Asp Thr Cys Val 690 695 700 Ser Glu His Gly Val Ile Glu Thr Val Ala Leu Pro His Pro Asp Asn 705 710 715 720 Leu Lys Glu Cys Leu Tyr Cys Gly Ser Val Phe Leu Arg Tyr Leu Thr 725 730 735 Thr Gly Ala Ile Met Asp Ile Ile Ile Ile Asp Ser Lys Asp Thr Glu 740 745 750 Arg Gln Leu Ala Ala Met Gly Asn Ser Thr Ile Pro Pro Phe Asn Pro 755 760 765 Asp Met His Gly Asp Asp Ser Lys Ala Val Leu Leu Phe Pro Asn Gly 770 775 780 Thr Val Val Thr Leu Leu Gly Phe Glu Arg Arg Gln Ala Ile Arg Met 785 790 795 800 Ser Gly Gln Tyr Leu Gly Ala Ser Leu Gly Gly Ala Phe Leu Ala Val 805 810 815 Val Gly Phe Gly Ile Ile Gly Trp Met Leu Cys Gly Asn Ser Arg Leu 820 825 830 Arg Glu Tyr Asn Lys Ile Pro Leu Thr 835 840 <210> 70 <211> 160 <212> PRT <213> Varicella zoster virus <400> 70 Met Ala Ser His Lys Trp Leu Leu Gln Met Ile Val Phe Leu Lys Thr 1 5 10 15 Ile Thr Ile Ala Tyr Cys Leu His Leu Gln Asp Asp Thr Pro Leu Phe 20 25 30 Phe Gly Ala Lys Pro Leu Ser Asp Val Ser Leu Ile Ile Thr Glu Pro 35 40 45 Cys Val Ser Ser Val Tyr Glu Ala Trp Asp Tyr Ala Ala Pro Pro Val 50 55 60 Ser Asn Leu Ser Glu Ala Leu Ser Gly Ile Val Val Lys Thr Lys Cys 65 70 75 80 Pro Val Pro Glu Val Ile Leu Trp Phe Lys Asp Lys Gln Met Ala Tyr 85 90 95 Trp Thr Asn Pro Tyr Val Thr Leu Lys Gly Leu Thr Gln Ser Val Gly 100 105 110 Glu Glu His Lys Ser Gly Asp Ile Arg Asp Ala Leu Leu Asp Ala Leu 115 120 125 Ser Gly Val Trp Val Asp Ser Thr Pro Ser Ser Thr Asn Ile Pro Glu 130 135 140 Asn Gly Cys Val Trp Gly Ala Asp Arg Leu Phe Gln Arg Val Cys Gln 145 150 155 160 <210> 71 <211> 354 <212> PRT <213> Varicella zoster virus <400> 71 Met Phe Leu Ile Gln Cys Leu Ile Ser Ala Val Ile Phe Tyr Ile Gln 1 5 10 15 Val Thr Asn Ala Leu Ile Phe Lys Gly Asp His Val Ser Leu Gln Val 20 25 30 Asn Ser Ser Leu Thr Ser Ile Leu Ile Pro Met Gln Asn Asp Asn Tyr 35 40 45 Thr Glu Ile Lys Gly Gln Leu Val Phe Ile Gly Glu Gln Leu Pro Thr 50 55 60 Gly Thr Asn Tyr Ser Gly Thr Leu Glu Leu Leu Tyr Ala Asp Thr Val 65 70 75 80 Ala Phe Cys Phe Arg Ser Val Gln Val Ile Arg Tyr Asp Gly Cys Pro 85 90 95 Arg Ile Arg Thr Ser Ala Phe Ile Ser Cys Arg Tyr Lys His Ser Trp 100 105 110 His Tyr Gly Asn Ser Thr Asp Arg Ile Ser Thr Glu Pro Asp Ala Gly 115 120 125 Val Met Leu Lys Ile Thr Lys Pro Gly Ile Asn Asp Ala Gly Val Tyr 130 135 140 Val Leu Leu Val Arg Leu Asp His Ser Arg Ser Thr Asp Gly Phe Ile 145 150 155 160 Leu Gly Val Asn Val Tyr Thr Ala Gly Ser His His Asn Ile His Gly 165 170 175 Val Ile Tyr Thr Ser Pro Ser Leu Gln Asn Gly Tyr Ser Thr Arg Ala 180 185 190 Leu Phe Gln Gln Ala Arg Leu Cys Asp Leu Pro Ala Thr Pro Lys Gly 195 200 205 Ser Gly Thr Ser Leu Phe Gln His Met Leu Asp Leu Arg Ala Gly Lys 210 215 220 Ser Leu Glu Asp Asn Pro Trp Leu His Glu Asp Val Val Thr Thr Glu 225 230 235 240 Thr Lys Ser Val Val Lys Glu Gly Ile Glu Asn His Val Tyr Pro Thr 245 250 255 Asp Met Ser Thr Leu Pro Glu Lys Ser Leu Asn Asp Pro Pro Glu Asn 260 265 270 Leu Leu Ile Ile Ile Pro Ile Val Ala Ser Val Met Ile Leu Thr Ala 275 280 285 Met Val Ile Val Ile Val Ile Ser Val Lys Arg Arg Arg Ile Lys Lys 290 295 300 His Pro Ile Tyr Arg Pro Asn Thr Lys Thr Arg Arg Gly Ile Gln Asn 305 310 315 320 Ala Thr Pro Glu Ser Asp Val Met Leu Glu Ala Ala Ile Ala Gln Leu 325 330 335 Ala Thr Ile Arg Glu Glu Ser Pro Pro His Ser Val Val Asn Pro Phe 340 345 350 Val Lys <210> 72 <211> 623 <212> PRT <213> Varicella zoster virus <400> 72 Met Gly Thr Val Asn Lys Pro Val Val Gly Val Leu Met Gly Phe Gly 1 5 10 15 Ile Ile Thr Gly Thr Leu Arg Ile Thr Asn Pro Val Arg Ala Ser Val 20 25 30 Leu Arg Tyr Asp Asp Phe His Ile Asp Glu Asp Lys Leu Asp Thr Asn 35 40 45 Ser Val Tyr Glu Pro Tyr Tyr His Ser Asp His Ala Glu Ser Ser Trp 50 55 60 Val Asn Arg Gly Glu Ser Ser Arg Lys Ala Tyr Asp His Asn Ser Pro 65 70 75 80 Tyr Ile Trp Pro Arg Asn Asp Tyr Asp Gly Phe Leu Glu Asn Ala His 85 90 95 Glu His His Gly Val Tyr Asn Gln Gly Arg Gly Ile Asp Ser Gly Glu 100 105 110 Arg Leu Met Gln Pro Thr Gln Met Ser Ala Gln Glu Asp Leu Gly Asp 115 120 125 Asp Thr Gly Ile His Val Ile Pro Thr Leu Asn Gly Asp Asp Arg His 130 135 140 Lys Ile Val Asn Val Asp Gln Arg Gln Tyr Gly Asp Val Phe Lys Gly 145 150 155 160 Asp Leu Asn Pro Lys Pro Gln Gly Gln Arg Leu Ile Glu Val Ser Val 165 170 175 Glu Glu Asn His Pro Phe Thr Leu Arg Ala Pro Ile Gln Arg Ile Tyr 180 185 190 Gly Val Arg Tyr Thr Glu Thr Trp Ser Phe Leu Pro Ser Leu Thr Cys 195 200 205 Thr Gly Asp Ala Ala Pro Ala Ile Gln His Ile Cys Leu Lys His Thr 210 215 220 Thr Cys Phe Gln Asp Val Val Val Asp Val Asp Cys Ala Glu Asn Thr 225 230 235 240 Lys Glu Asp Gln Leu Ala Glu Ile Ser Tyr Arg Phe Gln Gly Lys Lys 245 250 255 Glu Ala Asp Gln Pro Trp Ile Val Val Asn Thr Ser Thr Leu Phe Asp 260 265 270 Glu Leu Glu Leu Asp Pro Pro Glu Ile Glu Pro Gly Val Leu Lys Val 275 280 285 Leu Arg Thr Glu Lys Gln Tyr Leu Gly Val Tyr Ile Trp Asn Met Arg 290 295 300 Gly Ser Asp Gly Thr Ser Thr Tyr Ala Thr Phe Leu Val Thr Trp Lys 305 310 315 320 Gly Asp Glu Lys Thr Arg Asn Pro Thr Pro Ala Val Thr Pro Gln Pro 325 330 335 Arg Gly Ala Glu Phe His Met Trp Asn Tyr His Ser His Val Phe Ser 340 345 350 Val Gly Asp Thr Phe Ser Leu Ala Met His Leu Gln Tyr Lys Ile His 355 360 365 Glu Ala Pro Phe Asp Leu Leu Leu Glu Trp Leu Tyr Val Pro Ile Asp 370 375 380 Pro Thr Cys Gln Pro Met Arg Leu Tyr Ser Thr Cys Leu Tyr His Pro 385 390 395 400 Asn Ala Pro Gln Cys Leu Ser His Met Asn Ser Gly Cys Thr Phe Thr 405 410 415 Ser Pro His Leu Ala Gln Arg Val Ala Ser Thr Val Tyr Gln Asn Cys 420 425 430 Glu His Ala Asp Asn Tyr Thr Ala Tyr Cys Leu Gly Ile Ser His Met 435 440 445 Glu Pro Ser Phe Gly Leu Ile Leu His Asp Gly Gly Thr Thr Leu Lys 450 455 460 Phe Val Asp Thr Pro Glu Ser Leu Ser Gly Leu Tyr Val Phe Val Val 465 470 475 480 Tyr Phe Asn Gly His Val Glu Ala Val Ala Tyr Thr Val Val Ser Thr 485 490 495 Val Asp His Phe Val Asn Ala Ile Glu Glu Arg Gly Phe Pro Pro Thr 500 505 510 Ala Gly Gln Pro Pro Ala Thr Thr Lys Pro Lys Glu Ile Thr Pro Val 515 520 525 Asn Pro Gly Thr Ser Pro Leu Leu Arg Tyr Ala Ala Trp Thr Gly Gly 530 535 540 Leu Ala Ala Val Val Leu Leu Cys Leu Val Ile Phe Leu Ile Cys Thr 545 550 555 560 Ala Lys Arg Met Arg Val Lys Ala Tyr Arg Val Asp Lys Ser Pro Tyr 565 570 575 Asn Gln Ser Met Tyr Tyr Ala Gly Leu Pro Val Asp Asp Phe Glu Asp 580 585 590 Ser Glu Ser Thr Asp Thr Glu Glu Glu Phe Gly Asn Ala Ile Gly Gly 595 600 605 Ser His Gly Gly Ser Ser Tyr Thr Val Tyr Ile Asp Lys Thr Arg 610 615 620 <210> 73 <211> 13339 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 73 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgagtct 7560 agtcgacgcc accatgttcg tgaccgccgt ggtgtccgtg tcccccagca gcttttacga 7620 gagcctgcag gtcgagccca cccagagcga ggacatcaca agatctgccc acctgggcga 7680 cggcgacgag atcagagagg ccatccacaa gagccaggac gccgagacaa agcccacctt 7740 ctacgtgtgc cccccaccta ccggctctac aattgtgcgg ctggaacccc ccagaacctg 7800 ccctgattac cacctgggca agaacttcac cgagggaatt gccgtggtgt acaaagagaa 7860 tatcgccgcc tacaagttca aggccaccgt gtactacaag gacgtgatcg tgtccaccgc 7920 ctgggccggc agcagctaca cccagatcac caacagatac gccgaccggg tgcccatccc 7980 cgtgtctgag atcaccgaca ccatcgacaa gttcggcaag tgcagcagca aggccaccta 8040 cgtgcggaac aaccacaagg tggaagcctt caacgaggac aagaaccccc aggacatgcc 8100 cctgatcgcc agcaagtaca acagcgtggg ctccaaggcc tggcacacca ccaacgacac 8160 ctacatggtg gccggcaccc ccggcacata cagaacaggc accagcgtga actgcatcat 8220 cgaggaagtg gaagcccggt ccatcttccc atacgacagc ttcggcctga gcaccggcga 8280 cattatctac atgagccctt tcttcggcct gcgggacggc gcctacagag agcacagcaa 8340 ctacgccatg gaccggttcc accagttcga gggctacaga cagcgggacc tggacacaag 8400 agccctgctg gaacctgccg ccagaaactt cctggtcacc cctcacctga ccgtgggctg 8460 gaactggaag cccaagcgga ccgaagtgtg cagcctggtc aagtggcgcg aggtggaaga 8520 tgtcgtgcgg gatgagtacg cccacaactt ccggttcacc atgaagaccc tgagcaccac 8580 cttcatcagc gagacaaacg agttcaacct gaaccagatc cacctgagcc agtgcgtgaa 8640 agaggaagcc agagccatca tcaaccggat ctacaccacc cggtacaaca gcagccacgt 8700 gcggaccggc gatatccaga cctatctggc tagaggcggc ttcgtggtgg tgtttcagcc 8760 cctgctgagc aacagcctgg ctagactgta cctgcaggaa ctcgtcagag agaacaccaa 8820 ccacagcccc cagaagcacc ccacccggaa taccagatcc agacgcagcg tgcccgtgga 8880 actgagagcc aaccggacca tcaccaccac cagcagcgtg gaattcgcca tgctgcagtt 8940 cacctacgac cacatccagg aacacgtgaa cgagatgctg gcccggatca gcagcagttg 9000 gtgccagctg cagaatcggg aaagggccct gtggtccggc ctgttcccca tcaatccaag 9060 cgccctggcc agcaccatcc tggaccagag agtgaaggcc agaatcctgg gggacgtgat 9120 cagcgtgtcc aactgtcctg agctgggcag cgacacccgg atcatcctgc agaacagcat 9180 gcgggtgtcc ggcagcacca ccagatgcta cagcagaccc ctgatcagca tcgtgtccct 9240 gaacggcagc ggcacagtgg aaggccagct gggcaccgat aacgagctga tcatgagccg 9300 ggacctgctc gaaccctgcg tggccaatca caagcggtac tttctgttcg gccaccacta 9360 cgtgtactat gaggactaca gatacgtgcg cgagatcgcc gtgcacgacg tgggcatgat 9420 cagcacctac gtggacctga acctgaccct gctgaaggac cgcgagttca tgccactgca 9480 ggtctacacc cgggacgagc tgagagatac cggcctgctg gactacagcg agatccagcg 9540 gcggaaccag atgcactccc tgcggttcta cgacatcgac aaggtggtgc agtacgacag 9600 cggcaccgcc atcatgcagg gcatggccca gttctttcag ggcctgggaa cagccggaca 9660 ggccgtggga catgtggtgc tgggagctac aggcgccctg ctgtctaccg tgcacggctt 9720 caccaccttt ctgagcaacc ccttcggagc cctggctgtg ggactgctgg tcctggctgg 9780 actggtggcc gccttctttg cctaccgcta cgtgctgaag ctgaaaacca gccccatgaa 9840 ggccctgtac cccctgacca ccaagggcct gaagcagctg cctgagggca tggacccctt 9900 cgccgagaag cccaatgcca ccgacacccc catcgaggaa atcggcgaca gccagaacac 9960 cgagccctcc gtgaacagcg gcttcgaccc cgacaagttt cgcgaggccc aggaaatgat 10020 caagtacatg accctggtgt ctgctgccga gcggcaggaa agcaaggccc ggaagaagaa 10080 caagacctcc gccctgctga ccagcagact gacaggactg gccctgcgga acagacgggg 10140 ctatagcaga gtgcggaccg agaatgtgac cggcgtgtaa tctagacgcg gccgcataca 10200 gcagcaattg gcaagctgct tacatagaac tcgcggcgat tggcatgccg ccttaaaatt 10260 tttattttat ttttcttttc ttttccgaat cggattttgt ttttaatatt tcaaaaaaaa 10320 aaaaaaaaaa aaaaaaaaaa aaaaaaaggg tcggcatggc atctccacct cctcgcggtc 10380 cgacctgggc atccgaagga ggacgcacgt ccactcggat ggctaaggga gagccacgtt 10440 taaaccagct ccaattcgcc ctatagtgag tcgtattacg cgcgctcact ggccgtcgtt 10500 ttacaacgtc gtgactggga aaaccctggc gttacccaac ttaatcgcct tgcagcacat 10560 ccccctttcg ccagctggcg taatagcgaa gaggcccgca ccgatcgccc ttcccaacag 10620 ttgcgcagcc tgaatggcga atgggacgcg ccctgtagcg gcgcattaag cgcggcgggt 10680 gtggtggtta cgcgcagcgt gaccgctaca cttgccagcg ccctagcgcc cgctcctttc 10740 gctttcttcc cttcctttct cgccacgttc gccggctttc cccgtcaagc tctaaatcgg 10800 gggctccctt tagggttccg atttagtgct ttacggcacc tcgaccccaa aaaacttgat 10860 tagggtgatg gttcacgtag tgggccatcg ccctgataga cggtttttcg ccctttgacg 10920 ttggagtcca cgttctttaa tagtggactc ttgttccaaa ctggaacaac actcaaccct 10980 atctcggtct attcttttga tttataaggg attttgccga tttcggccta ttggttaaaa 11040 aatgagctga tttaacaaaa atttaacgcg aattttaaca aaatattaac gcttacaatt 11100 taggtggcac ttttcgggga aatgtgcgcg gaacccctat ttgtttattt ttctaaatac 11160 attcaaatat gtatccgctc atgagacaat aaccctgata aatgcttcaa taatattgaa 11220 aaaggaagag tatgagtatt caacatttcc gtgtcgccct tattcccttt tttgcggcat 11280 tttgccttcc tgtttttgct cacccagaaa cgctggtgaa agtaaaagat gctgaagatc 11340 agttgggtgc acgagtgggt tacatcgaac tggatctcaa cagcggtaag atccttgaga 11400 gttttcgccc cgaagaacgt tttccaatga tgagcacttt taaagttctg ctatgtggcg 11460 cggtattatc ccgtattgac gccgggcaag agcaactcgg tcgccgcata cactattctc 11520 agaatgactt ggttgagtac tcaccagtca cagaaaagca tcttacggat ggcatgacag 11580 taagagaatt atgcagtgct gccataacca tgagtgataa cactgcggcc aacttacttc 11640 tgacaacgat cggaggaccg aaggagctaa ccgctttttt gcacaacatg ggggatcatg 11700 taactcgcct tgatcgttgg gaaccggagc tgaatgaagc cataccaaac gacgagcgtg 11760 acaccacgat gcctgtagca atggcaacaa cgttgcgcaa actattaact ggcgaactac 11820 ttactctagc ttcccggcaa caattaatag actggatgga ggcggataaa gttgcaggac 11880 cacttctgcg ctcggccctt ccggctggct ggtttattgc tgataaatct ggagccggtg 11940 agcgtgggtc tcgcggtatc attgcagcac tggggccaga tggtaagccc tcccgtatcg 12000 tagttatcta cacgacgggg agtcaggcaa ctatggatga acgaaataga cagatcgctg 12060 agataggtgc ctcactgatt aagcattggt aactgtcaga ccaagtttac tcatatatac 12120 tttagattga tttaaaactt catttttaat ttaaaaggat ctaggtgaag atcctttttg 12180 ataatctcat gaccaaaatc ccttaacgtg agttttcgtt ccactgagcg tcagaccccg 12240 tagaaaagat caaaggatct tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc 12300 aaacaaaaaa accaccgcta ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc 12360 tttttccgaa ggtaactggc ttcagcagag cgcagatacc aaatactgtt cttctagtgt 12420 agccgtagtt aggccaccac ttcaagaact ctgtagcacc gcctacatac ctcgctctgc 12480 taatcctgtt accagtggct gctgccagtg gcgataagtc gtgtcttacc gggttggact 12540 caagacgata gttaccggat aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac 12600 agcccagctt ggagcgaacg acctacaccg aactgagata cctacagcgt gagctatgag 12660 aaagcgccac gcttcccgaa gggagaaagg cggacaggta tccggtaagc ggcagggtcg 12720 gaacaggaga gcgcacgagg gagcttccag ggggaaacgc ctggtatctt tatagtcctg 12780 tcgggtttcg ccacctctga cttgagcgtc gatttttgtg atgctcgtca ggggggcgga 12840 gcctatggaa aaacgccagc aacgcggcct ttttacggtt cctggccttt tgctggcctt 12900 ttgctcacat gttctttcct gcgttatccc ctgattctgt ggataaccgt attaccgcct 12960 ttgagtgagc tgataccgct cgccgcagcc gaacgaccga gcgcagcgag tcagtgagcg 13020 aggaagcgga agagcgccca atacgcaaac cgcctctccc cgcgcgttgg ccgattcatt 13080 aatgcagctg gcacgacagg tttcccgact ggaaagcggg cagtgagcgc aacgcaatta 13140 atgtgagtta gctcactcat taggcacccc aggctttaca ctttatgctc ccggctcgta 13200 tgttgtgtgg aattgtgagc ggataacaat ttcacacagg aaacagctat gaccatgatt 13260 acgccaagcg cgcaattaac cctcactaaa gggaacaaaa gctgggtacc gggcccacgc 13320 gtaatacgac tcactatag 13339 <210> 74 <211> 13258 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 74 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgagtct 7560 agtcgacgcc accatgttcg ccctggtgct ggccgtggtc atcctgcctc tgtggaccac 7620 cgccaacaag agctacgtga cccccacacc cgccaccaga tccatcggac acatgagcgc 7680 cctgctgaga gagtacagcg accggaacat gagcctgaag ctggaagcct tctaccccac 7740 cggcttcgac gaggaactga tcaagagcct gcactggggc aacgaccgga agcacgtgtt 7800 cctcgtgatc gtgaaagtga accccaccac ccacgagggc gacgtcggcc tggtcatctt 7860 ccccaagtac ctgctgagcc cctaccactt caaggccgag cacagagccc ccttccctgc 7920 tggccgcttt ggctttctga gccaccctgt gacccccgac gtgtcattct tcgacagcag 7980 cttcgccccc tacctgacca cacagcacct ggtggccttc accaccttcc cccccaatcc 8040 tctcgtgtgg cacctggaaa gagccgagac agccgccacc gccgaaagac cttttggcgt 8100 gtccctgctg cccgccagac ctaccgtgcc caagaacacc atcctggaac acaaggccca 8160 cttcgccacc tgggatgccc tggccagaca caccttcttt agcgccgagg ccatcatcac 8220 caacagcacc ctgagaatcc acgtgcccct gttcggcagc gtgtggccca tcagatactg 8280 ggccacaggc agcgtgctgc tgaccagcga tagcggcaga gtggaagtga acatcggcgt 8340 gggcttcatg agcagcctga tcagcctgag cagcggcctg cccatcgagc tgattgtggt 8400 gccccacacc gtgaagctga acgccgtgac cagcgacacc acctggttcc agctgaaccc 8460 ccctggccct gatcctggcc ctagttacag agtgtacctg ctgggcagag gcctggacat 8520 gaacttcagc aagcacgcca ccgtggacat ctgcgcctac cctgaggaaa gcctggacta 8580 cagataccac ctgagcatgg cccacaccga ggccctgaga atgaccacca aggccgacca 8640 gcacgacatc aacgaggaaa gctactacca cattgccgcc agaatcgcca ccagcatctt 8700 cgccctgagc gagatgggcc ggaccaccga gtactttctg ctggacgaga tcgtggacgt 8760 gcagtaccag ctgaagttcc tgaactacat cctgatgcgg atcggcgctg gcgcccaccc 8820 taataccatc agcggcacca gcgacctgat cttcgccgat cctagccagc tgcacgacga 8880 gctgagcctg ctgttcggcc aggtcaaacc cgccaacgtg gactacttca tcagctacga 8940 cgaggcccgg gaccagctga aaacagccta cgccctgtcc agaggccagg atcatgtgaa 9000 cgccctgtcc ctggccaggc gcgtgatcat gagcatctac aagggcctgc tggtcaagca 9060 gaacctgaac gccaccgagc ggcaggccct gttcttcgcc agcatgatcc tgctgaactt 9120 cagagagggc ctggaaaaca gcagccgggt gctggatggc agaaccaccc tgctgctgat 9180 gaccagcatg tgcacagccg cccatgccac acaggccgcc ctgaatatcc aggaaggcct 9240 ggcttacctg aaccccagca agcacatgtt caccatcccc aacgtgtaca gcccctgcat 9300 gggcagcctg agaaccgacc tgaccgaaga gatccacgtg atgaacctgc tgtccgccat 9360 ccccaccaga cccggactga atgaggtgct gcacacccag ctggacgagt ccgagatctt 9420 cgacgccgcc ttcaagacca tgatgatctt taccacctgg accgccaagg acctgcacat 9480 cctgcacaca cacgtgcccg aggtgttcac atgccaagat gccgccgctc ggaacggcga 9540 gtatgtgctg attctgcctg ccgtgcaggg ccacagctac gtgatcaccc ggaacaagcc 9600 ccagcggggc ctggtgtata gcctggctga cgtggacgtg tacaacccca tcagcgtggt 9660 gtacctgagc aaggatacct gcgtgtccga gcacggcgtg atcgaaacag tggccctgcc 9720 ccaccccgac aacctgaaag agtgcctgta ctgcggctcc gtgttcctgc ggtatctgac 9780 caccggcgcc atcatggaca tcatcatcat cgacagcaag gacaccgaga gacagctggc 9840 cgccatgggc aacagcacca tccccccctt caaccccgac atgcacggcg acgatagcaa 9900 ggccgtgctg ctgttcccca acggcaccgt ggtcacactg ctgggcttcg agcggagaca 9960 ggccatcaga atgagcggcc agtacctggg cgcctctctg ggtggtgcct ttctggccgt 10020 cgtgggcttt ggcatcatcg gctggatgct gtgcggcaac agcagactgc gcgagtacaa 10080 caagatcccc ctgacctaat ctagacgcgg ccgcatacag cagcaattgg caagctgctt 10140 acatagaact cgcggcgatt ggcatgccgc cttaaaattt ttattttatt tttcttttct 10200 tttccgaatc ggattttgtt tttaatattt caaaaaaaaa aaaaaaaaaa aaaaaaaaaa 10260 aaaaaagggt cggcatggca tctccacctc ctcgcggtcc gacctgggca tccgaaggag 10320 gacgcacgtc cactcggatg gctaagggag agccacgttt aaaccagctc caattcgccc 10380 tatagtgagt cgtattacgc gcgctcactg gccgtcgttt tacaacgtcg tgactgggaa 10440 aaccctggcg ttacccaact taatcgcctt gcagcacatc cccctttcgc cagctggcgt 10500 aatagcgaag aggcccgcac cgatcgccct tcccaacagt tgcgcagcct gaatggcgaa 10560 tgggacgcgc cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg 10620 accgctacac ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc 10680 gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga 10740 tttagtgctt tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt 10800 gggccatcgc cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat 10860 agtggactct tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat 10920 ttataaggga ttttgccgat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa 10980 tttaacgcga attttaacaa aatattaacg cttacaattt aggtggcact tttcggggaa 11040 atgtgcgcgg aacccctatt tgtttatttt tctaaataca ttcaaatatg tatccgctca 11100 tgagacaata accctgataa atgcttcaat aatattgaaa aaggaagagt atgagtattc 11160 aacatttccg tgtcgccctt attccctttt ttgcggcatt ttgccttcct gtttttgctc 11220 acccagaaac gctggtgaaa gtaaaagatg ctgaagatca gttgggtgca cgagtgggtt 11280 acatcgaact ggatctcaac agcggtaaga tccttgagag ttttcgcccc gaagaacgtt 11340 ttccaatgat gagcactttt aaagttctgc tatgtggcgc ggtattatcc cgtattgacg 11400 ccgggcaaga gcaactcggt cgccgcatac actattctca gaatgacttg gttgagtact 11460 caccagtcac agaaaagcat cttacggatg gcatgacagt aagagaatta tgcagtgctg 11520 ccataaccat gagtgataac actgcggcca acttacttct gacaacgatc ggaggaccga 11580 aggagctaac cgcttttttg cacaacatgg gggatcatgt aactcgcctt gatcgttggg 11640 aaccggagct gaatgaagcc ataccaaacg acgagcgtga caccacgatg cctgtagcaa 11700 tggcaacaac gttgcgcaaa ctattaactg gcgaactact tactctagct tcccggcaac 11760 aattaataga ctggatggag gcggataaag ttgcaggacc acttctgcgc tcggcccttc 11820 cggctggctg gtttattgct gataaatctg gagccggtga gcgtgggtct cgcggtatca 11880 ttgcagcact ggggccagat ggtaagccct cccgtatcgt agttatctac acgacgggga 11940 gtcaggcaac tatggatgaa cgaaatagac agatcgctga gataggtgcc tcactgatta 12000 agcattggta actgtcagac caagtttact catatatact ttagattgat ttaaaacttc 12060 atttttaatt taaaaggatc taggtgaaga tcctttttga taatctcatg accaaaatcc 12120 cttaacgtga gttttcgttc cactgagcgt cagaccccgt agaaaagatc aaaggatctt 12180 cttgagatcc tttttttctg cgcgtaatct gctgcttgca aacaaaaaaa ccaccgctac 12240 cagcggtggt ttgtttgccg gatcaagagc taccaactct ttttccgaag gtaactggct 12300 tcagcagagc gcagatacca aatactgttc ttctagtgta gccgtagtta ggccaccact 12360 tcaagaactc tgtagcaccg cctacatacc tcgctctgct aatcctgtta ccagtggctg 12420 ctgccagtgg cgataagtcg tgtcttaccg ggttggactc aagacgatag ttaccggata 12480 aggcgcagcg gtcgggctga acggggggtt cgtgcacaca gcccagcttg gagcgaacga 12540 cctacaccga actgagatac ctacagcgtg agctatgaga aagcgccacg cttcccgaag 12600 ggagaaaggc ggacaggtat ccggtaagcg gcagggtcgg aacaggagag cgcacgaggg 12660 agcttccagg gggaaacgcc tggtatcttt atagtcctgt cgggtttcgc cacctctgac 12720 ttgagcgtcg atttttgtga tgctcgtcag gggggcggag cctatggaaa aacgccagca 12780 acgcggcctt tttacggttc ctggcctttt gctggccttt tgctcacatg ttctttcctg 12840 cgttatcccc tgattctgtg gataaccgta ttaccgcctt tgagtgagct gataccgctc 12900 gccgcagccg aacgaccgag cgcagcgagt cagtgagcga ggaagcggaa gagcgcccaa 12960 tacgcaaacc gcctctcccc gcgcgttggc cgattcatta atgcagctgg cacgacaggt 13020 ttcccgactg gaaagcgggc agtgagcgca acgcaattaa tgtgagttag ctcactcatt 13080 aggcacccca ggctttacac tttatgctcc cggctcgtat gttgtgtgga attgtgagcg 13140 gataacaatt tcacacagga aacagctatg accatgatta cgccaagcgc gcaattaacc 13200 ctcactaaag ggaacaaaag ctgggtaccg ggcccacgcg taatacgact cactatag 13258 <210> 75 <211> 11215 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 75 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgagtct 7560 agtcgacgcc accatggcca gccacaagtg gctgctgcag atgatcgtgt tcctgaaaac 7620 catcacaatc gcctactgcc tgcatctgca ggacgacacc cctctgttct tcggcgccaa 7680 gcctctgagc gacgtgtccc tgatcatcac cgagccttgc gtgtccagcg tgtacgaggc 7740 ctgggattat gccgcccctc ccgtgtccaa tctgagcgaa gccctgagcg gcatcgtggt 7800 caagaccaag tgccccgtgc ccgaagtgat cctgtggttc aaggacaagc agatggccta 7860 ctggaccaac ccttacgtga ccctgaaggg cctgacccag agcgtgggcg aggaacacaa 7920 gagcggcgac atcagagatg ccctgctgga tgccctgtcc ggtgtctggg tggacagcac 7980 accctccagc accaacatcc ccgagaacgg ctgtgtgtgg ggagccgacc ggctgttcca 8040 gagagtgtgt cagtaatcta gacgcggccg catacagcag caattggcaa gctgcttaca 8100 tagaactcgc ggcgattggc atgccgcctt aaaattttta ttttattttt cttttctttt 8160 ccgaatcgga ttttgttttt aatatttcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 8220 aaagggtcgg catggcatct ccacctcctc gcggtccgac ctgggcatcc gaaggaggac 8280 gcacgtccac tcggatggct aagggagagc cacgtttaaa ccagctccaa ttcgccctat 8340 agtgagtcgt attacgcgcg ctcactggcc gtcgttttac aacgtcgtga ctgggaaaac 8400 cctggcgtta cccaacttaa tcgccttgca gcacatcccc ctttcgccag ctggcgtaat 8460 agcgaagagg cccgcaccga tcgcccttcc caacagttgc gcagcctgaa tggcgaatgg 8520 gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc 8580 gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc 8640 acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg gttccgattt 8700 agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg 8760 ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt 8820 ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta 8880 taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt 8940 aacgcgaatt ttaacaaaat attaacgctt acaatttagg tggcactttt cggggaaatg 9000 tgcgcggaac ccctatttgt ttatttttct aaatacattc aaatatgtat ccgctcatga 9060 gacaataacc ctgataaatg cttcaataat attgaaaaag gaagagtatg agtattcaac 9120 atttccgtgt cgcccttatt cccttttttg cggcattttg ccttcctgtt tttgctcacc 9180 cagaaacgct ggtgaaagta aaagatgctg aagatcagtt gggtgcacga gtgggttaca 9240 tcgaactgga tctcaacagc ggtaagatcc ttgagagttt tcgccccgaa gaacgttttc 9300 caatgatgag cacttttaaa gttctgctat gtggcgcggt attatcccgt attgacgccg 9360 ggcaagagca actcggtcgc cgcatacact attctcagaa tgacttggtt gagtactcac 9420 cagtcacaga aaagcatctt acggatggca tgacagtaag agaattatgc agtgctgcca 9480 taaccatgag tgataacact gcggccaact tacttctgac aacgatcgga ggaccgaagg 9540 agctaaccgc ttttttgcac aacatggggg atcatgtaac tcgccttgat cgttgggaac 9600 cggagctgaa tgaagccata ccaaacgacg agcgtgacac cacgatgcct gtagcaatgg 9660 caacaacgtt gcgcaaacta ttaactggcg aactacttac tctagcttcc cggcaacaat 9720 taatagactg gatggaggcg gataaagttg caggaccact tctgcgctcg gcccttccgg 9780 ctggctggtt tattgctgat aaatctggag ccggtgagcg tgggtctcgc ggtatcattg 9840 cagcactggg gccagatggt aagccctccc gtatcgtagt tatctacacg acggggagtc 9900 aggcaactat ggatgaacga aatagacaga tcgctgagat aggtgcctca ctgattaagc 9960 attggtaact gtcagaccaa gtttactcat atatacttta gattgattta aaacttcatt 10020 tttaatttaa aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt 10080 aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt 10140 gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag 10200 cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta actggcttca 10260 gcagagcgca gataccaaat actgttcttc tagtgtagcc gtagttaggc caccacttca 10320 agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg 10380 ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg 10440 cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct 10500 acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga 10560 gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc 10620 ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg 10680 agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg 10740 cggccttttt acggttcctg gccttttgct ggccttttgc tcacatgttc tttcctgcgt 10800 tatcccctga ttctgtggat aaccgtatta ccgcctttga gtgagctgat accgctcgcc 10860 gcagccgaac gaccgagcgc agcgagtcag tgagcgagga agcggaagag cgcccaatac 10920 gcaaaccgcc tctccccgcg cgttggccga ttcattaatg cagctggcac gacaggtttc 10980 ccgactggaa agcgggcagt gagcgcaacg caattaatgt gagttagctc actcattagg 11040 caccccaggc tttacacttt atgctcccgg ctcgtatgtt gtgtggaatt gtgagcggat 11100 aacaatttca cacaggaaac agctatgacc atgattacgc caagcgcgca attaaccctc 11160 actaaaggga acaaaagctg ggtaccgggc ccacgcgtaa tacgactcac tatag 11215 <210> 76 <211> 13827 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 76 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgagtct 7560 agtcgacgcc accatgttcg ccctggtgct ggccgtggtc atcctgcctc tgtggaccac 7620 cgccaacaag agctacgtga cccccacacc cgccaccaga tccatcggac acatgagcgc 7680 cctgctgaga gagtacagcg accggaacat gagcctgaag ctggaagcct tctaccccac 7740 cggcttcgac gaggaactga tcaagagcct gcactggggc aacgaccgga agcacgtgtt 7800 cctcgtgatc gtgaaagtga accccaccac ccacgagggc gacgtcggcc tggtcatctt 7860 ccccaagtac ctgctgagcc cctaccactt caaggccgag cacagagccc ccttccctgc 7920 tggccgcttt ggctttctga gccaccctgt gacccccgac gtgtcattct tcgacagcag 7980 cttcgccccc tacctgacca cacagcacct ggtggccttc accaccttcc cccccaatcc 8040 tctcgtgtgg cacctggaaa gagccgagac agccgccacc gccgaaagac cttttggcgt 8100 gtccctgctg cccgccagac ctaccgtgcc caagaacacc atcctggaac acaaggccca 8160 cttcgccacc tgggatgccc tggccagaca caccttcttt agcgccgagg ccatcatcac 8220 caacagcacc ctgagaatcc acgtgcccct gttcggcagc gtgtggccca tcagatactg 8280 ggccacaggc agcgtgctgc tgaccagcga tagcggcaga gtggaagtga acatcggcgt 8340 gggcttcatg agcagcctga tcagcctgag cagcggcctg cccatcgagc tgattgtggt 8400 gccccacacc gtgaagctga acgccgtgac cagcgacacc acctggttcc agctgaaccc 8460 ccctggccct gatcctggcc ctagttacag agtgtacctg ctgggcagag gcctggacat 8520 gaacttcagc aagcacgcca ccgtggacat ctgcgcctac cctgaggaaa gcctggacta 8580 cagataccac ctgagcatgg cccacaccga ggccctgaga atgaccacca aggccgacca 8640 gcacgacatc aacgaggaaa gctactacca cattgccgcc agaatcgcca ccagcatctt 8700 cgccctgagc gagatgggcc ggaccaccga gtactttctg ctggacgaga tcgtggacgt 8760 gcagtaccag ctgaagttcc tgaactacat cctgatgcgg atcggcgctg gcgcccaccc 8820 taataccatc agcggcacca gcgacctgat cttcgccgat cctagccagc tgcacgacga 8880 gctgagcctg ctgttcggcc aggtcaaacc cgccaacgtg gactacttca tcagctacga 8940 cgaggcccgg gaccagctga aaacagccta cgccctgtcc agaggccagg atcatgtgaa 9000 cgccctgtcc ctggccaggc gcgtgatcat gagcatctac aagggcctgc tggtcaagca 9060 gaacctgaac gccaccgagc ggcaggccct gttcttcgcc agcatgatcc tgctgaactt 9120 cagagagggc ctggaaaaca gcagccgggt gctggatggc agaaccaccc tgctgctgat 9180 gaccagcatg tgcacagccg cccatgccac acaggccgcc ctgaatatcc aggaaggcct 9240 ggcttacctg aaccccagca agcacatgtt caccatcccc aacgtgtaca gcccctgcat 9300 gggcagcctg agaaccgacc tgaccgaaga gatccacgtg atgaacctgc tgtccgccat 9360 ccccaccaga cccggactga atgaggtgct gcacacccag ctggacgagt ccgagatctt 9420 cgacgccgcc ttcaagacca tgatgatctt taccacctgg accgccaagg acctgcacat 9480 cctgcacaca cacgtgcccg aggtgttcac atgccaagat gccgccgctc ggaacggcga 9540 gtatgtgctg attctgcctg ccgtgcaggg ccacagctac gtgatcaccc ggaacaagcc 9600 ccagcggggc ctggtgtata gcctggctga cgtggacgtg tacaacccca tcagcgtggt 9660 gtacctgagc aaggatacct gcgtgtccga gcacggcgtg atcgaaacag tggccctgcc 9720 ccaccccgac aacctgaaag agtgcctgta ctgcggctcc gtgttcctgc ggtatctgac 9780 caccggcgcc atcatggaca tcatcatcat cgacagcaag gacaccgaga gacagctggc 9840 cgccatgggc aacagcacca tccccccctt caaccccgac atgcacggcg acgatagcaa 9900 ggccgtgctg ctgttcccca acggcaccgt ggtcacactg ctgggcttcg agcggagaca 9960 ggccatcaga atgagcggcc agtacctggg cgcctctctg ggtggtgcct ttctggccgt 10020 cgtgggcttt ggcatcatcg gctggatgct gtgcggcaac agcagactgc gcgagtacaa 10080 caagatcccc ctgacctaat ctagacgtcg cgaccaccca ggatccgcct ataactctct 10140 acggctaacc tgaatggact acgacatagt ctagtcgacg ccaccatggc cagccacaag 10200 tggctgctgc agatgatcgt gttcctgaaa accatcacaa tcgcctactg cctgcatctg 10260 caggacgaca cccctctgtt cttcggcgcc aagcctctga gcgacgtgtc cctgatcatc 10320 accgagcctt gcgtgtccag cgtgtacgag gcctgggatt atgccgcccc tcccgtgtcc 10380 aatctgagcg aagccctgag cggcatcgtg gtcaagacca agtgccccgt gcccgaagtg 10440 atcctgtggt tcaaggacaa gcagatggcc tactggacca acccttacgt gaccctgaag 10500 ggcctgaccc agagcgtggg cgaggaacac aagagcggcg acatcagaga tgccctgctg 10560 gatgccctgt ccggtgtctg ggtggacagc acaccctcca gcaccaacat ccccgagaac 10620 ggctgtgtgt ggggagccga ccggctgttc cagagagtgt gtcagtaatc tagacgcggc 10680 cgcatacagc agcaattggc aagctgctta catagaactc gcggcgattg gcatgccgcc 10740 ttaaaatttt tattttattt ttcttttctt ttccgaatcg gattttgttt ttaatatttc 10800 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaagggtc ggcatggcat ctccacctcc 10860 tcgcggtccg acctgggcat ccgaaggagg acgcacgtcc actcggatgg ctaagggaga 10920 gccacgttta aaccagctcc aattcgccct atagtgagtc gtattacgcg cgctcactgg 10980 ccgtcgtttt acaacgtcgt gactgggaaa accctggcgt tacccaactt aatcgccttg 11040 cagcacatcc ccctttcgcc agctggcgta atagcgaaga ggcccgcacc gatcgccctt 11100 cccaacagtt gcgcagcctg aatggcgaat gggacgcgcc ctgtagcggc gcattaagcg 11160 cggcgggtgt ggtggttacg cgcagcgtga ccgctacact tgccagcgcc ctagcgcccg 11220 ctcctttcgc tttcttccct tcctttctcg ccacgttcgc cggctttccc cgtcaagctc 11280 taaatcgggg gctcccttta gggttccgat ttagtgcttt acggcacctc gaccccaaaa 11340 aacttgatta gggtgatggt tcacgtagtg ggccatcgcc ctgatagacg gtttttcgcc 11400 ctttgacgtt ggagtccacg ttctttaata gtggactctt gttccaaact ggaacaacac 11460 tcaaccctat ctcggtctat tcttttgatt tataagggat tttgccgatt tcggcctatt 11520 ggttaaaaaa tgagctgatt taacaaaaat ttaacgcgaa ttttaacaaa atattaacgc 11580 ttacaattta ggtggcactt ttcggggaaa tgtgcgcgga acccctattt gtttattttt 11640 ctaaatacat tcaaatatgt atccgctcat gagacaataa ccctgataaa tgcttcaata 11700 atattgaaaa aggaagagta tgagtattca acatttccgt gtcgccctta ttcccttttt 11760 tgcggcattt tgccttcctg tttttgctca cccagaaacg ctggtgaaag taaaagatgc 11820 tgaagatcag ttgggtgcac gagtgggtta catcgaactg gatctcaaca gcggtaagat 11880 ccttgagagt tttcgccccg aagaacgttt tccaatgatg agcactttta aagttctgct 11940 atgtggcgcg gtattatccc gtattgacgc cgggcaagag caactcggtc gccgcataca 12000 ctattctcag aatgacttgg ttgagtactc accagtcaca gaaaagcatc ttacggatgg 12060 catgacagta agagaattat gcagtgctgc cataaccatg agtgataaca ctgcggccaa 12120 cttacttctg acaacgatcg gaggaccgaa ggagctaacc gcttttttgc acaacatggg 12180 ggatcatgta actcgccttg atcgttggga accggagctg aatgaagcca taccaaacga 12240 cgagcgtgac accacgatgc ctgtagcaat ggcaacaacg ttgcgcaaac tattaactgg 12300 cgaactactt actctagctt cccggcaaca attaatagac tggatggagg cggataaagt 12360 tgcaggacca cttctgcgct cggcccttcc ggctggctgg tttattgctg ataaatctgg 12420 agccggtgag cgtgggtctc gcggtatcat tgcagcactg gggccagatg gtaagccctc 12480 ccgtatcgta gttatctaca cgacggggag tcaggcaact atggatgaac gaaatagaca 12540 gatcgctgag ataggtgcct cactgattaa gcattggtaa ctgtcagacc aagtttactc 12600 atatatactt tagattgatt taaaacttca tttttaattt aaaaggatct aggtgaagat 12660 cctttttgat aatctcatga ccaaaatccc ttaacgtgag ttttcgttcc actgagcgtc 12720 agaccccgta gaaaagatca aaggatcttc ttgagatcct ttttttctgc gcgtaatctg 12780 ctgcttgcaa acaaaaaaac caccgctacc agcggtggtt tgtttgccgg atcaagagct 12840 accaactctt tttccgaagg taactggctt cagcagagcg cagataccaa atactgttct 12900 tctagtgtag ccgtagttag gccaccactt caagaactct gtagcaccgc ctacatacct 12960 cgctctgcta atcctgttac cagtggctgc tgccagtggc gataagtcgt gtcttaccgg 13020 gttggactca agacgatagt taccggataa ggcgcagcgg tcgggctgaa cggggggttc 13080 gtgcacacag cccagcttgg agcgaacgac ctacaccgaa ctgagatacc tacagcgtga 13140 gctatgagaa agcgccacgc ttcccgaagg gagaaaggcg gacaggtatc cggtaagcgg 13200 cagggtcgga acaggagagc gcacgaggga gcttccaggg ggaaacgcct ggtatcttta 13260 tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat gctcgtcagg 13320 ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc tggccttttg 13380 ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg ataaccgtat 13440 taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc gcagcgagtc 13500 agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg cgcgttggcc 13560 gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa 13620 cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact ttatgctccc 13680 ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa acagctatga 13740 ccatgattac gccaagcgcg caattaaccc tcactaaagg gaacaaaagc tgggtaccgg 13800 gcccacgcgt aatacgactc actatag 13827 <210> 77 <211> 12604 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 77 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgagtct 7560 agtcgacgcc accatgggca ccgtgaacaa gcctgtcgtg ggcgtgctga tgggcttcgg 7620 catcatcacc ggcaccctga gaatcaccaa ccctgtgcgg gccagcgtgc tgagatacga 7680 cgacttccac atcgacgagg acaagctgga caccaacagc gtgtacgagc cctactacca 7740 cagcgaccac gccgagagca gctgggtcaa cagaggcgag agcagccgga aggcctacga 7800 ccacaacagc ccctacatct ggccccggaa cgactacgac ggcttcctgg aaaacgccca 7860 cgagcaccac ggcgtgtaca atcagggcag aggcatcgac agcggcgaga gactgatgca 7920 gcccacacag atgagcgccc aggaagatct gggcgacgac acaggcatcc acgtgatccc 7980 caccctgaac ggcgacgacc ggcacaagat cgtgaacgtg gaccagcggc agtacggcga 8040 cgtgttcaag ggcgacctga accctaagcc ccagggccag agactgatcg aggtgtccgt 8100 ggaagagaac caccccttca ccctgagagc ccccatccag agaatctacg gcgtgcggta 8160 taccgagact tggagcttcc tgcccagcct gacctgtaca ggcgacgccg ctcctgccat 8220 ccagcacatc tgcctgaagc acaccacctg tttccaggac gtggtggtgg acgtggactg 8280 cgccgagaac accaaagagg accagctggc cgagatcagc taccggttcc agggcaagaa 8340 agaggccgac cagccctgga tcgtggtcaa taccagcacc ctgttcgacg agctggaact 8400 ggaccccccc gagattgaac ccggcgtgct gaaggtgctg cggaccgaga agcagtacct 8460 gggcgtgtac atctggaaca tgcggggctc cgacggcacc tctacctacg ccaccttcct 8520 ggtcacatgg aagggcgacg agaaaacccg gaaccctacc cctgccgtga cccctcagcc 8580 tagaggcgcc gagttccata tgtggaatta ccactcccac gtgttcagcg tgggcgacac 8640 cttcagcctg gccatgcatc tgcagtacaa gatccacgag gcccccttcg acctgctgct 8700 ggaatggctg tacgtgccca tcgaccctac ctgccagccc atgcggctgt acagcacctg 8760 tctgtaccac cccaacgccc ctcagtgcct gagccacatg aacagcggct gcaccttcac 8820 cagccctcac ctggctcaga gggtggccag caccgtgtac cagaattgcg agcacgccga 8880 caactacacc gcctactgcc tgggcatcag ccacatggaa cccagcttcg gcctgatcct 8940 gcacgatggc ggcaccaccc tgaagttcgt ggacacaccc gagagcctga gcggcctgta 9000 cgtgttcgtg gtgtacttca acggccacgt ggaagccgtg gcctacaccg tggtgtccac 9060 cgtggaccac ttcgtgaacg ccatcgagga aagaggcttc ccacccacag ccggacagcc 9120 tccagccacc accaagccca aagaaatcac ccccgtgaac cccggcacca gccccctgct 9180 gagatatgct gcttggacag gcggactggc cgctgtggtg ctgctgtgcc tggtcatctt 9240 cctgatctgc accgccaagc ggatgagagt gaaggcctac cgggtggaca agtcccccta 9300 caaccagagc atgtactacg ccggcctgcc cgtggacgat ttcgaggata gcgagagcac 9360 cgacaccgag gaagagttcg gcaacgccat cggcggatct cacggcggca gcagctacac 9420 cgtgtacatc gacaagacca gataatctag acgcggccgc atacagcagc aattggcaag 9480 ctgcttacat agaactcgcg gcgattggca tgccgcctta aaatttttat tttatttttc 9540 ttttcttttc cgaatcggat tttgttttta atatttcaaa aaaaaaaaaa aaaaaaaaaa 9600 aaaaaaaaaa aagggtcggc atggcatctc cacctcctcg cggtccgacc tgggcatccg 9660 aaggaggacg cacgtccact cggatggcta agggagagcc acgtttaaac cagctccaat 9720 tcgccctata gtgagtcgta ttacgcgcgc tcactggccg tcgttttaca acgtcgtgac 9780 tgggaaaacc ctggcgttac ccaacttaat cgccttgcag cacatccccc tttcgccagc 9840 tggcgtaata gcgaagaggc ccgcaccgat cgcccttccc aacagttgcg cagcctgaat 9900 ggcgaatggg acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt ggttacgcgc 9960 agcgtgaccg ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt cttcccttcc 10020 tttctcgcca cgttcgccgg ctttccccgt caagctctaa atcgggggct ccctttaggg 10080 ttccgattta gtgctttacg gcacctcgac cccaaaaaac ttgattaggg tgatggttca 10140 cgtagtgggc catcgccctg atagacggtt tttcgccctt tgacgttgga gtccacgttc 10200 tttaatagtg gactcttgtt ccaaactgga acaacactca accctatctc ggtctattct 10260 tttgatttat aagggatttt gccgatttcg gcctattggt taaaaaatga gctgatttaa 10320 caaaaattta acgcgaattt taacaaaata ttaacgctta caatttaggt ggcacttttc 10380 ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca aatatgtatc 10440 cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg aagagtatga 10500 gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc cttcctgttt 10560 ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg ggtgcacgag 10620 tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt cgccccgaag 10680 aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta ttatcccgta 10740 ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat gacttggttg 10800 agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga gaattatgca 10860 gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca acgatcggag 10920 gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact cgccttgatc 10980 gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc acgatgcctg 11040 tagcaatggc aacaacgttg cgcaaactat taactggcga actacttact ctagcttccc 11100 ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt ctgcgctcgg 11160 cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt gggtctcgcg 11220 gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt atctacacga 11280 cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata ggtgcctcac 11340 tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag attgatttaa 11400 aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat ctcatgacca 11460 aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa aagatcaaag 11520 gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca aaaaaaccac 11580 cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt ccgaaggtaa 11640 ctggcttcag cagagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc 11700 accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc ctgttaccag 11760 tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga cgatagttac 11820 cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc agcttggagc 11880 gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc gccacgcttc 11940 ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca 12000 cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg tttcgccacc 12060 tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta tggaaaaacg 12120 ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct cacatgttct 12180 ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag tgagctgata 12240 ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa gcggaagagc 12300 gcccaatacg caaaccgcct ctccccgcgc gttggccgat tcattaatgc agctggcacg 12360 acaggtttcc cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg agttagctca 12420 ctcattaggc accccaggct ttacacttta tgctcccggc tcgtatgttg tgtggaattg 12480 tgagcggata acaatttcac acaggaaaca gctatgacca tgattacgcc aagcgcgcaa 12540 ttaaccctca ctaaagggaa caaaagctgg gtaccgggcc cacgcgtaat acgactcact 12600 atag 12604 <210> 78 <211> 11797 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 78 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgagtct 7560 agtcgacgcc accatgtttc tgatccagtg cctgatcagc gccgtgatct tctatattca 7620 agtcacaaac gccctgatct ttaagggcga ccacgtgtca ctgcaggtca acagcagcct 7680 gaccagcatc ctgatcccca tgcagaacga caattacacc gagatcaagg gccagctggt 7740 gttcatcggc gagcagctgc ccaccggcac caattacagc ggcaccctgg aactgctgta 7800 cgccgatacc gtggccttct gcttcagaag cgtgcaggtc atcagatacg acggctgccc 7860 ccggatcaga accagcgcct tcatcagctg ccggtacaag cacagctggc actacggcaa 7920 cagcaccgac cggatcagca ccgaacctga tgccggcgtg atgctgaaga tcaccaagcc 7980 cggcatcaac gacgccggcg tgtacgtgct gctcgtgcgg ctggatcaca gcagaagcac 8040 cgacggcttc atcctgggcg tgaacgtgta caccgccggc agccaccaca acatccacgg 8100 cgtgatctac accagcccca gcctgcagaa cggctacagc accagagccc tgttccagca 8160 ggccagactg tgcgatctgc ccgccacacc taagggcagc ggcacaagcc tgtttcagca 8220 catgctggac ctgagagccg gcaagagcct ggaagataac ccctggctgc acgaggacgt 8280 ggtcaccacc gagacaaaga gcgtggtcaa agagggcatc gagaaccacg tgtaccccac 8340 cgacatgagc accctgcccg agaagtccct gaacgacccc cctgagaacc tgctgatcat 8400 catccccatc gtggccagcg tgatgatcct gaccgccatg gtcatcgtga tcgtgatcag 8460 cgtgaagcgg cggagaatca agaagcaccc catctaccgg cccaacacca agaccagacg 8520 gggcatccag aacgccaccc ctgagtccga cgtgatgctg gaagccgcca ttgcccagct 8580 ggccaccatc agagaggaaa gcccccctca cagcgtcgtg aaccccttcg tgaagtaatc 8640 tagacgcggc cgcatacagc agcaattggc aagctgctta catagaactc gcggcgattg 8700 gcatgccgcc ttaaaatttt tattttattt ttcttttctt ttccgaatcg gattttgttt 8760 ttaatatttc aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaagggtc ggcatggcat 8820 ctccacctcc tcgcggtccg acctgggcat ccgaaggagg acgcacgtcc actcggatgg 8880 ctaagggaga gccacgttta aaccagctcc aattcgccct atagtgagtc gtattacgcg 8940 cgctcactgg ccgtcgtttt acaacgtcgt gactgggaaa accctggcgt tacccaactt 9000 aatcgccttg cagcacatcc ccctttcgcc agctggcgta atagcgaaga ggcccgcacc 9060 gatcgccctt cccaacagtt gcgcagcctg aatggcgaat gggacgcgcc ctgtagcggc 9120 gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga ccgctacact tgccagcgcc 9180 ctagcgcccg ctcctttcgc tttcttccct tcctttctcg ccacgttcgc cggctttccc 9240 cgtcaagctc taaatcgggg gctcccttta gggttccgat ttagtgcttt acggcacctc 9300 gaccccaaaa aacttgatta gggtgatggt tcacgtagtg ggccatcgcc ctgatagacg 9360 gtttttcgcc ctttgacgtt ggagtccacg ttctttaata gtggactctt gttccaaact 9420 ggaacaacac tcaaccctat ctcggtctat tcttttgatt tataagggat tttgccgatt 9480 tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat ttaacgcgaa ttttaacaaa 9540 atattaacgc ttacaattta ggtggcactt ttcggggaaa tgtgcgcgga acccctattt 9600 gtttattttt ctaaatacat tcaaatatgt atccgctcat gagacaataa ccctgataaa 9660 tgcttcaata atattgaaaa aggaagagta tgagtattca acatttccgt gtcgccctta 9720 ttcccttttt tgcggcattt tgccttcctg tttttgctca cccagaaacg ctggtgaaag 9780 taaaagatgc tgaagatcag ttgggtgcac gagtgggtta catcgaactg gatctcaaca 9840 gcggtaagat ccttgagagt tttcgccccg aagaacgttt tccaatgatg agcactttta 9900 aagttctgct atgtggcgcg gtattatccc gtattgacgc cgggcaagag caactcggtc 9960 gccgcataca ctattctcag aatgacttgg ttgagtactc accagtcaca gaaaagcatc 10020 ttacggatgg catgacagta agagaattat gcagtgctgc cataaccatg agtgataaca 10080 ctgcggccaa cttacttctg acaacgatcg gaggaccgaa ggagctaacc gcttttttgc 10140 acaacatggg ggatcatgta actcgccttg atcgttggga accggagctg aatgaagcca 10200 taccaaacga cgagcgtgac accacgatgc ctgtagcaat ggcaacaacg ttgcgcaaac 10260 tattaactgg cgaactactt actctagctt cccggcaaca attaatagac tggatggagg 10320 cggataaagt tgcaggacca cttctgcgct cggcccttcc ggctggctgg tttattgctg 10380 ataaatctgg agccggtgag cgtgggtctc gcggtatcat tgcagcactg gggccagatg 10440 gtaagccctc ccgtatcgta gttatctaca cgacggggag tcaggcaact atggatgaac 10500 gaaatagaca gatcgctgag ataggtgcct cactgattaa gcattggtaa ctgtcagacc 10560 aagtttactc atatatactt tagattgatt taaaacttca tttttaattt aaaaggatct 10620 aggtgaagat cctttttgat aatctcatga ccaaaatccc ttaacgtgag ttttcgttcc 10680 actgagcgtc agaccccgta gaaaagatca aaggatcttc ttgagatcct ttttttctgc 10740 gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc agcggtggtt tgtttgccgg 10800 atcaagagct accaactctt tttccgaagg taactggctt cagcagagcg cagataccaa 10860 atactgttct tctagtgtag ccgtagttag gccaccactt caagaactct gtagcaccgc 10920 ctacatacct cgctctgcta atcctgttac cagtggctgc tgccagtggc gataagtcgt 10980 gtcttaccgg gttggactca agacgatagt taccggataa ggcgcagcgg tcgggctgaa 11040 cggggggttc gtgcacacag cccagcttgg agcgaacgac ctacaccgaa ctgagatacc 11100 tacagcgtga gctatgagaa agcgccacgc ttcccgaagg gagaaaggcg gacaggtatc 11160 cggtaagcgg cagggtcgga acaggagagc gcacgaggga gcttccaggg ggaaacgcct 11220 ggtatcttta tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat 11280 gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc 11340 tggccttttg ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg 11400 ataaccgtat taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc 11460 gcagcgagtc agtgagcgag gaagcggaag agcgcccaat acgcaaaccg cctctccccg 11520 cgcgttggcc gattcattaa tgcagctggc acgacaggtt tcccgactgg aaagcgggca 11580 gtgagcgcaa cgcaattaat gtgagttagc tcactcatta ggcaccccag gctttacact 11640 ttatgctccc ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt cacacaggaa 11700 acagctatga ccatgattac gccaagcgcg caattaaccc tcactaaagg gaacaaaagc 11760 tgggtaccgg gcccacgcgt aatacgactc actatag 11797 <210> 79 <211> 13755 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 79 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgagtct 7560 agtcgacgcc accatgggca ccgtgaacaa gcctgtcgtg ggcgtgctga tgggcttcgg 7620 catcatcacc ggcaccctga gaatcaccaa ccctgtgcgg gccagcgtgc tgagatacga 7680 cgacttccac atcgacgagg acaagctgga caccaacagc gtgtacgagc cctactacca 7740 cagcgaccac gccgagagca gctgggtcaa cagaggcgag agcagccgga aggcctacga 7800 ccacaacagc ccctacatct ggccccggaa cgactacgac ggcttcctgg aaaacgccca 7860 cgagcaccac ggcgtgtaca atcagggcag aggcatcgac agcggcgaga gactgatgca 7920 gcccacacag atgagcgccc aggaagatct gggcgacgac acaggcatcc acgtgatccc 7980 caccctgaac ggcgacgacc ggcacaagat cgtgaacgtg gaccagcggc agtacggcga 8040 cgtgttcaag ggcgacctga accctaagcc ccagggccag agactgatcg aggtgtccgt 8100 ggaagagaac caccccttca ccctgagagc ccccatccag agaatctacg gcgtgcggta 8160 taccgagact tggagcttcc tgcccagcct gacctgtaca ggcgacgccg ctcctgccat 8220 ccagcacatc tgcctgaagc acaccacctg tttccaggac gtggtggtgg acgtggactg 8280 cgccgagaac accaaagagg accagctggc cgagatcagc taccggttcc agggcaagaa 8340 agaggccgac cagccctgga tcgtggtcaa taccagcacc ctgttcgacg agctggaact 8400 ggaccccccc gagattgaac ccggcgtgct gaaggtgctg cggaccgaga agcagtacct 8460 gggcgtgtac atctggaaca tgcggggctc cgacggcacc tctacctacg ccaccttcct 8520 ggtcacatgg aagggcgacg agaaaacccg gaaccctacc cctgccgtga cccctcagcc 8580 tagaggcgcc gagttccata tgtggaatta ccactcccac gtgttcagcg tgggcgacac 8640 cttcagcctg gccatgcatc tgcagtacaa gatccacgag gcccccttcg acctgctgct 8700 ggaatggctg tacgtgccca tcgaccctac ctgccagccc atgcggctgt acagcacctg 8760 tctgtaccac cccaacgccc ctcagtgcct gagccacatg aacagcggct gcaccttcac 8820 cagccctcac ctggctcaga gggtggccag caccgtgtac cagaattgcg agcacgccga 8880 caactacacc gcctactgcc tgggcatcag ccacatggaa cccagcttcg gcctgatcct 8940 gcacgatggc ggcaccaccc tgaagttcgt ggacacaccc gagagcctga gcggcctgta 9000 cgtgttcgtg gtgtacttca acggccacgt ggaagccgtg gcctacaccg tggtgtccac 9060 cgtggaccac ttcgtgaacg ccatcgagga aagaggcttc ccacccacag ccggacagcc 9120 tccagccacc accaagccca aagaaatcac ccccgtgaac cccggcacca gccccctgct 9180 gagatatgct gcttggacag gcggactggc cgctgtggtg ctgctgtgcc tggtcatctt 9240 cctgatctgc accgccaagc ggatgagagt gaaggcctac cgggtggaca agtcccccta 9300 caaccagagc atgtactacg ccggcctgcc cgtggacgat ttcgaggata gcgagagcac 9360 cgacaccgag gaagagttcg gcaacgccat cggcggatct cacggcggca gcagctacac 9420 cgtgtacatc gacaagacca gataatctag acgtcgcgac cacccaggat ccgcctataa 9480 ctctctacgg ctaacctgaa tggactacga catagtctag tcgacgccac catgtttctg 9540 atccagtgcc tgatcagcgc cgtgatcttc tatattcaag tcacaaacgc cctgatcttt 9600 aagggcgacc acgtgtcact gcaggtcaac agcagcctga ccagcatcct gatccccatg 9660 cagaacgaca attacaccga gatcaagggc cagctggtgt tcatcggcga gcagctgccc 9720 accggcacca attacagcgg caccctggaa ctgctgtacg ccgataccgt ggccttctgc 9780 ttcagaagcg tgcaggtcat cagatacgac ggctgccccc ggatcagaac cagcgccttc 9840 atcagctgcc ggtacaagca cagctggcac tacggcaaca gcaccgaccg gatcagcacc 9900 gaacctgatg ccggcgtgat gctgaagatc accaagcccg gcatcaacga cgccggcgtg 9960 tacgtgctgc tcgtgcggct ggatcacagc agaagcaccg acggcttcat cctgggcgtg 10020 aacgtgtaca ccgccggcag ccaccacaac atccacggcg tgatctacac cagccccagc 10080 ctgcagaacg gctacagcac cagagccctg ttccagcagg ccagactgtg cgatctgccc 10140 gccacaccta agggcagcgg cacaagcctg tttcagcaca tgctggacct gagagccggc 10200 aagagcctgg aagataaccc ctggctgcac gaggacgtgg tcaccaccga gacaaagagc 10260 gtggtcaaag agggcatcga gaaccacgtg taccccaccg acatgagcac cctgcccgag 10320 aagtccctga acgacccccc tgagaacctg ctgatcatca tccccatcgt ggccagcgtg 10380 atgatcctga ccgccatggt catcgtgatc gtgatcagcg tgaagcggcg gagaatcaag 10440 aagcacccca tctaccggcc caacaccaag accagacggg gcatccagaa cgccacccct 10500 gagtccgacg tgatgctgga agccgccatt gcccagctgg ccaccatcag agaggaaagc 10560 ccccctcaca gcgtcgtgaa ccccttcgtg aagtaatcta gacgcggccg catacagcag 10620 caattggcaa gctgcttaca tagaactcgc ggcgattggc atgccgcctt aaaattttta 10680 ttttattttt cttttctttt ccgaatcgga ttttgttttt aatatttcaa aaaaaaaaaa 10740 aaaaaaaaaa aaaaaaaaaa aaagggtcgg catggcatct ccacctcctc gcggtccgac 10800 ctgggcatcc gaaggaggac gcacgtccac tcggatggct aagggagagc cacgtttaaa 10860 ccagctccaa ttcgccctat agtgagtcgt attacgcgcg ctcactggcc gtcgttttac 10920 aacgtcgtga ctgggaaaac cctggcgtta cccaacttaa tcgccttgca gcacatcccc 10980 ctttcgccag ctggcgtaat agcgaagagg cccgcaccga tcgcccttcc caacagttgc 11040 gcagcctgaa tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg 11100 tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt 11160 tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc 11220 tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg 11280 gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg 11340 agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct 11400 cggtctattc ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg 11460 agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgctt acaatttagg 11520 tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 11580 aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 11640 gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg 11700 ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 11760 gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 11820 tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 11880 attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 11940 tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 12000 agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 12060 aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 12120 tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 12180 cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac 12240 tctagcttcc cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact 12300 tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg 12360 tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt 12420 tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat 12480 aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta 12540 gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa 12600 tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga 12660 aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac 12720 aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt 12780 tccgaaggta actggcttca gcagagcgca gataccaaat actgttcttc tagtgtagcc 12840 gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat 12900 cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag 12960 acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc 13020 cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag 13080 cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac 13140 aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg 13200 gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct 13260 atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc 13320 tcacatgttc tttcctgcgt tatcccctga ttctgtggat aaccgtatta ccgcctttga 13380 gtgagctgat accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga 13440 agcggaagag cgcccaatac gcaaaccgcc tctccccgcg cgttggccga ttcattaatg 13500 cagctggcac gacaggtttc ccgactggaa agcgggcagt gagcgcaacg caattaatgt 13560 gagttagctc actcattagg caccccaggc tttacacttt atgctcccgg ctcgtatgtt 13620 gtgtggaatt gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc 13680 caagcgcgca attaaccctc actaaaggga acaaaagctg ggtaccgggc ccacgcgtaa 13740 tacgactcac tatag 13755 <210> 80 <211> 11459 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 80 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgacgcc 7560 accatggtga gcaagggcga ggagctgttc accggggtgg tgcccatcct ggtcgagctg 7620 gacggcgacg taaacggcca caagttcagc gtgtccggcg agggcgaggg cgatgccacc 7680 tacggcaagc tgaccctgaa gttcatctgc accaccggca agctgcccgt gccctggccc 7740 accctcgtga ccaccctgac ctacggcgtg cagtgcttca gccgctaccc cgaccacatg 7800 aagcagcacg acttcttcaa gtccgccatg cccgaaggct acgtccagga gcgcaccatc 7860 ttcttcaagg acgacggcaa ctacaagacc cgcgccgagg tgaagttcga gggcgacacc 7920 ctggtgaacc gcatcgagct gaagggcatc gacttcaagg aggacggcaa catcctgggg 7980 cacaagctgg agtacaacta caacagccac aacgtctata tcatggccga caagcagaag 8040 aacggcatca aggtgaactt caagatccgc cacaacatcg aggacggcag cgtgcagctc 8100 gccgaccact accagcagaa cacccccatc ggcgacggcc ccgtgctgct gcccgacaac 8160 cactacctga gcacccagtc cgccctgagc aaagacccca acgagaagcg cgatcacatg 8220 gtcctgctgg agttcgtgac cgccgccggg atcactctcg gcatggacga gctgtacaag 8280 tgataatcta gacggcgcgc ccacccagcg gccgcataca gcagcaattg gcaagctgct 8340 tacatagaac tcgcggcgat tggcatgccg ccttaaaatt tttattttat ttttcttttc 8400 ttttccgaat cggattttgt ttttaatatt tcaaaaaaaa aaaaaaaaaa aaaaaaaaaa 8460 aaaaaaaggg tcggcatggc atctccacct cctcgcggtc cgacctgggc atccgaagga 8520 ggacgcacgt ccactcggat ggctaaggga gagccacgtt taaaccagct ccaattcgcc 8580 ctatagtgag tcgtattacg cgcgctcact ggccgtcgtt ttacaacgtc gtgactggga 8640 aaaccctggc gttacccaac ttaatcgcct tgcagcacat ccccctttcg ccagctggcg 8700 taatagcgaa gaggcccgca ccgatcgccc ttcccaacag ttgcgcagcc tgaatggcga 8760 atgggacgcg ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt 8820 gaccgctaca cttgccagcg ccctagcgcc cgctcctttc gctttcttcc cttcctttct 8880 cgccacgttc gccggctttc cccgtcaagc tctaaatcgg gggctccctt tagggttccg 8940 atttagtgct ttacggcacc tcgaccccaa aaaacttgat tagggtgatg gttcacgtag 9000 tgggccatcg ccctgataga cggtttttcg ccctttgacg ttggagtcca cgttctttaa 9060 tagtggactc ttgttccaaa ctggaacaac actcaaccct atctcggtct attcttttga 9120 tttataaggg attttgccga tttcggccta ttggttaaaa aatgagctga tttaacaaaa 9180 atttaacgcg aattttaaca aaatattaac gcttacaatt taggtggcac ttttcgggga 9240 aatgtgcgcg gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc 9300 atgagacaat aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt 9360 caacatttcc gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct 9420 cacccagaaa cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt 9480 tacatcgaac tggatctcaa cagcggtaag atccttgaga gttttcgccc cgaagaacgt 9540 tttccaatga tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac 9600 gccgggcaag agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac 9660 tcaccagtca cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct 9720 gccataacca tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg 9780 aaggagctaa ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg 9840 gaaccggagc tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgtagca 9900 atggcaacaa cgttgcgcaa actattaact ggcgaactac ttactctagc ttcccggcaa 9960 caattaatag actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt 10020 ccggctggct ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc 10080 attgcagcac tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg 10140 agtcaggcaa ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt 10200 aagcattggt aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt 10260 catttttaat ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc 10320 ccttaacgtg agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct 10380 tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta 10440 ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc 10500 ttcagcagag cgcagatacc aaatactgtt cttctagtgt agccgtagtt aggccaccac 10560 ttcaagaact ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct 10620 gctgccagtg gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat 10680 aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg 10740 acctacaccg aactgagata cctacagcgt gagctatgag aaagcgccac gcttcccgaa 10800 gggagaaagg cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg 10860 gagcttccag ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga 10920 cttgagcgtc gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc 10980 aacgcggcct ttttacggtt cctggccttt tgctggcctt ttgctcacat gttctttcct 11040 gcgttatccc ctgattctgt ggataaccgt attaccgcct ttgagtgagc tgataccgct 11100 cgccgcagcc gaacgaccga gcgcagcgag tcagtgagcg aggaagcgga agagcgccca 11160 atacgcaaac cgcctctccc cgcgcgttgg ccgattcatt aatgcagctg gcacgacagg 11220 tttcccgact ggaaagcggg cagtgagcgc aacgcaatta atgtgagtta gctcactcat 11280 taggcacccc aggctttaca ctttatgctc ccggctcgta tgttgtgtgg aattgtgagc 11340 ggataacaat ttcacacagg aaacagctat gaccatgatt acgccaagcg cgcaattaac 11400 cctcactaaa gggaacaaaa gctgggtacc gggcccacgc gtaatacgac tcactatag 11459 <210> 81 <211> 3567 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 81 ataggcggcg catgagagaa gcccagacca attacctacc caaataggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggac 240 ggaccgacca tgttcccgtt ccagccaatg tatccgatgc agccaatgcc ctatcgcaac 300 ccgttcgcgg ccccgcgcag gccctggttc cccagaaccg acccttttct ggcgatgcag 360 gtgcaggaat taacccgctc gatggctaac ctgacgttca agcaacgccg ggacgcgcca 420 cctgaggggc catccgctaa gaaaccgaag aaggaggcct cgcaaaaaca gaaaggggga 480 ggccaaggga agaagaagaa gaaccaaggg aagaagaagg ctaagacagg gccgcctaat 540 ccgaaggcac agaatggaaa caagaagaag accaacaaga aaccaggcaa gagacagcgc 600 atggtcatga aattggaatc tgacaagacg ttcccaatca tgttggaagg gaagataaac 660 ggctacgctt gtgtggtcgg agggaagtta ttcaggccga tgggtgtgga aggcaagatc 720 gacaacgacg ttctggccgc gcttaagacg aagaaagcat ccaaatacga tcttgagtat 780 gcagatgtgc cacagaacat gcgggccgat acattcaaat acacccatga gaaaccccaa 840 ggctattaca gctggcatca tggagcagtc caatatgaaa atgggcgttt cacggtgccg 900 aaaggagttg gggccaaggg agacagcgga cgacccattc tggataacca gggacgggtg 960 gtcgctattg tgctgggagg tgtgaatgaa ggatctagga cagccctttc agtcgtcatg 1020 tggaacgaga agggagttac cgtgaagtat actccggaga actgcgagca atggtaatag 1080 taagcggccg catacagcag caattggcaa gctgcttaca tagaactcgc ggcgattggc 1140 atgccgcctt aaaattttta ttttattttt cttttctttt ccgaatcgga ttttgttttt 1200 aatatttcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaagggtcgg catggcatct 1260 ccacctcctc gcggtccgac ctgggcatcc gaaggaggac gcacgtccac tcggatggct 1320 aagggagagc cacgtttaaa cacgtgatat ctggcctcat gggccttcct ttcactgccc 1380 gctttccagt cgggaaacct gtcgtgccag ctgcattaac atggtcatag ctgtttcctt 1440 gcgtattggg cgctctccgc ttcctcgctc actgactcgc tgcgctcggt cgttcgggta 1500 aagcctgggg tgcctaatga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 1560 cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 1620 caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 1680 gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 1740 tcccttcggg aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 1800 aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 1860 ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 1920 cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 1980 tgaagtggtg gcctaactac ggctacacta gaagaacagt atttggtatc tgcgctctgc 2040 tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 2100 ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 2160 aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 2220 aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 2280 aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttattaga 2340 aaaattcatc cagcagacga taaaacgcaa tacgctggct atccggtgcc gcaatgccat 2400 acagcaccag aaaacgatcc gcccattcgc cgcccagttc ttccgcaata tcacgggtgg 2460 ccagcgcaat atcctgataa cgatccgcca cgcccagacg gccgcaatca ataaagccgc 2520 taaaacggcc attttccacc ataatgttcg gcaggcacgc atcaccatgg gtcaccacca 2580 gatcttcgcc atccggcatg ctcgctttca gacgcgcaaa cagctctgcc ggtgccaggc 2640 cctgatgttc ttcatccaga tcatcctgat ccaccaggcc cgcttccata cgggtacgcg 2700 cacgttcaat acgatgtttc gcctgatgat caaacggaca ggtcgccggg tccagggtat 2760 gcagacgacg catggcatcc gccataatgc tcactttttc tgccggcgcc agatggctag 2820 acagcagatc ctgacccggc acttcgccca gcagcagcca atcacggccc gcttcggtca 2880 ccacatccag caccgccgca cacggaacac cggtggtggc cagccagctc agacgcgccg 2940 cttcatcctg cagctcgttc agcgcaccgc tcagatcggt tttcacaaac agcaccggac 3000 gaccctgcgc gctcagacga aacaccgccg catcagagca gccaatggtc tgctgcgccc 3060 aatcatagcc aaacagacgt tccacccacg ctgccgggct acccgcatgc aggccatcct 3120 gttcaatcat actcttcctt tttcaatatt attgaagcat ttatcagggt tattgtctca 3180 tgagcggata catatttgaa tgtatttaga aaaataaaca aataggggtt ccgcgcacat 3240 ttccccgaaa agtgccacct aaattgtaag cgttaatatt ttgttaaaat tcgcgttaaa 3300 tttttgttaa atcagctcat tttttaacca ataggccgaa atcggcaaaa tcccttataa 3360 atcaaaagaa tagaccgaga tagggttgag tggccgctac agggcgctcc cattcgccat 3420 tcaggctgcg caactgttgg gaagggcgtt tcggtgcggg cctcttcgct attacgccag 3480 ctggcgaaag ggggatgtgc tgcaaggcga ttaagttggg taacgccagg gttttcccag 3540 tcacacgcgt aatacgactc actatag 3567 <210> 82 <211> 5685 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 82 ataggcggcg catgagagaa gcccagacca attacctacc caaataggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggac 240 ggaccgacca tgtcactagt gaccaccatg tgtctgctcg ccaatgtgac gttcccatgt 300 gctcaaccac caatttgcta cgacagaaaa ccagcagaga ctttggccat gctcagcgtt 360 aacgttgaca acccgggcta cgatgagctg ctggaagcag ctgttaagtg ccccggaagg 420 aaaaggagat ccaccgagga gctgtttaat gagtataagc taacgcgccc ttacatggcc 480 agatgcatca gatgtgcagt tgggagctgc catagtccaa tagcaatcga ggcagtaaag 540 agcgacgggc acgacggtta tgttagactt cagacttcct cgcagtatgg cctggattcc 600 tccggcaact taaagggcag gaccatgcgg tatgacatgc acgggaccat taaagagata 660 ccactacatc aagtgtcact ctatacatct cgcccgtgtc acattgtgga tgggcacggt 720 tatttcctgc ttgccaggtg cccggcaggg gactccatca ccatggaatt taagaaagat 780 tccgtcagac actcctgctc ggtgccgtat gaagtgaaat ttaatcctgt aggcagagaa 840 ctctatactc atcccccaga acacggagta gagcaagcgt gccaagtcta cgcacatgat 900 gcacagaaca gaggagctta tgtcgagatg cacctcccgg gctcagaagt ggacagcagt 960 ttggtttcct tgagcggcag ttcagtcacc gtgacacctc ctgatgggac tagcgccctg 1020 gtggaatgcg agtgtggcgg cacaaagatc tccgagacca tcaacaagac aaaacagttc 1080 agccagtgca caaagaagga gcagtgcaga gcatatcggc tgcagaacga taagtgggtg 1140 tataattctg acaaactgcc caaagcagcg ggagccacct taaaaggaaa actgcatgtc 1200 ccattcttgc tggcagacgg caaatgcacc gtgcctctag caccagaacc tatgataacc 1260 ttcggtttca gatcagtgtc actgaaactg caccctaaga atcccacata tctaatcacc 1320 cgccaacttg ctgatgagcc tcactacacg cacgagctca tatctgaacc agctgttagg 1380 aattttaccg tcaccgaaaa agggtgggag tttgtatggg gaaaccaccc gccgaaaagg 1440 ttttgggcac aggaaacagc acccggaaat ccacatgggc taccgcacga ggtgataact 1500 cattattacc acagataccc tatgtccacc atcctgggtt tgtcaatttg tgccgccatt 1560 gcaaccgttt ccgttgcagc gtctacctgg ctgttttgca gatctagagt tgcgtgccta 1620 actccttacc ggctaacacc taacgctagg ataccatttt gtctggctgt gctttgctgc 1680 gcccgcactg cccgggccga gaccacctgg gagtccttgg atcacctatg gaacaataac 1740 caacagatgt tctggattca attgctgatc cctctggccg ccttgatcgt agtgactcgc 1800 ctgctcaggt gcgtgtgctg tgtcgtgcct tttttagtca tggccggcgc cgcaggcgcc 1860 ggcgcctacg agcacgcgac cacgatgccg agccaagcgg gaatctcgta taacactata 1920 gtcaacagag caggctacgc accactccct atcagcataa caccaacaaa gatcaagctg 1980 atacctacag tgaacttgga gtacgtcacc tgccactaca aaacaggaat ggattcacca 2040 gccatcaaat gctgcggatc tcaggaatgc actccaactt acaggcctga tgaacagtgc 2100 aaagtcttca caggggttta cccgttcatg tggggtggtg catattgctt ttgcgacact 2160 gagaacaccc aagtcagcaa ggcctacgta atgaaatctg acgactgcct tgcggatcat 2220 gctgaagcat ataaagcgca cacagcctca gtgcaggcgt tcctcaacat cacagtggga 2280 gaacactcta ttgtgactac cgtgtatgtg aatggagaaa ctcctgtgaa tttcaatggg 2340 gtcaaaataa ctgcaggtcc gctttccaca gcttggacac cctttgatcg caaaatcgtg 2400 cagtatgccg gggagatcta taattatgat tttcctgagt atggggcagg acaaccagga 2460 gcatttggag atatacaatc cagaacagtc tcaagctctg atctgtatgc caataccaac 2520 ctagtgctgc agagacccaa agcaggagcg atccacgtgc catacactca ggcaccttcg 2580 ggttttgagc aatggaagaa agataaagct ccatcattga aatttaccgc ccctttcgga 2640 tgcgaaatat atacaaaccc cattcgcgcc gaaaactgtg ctgtagggtc aattccatta 2700 gcctttgaca ttcccgacgc cttgttcacc agggtgtcag aaacaccgac actttcagcg 2760 gccgaatgca ctcttaacga gtgcgtgtat tcttccgact ttggtgggat cgccacggtc 2820 aagtactcgg ccagcaagtc aggcaagtgc gcagtccatg tgccatcagg gactgctacc 2880 ctaaaagaag cagcagtcga gctaaccgag caagggtcgg cgactatcca tttctcgacc 2940 gcaaatatcc acccggagtt caggctccaa atatgcacat catatgttac gtgcaaaggt 3000 gattgtcacc ccccgaaaga ccatattgtg acacaccctc agtatcacgc ccaaacattt 3060 acagccgcgg tgtcaaaaac cgcgtggacg tggttaacat ccctgctggg aggatcagcc 3120 gtaattatta taattggctt ggtgctggct actattgtgg ccatgtacgt gctgaccaac 3180 cagaaacata attaatagta agcggccgca tacagcagca attggcaagc tgcttacata 3240 gaactcgcgg cgattggcat gccgccttaa aatttttatt ttatttttct tttcttttcc 3300 gaatcggatt ttgtttttaa tatttcaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3360 agggtcggca tggcatctcc acctcctcgc ggtccgacct gggcatccga aggaggacgc 3420 acgtccactc ggatggctaa gggagagcca cgtttaaaca cgtgatatct ggcctcatgg 3480 gccttccttt cactgcccgc tttccagtcg ggaaacctgt cgtgccagct gcattaacat 3540 ggtcatagct gtttccttgc gtattgggcg ctctccgctt cctcgctcac tgactcgctg 3600 cgctcggtcg ttcgggtaaa gcctggggtg cctaatgagc aaaaggccag caaaaggcca 3660 ggaaccgtaa aaaggccgcg ttgctggcgt ttttccatag gctccgcccc cctgacgagc 3720 atcacaaaaa tcgacgctca agtcagaggt ggcgaaaccc gacaggacta taaagatacc 3780 aggcgtttcc ccctggaagc tccctcgtgc gctctcctgt tccgaccctg ccgcttaccg 3840 gatacctgtc cgcctttctc ccttcgggaa gcgtggcgct ttctcatagc tcacgctgta 3900 ggtatctcag ttcggtgtag gtcgttcgct ccaagctggg ctgtgtgcac gaaccccccg 3960 ttcagcccga ccgctgcgcc ttatccggta actatcgtct tgagtccaac ccggtaagac 4020 acgacttatc gccactggca gcagccactg gtaacaggat tagcagagcg aggtatgtag 4080 gcggtgctac agagttcttg aagtggtggc ctaactacgg ctacactaga agaacagtat 4140 ttggtatctg cgctctgctg aagccagtta ccttcggaaa aagagttggt agctcttgat 4200 ccggcaaaca aaccaccgct ggtagcggtg gtttttttgt ttgcaagcag cagattacgc 4260 gcagaaaaaa aggatctcaa gaagatcctt tgatcttttc tacggggtct gacgctcagt 4320 ggaacgaaaa ctcacgttaa gggattttgg tcatgagatt atcaaaaagg atcttcacct 4380 agatcctttt aaattaaaaa tgaagtttta aatcaatcta aagtatatat gagtaaactt 4440 ggtctgacag ttattagaaa aattcatcca gcagacgata aaacgcaata cgctggctat 4500 ccggtgccgc aatgccatac agcaccagaa aacgatccgc ccattcgccg cccagttctt 4560 ccgcaatatc acgggtggcc agcgcaatat cctgataacg atccgccacg cccagacggc 4620 cgcaatcaat aaagccgcta aaacggccat tttccaccat aatgttcggc aggcacgcat 4680 caccatgggt caccaccaga tcttcgccat ccggcatgct cgctttcaga cgcgcaaaca 4740 gctctgccgg tgccaggccc tgatgttctt catccagatc atcctgatcc accaggcccg 4800 cttccatacg ggtacgcgca cgttcaatac gatgtttcgc ctgatgatca aacggacagg 4860 tcgccgggtc cagggtatgc agacgacgca tggcatccgc cataatgctc actttttctg 4920 ccggcgccag atggctagac agcagatcct gacccggcac ttcgcccagc agcagccaat 4980 cacggcccgc ttcggtcacc acatccagca ccgccgcaca cggaacaccg gtggtggcca 5040 gccagctcag acgcgccgct tcatcctgca gctcgttcag cgcaccgctc agatcggttt 5100 tcacaaacag caccggacga ccctgcgcgc tcagacgaaa caccgccgca tcagagcagc 5160 caatggtctg ctgcgcccaa tcatagccaa acagacgttc cacccacgct gccgggctac 5220 ccgcatgcag gccatcctgt tcaatcatac tcttcctttt tcaatattat tgaagcattt 5280 atcagggtta ttgtctcatg agcggataca tatttgaatg tatttagaaa aataaacaaa 5340 taggggttcc gcgcacattt ccccgaaaag tgccacctaa attgtaagcg ttaatatttt 5400 gttaaaattc gcgttaaatt tttgttaaat cagctcattt tttaaccaat aggccgaaat 5460 cggcaaaatc ccttataaat caaaagaata gaccgagata gggttgagtg gccgctacag 5520 ggcgctccca ttcgccattc aggctgcgca actgttggga agggcgtttc ggtgcgggcc 5580 tcttcgctat tacgccagct ggcgaaaggg ggatgtgctg caaggcgatt aagttgggta 5640 acgccagggt tttcccagtc acacgcgtaa tacgactcac tatag 5685 <210> 83 <211> 13364 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 83 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgacgcc 7560 accatgaggc ctggcctgcc ctcctacctg atcatcctgg ccgtgtgcct gttcagccac 7620 ctgctgtcca gcagatacgg cgccgaggcc gtgagcgagc ccctggacaa ggctttccac 7680 ctgctgctga acacctacgg cagacccatc cggtttctgc gggagaacac cacccagtgc 7740 acctacaaca gcagcctgcg gaacagcacc gtcgtgagag agaacgccat cagcttcaac 7800 tttttccaga gctacaacca gtactacgtg ttccacatgc ccagatgcct gtttgccggc 7860 cctctggccg agcagttcct gaaccaggtg gacctgaccg agacactgga aagataccag 7920 cagcggctga atacctacgc cctggtgtcc aaggacctgg ccagctaccg gtcctttagc 7980 cagcagctca aggctcagga tagcctcggc gagcagccta ccaccgtgcc ccctcccatc 8040 gacctgagca tcccccacgt gtggatgcct ccccagacca cccctcacgg ctggaccgag 8100 agccacacca cctccggcct gcacagaccc cacttcaacc agacctgcat cctgttcgac 8160 ggccacgacc tgctgtttag caccgtgacc ccctgcctgc accagggctt ctacctgatc 8220 gacgagctga gatacgtgaa gatcaccctg accgaggatt tcttcgtggt caccgtgtcc 8280 atcgacgacg acacccccat gctgctgatc ttcggccacc tgcccagagt gctgttcaag 8340 gccccctacc agcgggacaa cttcatcctg cggcagaccg agaagcacga gctgctggtg 8400 ctggtcaaga aggaccagct gaaccggcac tcctacctga aggaccccga cttcctggac 8460 gccgccctgg acttcaacta cctggacctg agcgccctgc tgagaaacag cttccacaga 8520 tacgccgtgg acgtgctgaa gtccggacgg tgccagatgc tcgatcggcg gaccgtggag 8580 atggccttcg cctatgccct cgccctgttc gccgctgcca gacaggaaga ggctggcgcc 8640 caggtgtcag tgcccagagc cctggataga caggccgccc tgctgcagat ccaggaattc 8700 atgatcacct gcctgagcca gaccccccct agaaccaccc tgctgctgta ccccacagcc 8760 gtggatctgg ccaagagggc cctgtggacc cccaaccaga tcaccgacat cacaagcctc 8820 gtgcggctcg tgtacatcct gagcaagcag aaccagcagc acctgatccc ccagtgggcc 8880 ctgagacaga tcgccgactt cgccctgaag ctgcacaaga cccatctggc cagctttctg 8940 agcgccttcg ccaggcagga actgtacctg atgggcagcc tggtccacag catgctggtg 9000 cataccaccg agcggcggga gatcttcatc gtggagacag gcctgtgtag cctggccgag 9060 ctgtcccact ttacccagct gctggcccac cctcaccacg agtacctgag cgacctgtac 9120 accccctgca gcagcagcgg cagacgggac cacagcctgg aacggctgac cagactgttc 9180 cccgatgcca ccgtgcctgc tacagtgcct gccgccctgt ccatcctgtc caccatgcag 9240 cccagcaccc tggaaacctt ccccgacctg ttctgcctgc ccctgggcga gagctttagc 9300 gccctgaccg tgtccgagca cgtgtcctac atcgtgacca atcagtacct gatcaagggc 9360 atcagctacc ccgtgtccac cacagtcgtg ggccagagcc tgatcatcac ccagaccgac 9420 agccagacca agtgcgagct gacccggaac atgcacacca cacacagcat caccgtggcc 9480 ctgaacatca gcctggaaaa ctgcgctttc tgtcagtctg ccctgctgga atacgacgat 9540 acccagggcg tgatcaacat catgtacatg cacgacagcg acgacgtgct gttcgccctg 9600 gacccctaca acgaggtggt ggtgtccagc ccccggaccc actacctgat gctgctgaag 9660 aacggcaccg tgctggaagt gaccgacgtg gtggtggacg ccaccgacag cagactgctg 9720 atgatgagcg tgtacgccct gagcgccatc atcggcatct acctgctgta ccggatgctg 9780 aaaacctgct gataatctag acggcgcgcc cacccagcgg ccgcctataa ctctctacgg 9840 ctaacctgaa tggactacga catagtctag tcgacgccac catgtgcaga aggcccgact 9900 gcggcttcag cttcagccct ggacccgtga tcctgctgtg gtgctgcctg ctgctgccta 9960 tcgtgtcctc tgccgccgtg tctgtggccc ctacagccgc cgagaaggtg ccagccgagt 10020 gccccgagct gaccagaaga tgcctgctgg gcgaggtgtt cgagggcgac aagtacgaga 10080 gctggctgcg gcccctggtc aacgtgaccg gcagagatgg ccccctgagc cagctgatcc 10140 ggtacagacc cgtgaccccc gaggccgcca atagcgtgct gctggacgag gccttcctgg 10200 ataccctggc cctgctgtac aacaaccccg accagctgag agccctgctg accctgctgt 10260 ccagcgacac cgcccccaga tggatgaccg tgatgcgggg ctacagcgag tgtggagatg 10320 gcagccctgc cgtgtacacc tgcgtggacg acctgtgcag aggctacgac ctgaccagac 10380 tgagctacgg ccggtccatc ttcacagagc acgtgctggg cttcgagctg gtgcccccca 10440 gcctgttcaa cgtggtggtg gccatccgga acgaggccac cagaaccaac agagccgtgc 10500 ggctgcctgt gtctacagcc gctgcacctg agggcatcac actgttctac ggcctgtaca 10560 acgccgtgaa agagttctgc ctccggcacc agctggatcc ccccctgctg agacacctgg 10620 acaagtacta cgccggcctg cccccagagc tgaagcagac cagagtgaac ctgcccgccc 10680 acagcagata tggccctcag gccgtggacg ccagatgata atctagacgg cgcgcccacc 10740 cacctgcagg atacagcagc aattggcaag ctgcttacat agaactcgcg gcgattggca 10800 tgccgcctta aaatttttat tttatttttc ttttcttttc cgaatcggat tttgttttta 10860 atatttcaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aagggtcggc atggcatctc 10920 cacctcctcg cggtccgacc tgggcatccg aaggaggacg cacgtccact cggatggcta 10980 agggagagcc acgtttaaac gctagagcaa gacgtttccc gttgaatatg gctcataaca 11040 ccccttgtat tactgtttat gtaagcagac agttttattg ttcatgatga tatattttta 11100 tcttgtgcaa tgtaacatca gagattttga gacacaacgt ggctttgttg aataaatcga 11160 acttttgctg agttgaagga tcagatcacg catcttcccg acaacgcaga ccgttccgtg 11220 gcaaagcaaa agttcaaaat caccaactgg tccacctaca acaaagctct catcaaccgt 11280 ggctccctca ctttctggct ggatgatggg gcgattcagg cctggtatga gtcagcaaca 11340 ccttcttcac gaggcagacc tcagcgctag cggagtgtat actggcttac tatgttggca 11400 ctgatgaggg tgtcagtgaa gtgcttcatg tggcaggaga aaaaaggctg caccggtgcg 11460 tcagcagaat atgtgataca ggatatattc cgcttcctcg ctcactgact cgctacgctc 11520 ggtcgttcga ctgcggcgag cggaaatggc ttacgaacgg ggcggagatt tcctggaaga 11580 tgccaggaag atacttaaca gggaagtgag agggccgcgg caaagccgtt tttccatagg 11640 ctccgccccc ctgacaagca tcacgaaatc tgacgctcaa atcagtggtg gcgaaacccg 11700 acaggactat aaagatacca ggcgtttccc ctggcggctc cctcgtgcgc tctcctgttc 11760 ctgcctttcg gtttaccggt gtcattccgc tgttatggcc gcgtttgtct cattccacgc 11820 ctgacactca gttccgggta ggcagttcgc tccaagctgg actgtatgca cgaacccccc 11880 gttcagtccg accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggaaaga 11940 catgcaaaag caccactggc agcagccact ggtaattgat ttagaggagt tagtcttgaa 12000 gtcatgcgcc ggttaaggct aaactgaaag gacaagtttt ggtgactgcg ctcctccaag 12060 ccagttacct cggttcaaag agttggtagc tcagagaacc ttcgaaaaac cgccctgcaa 12120 ggcggttttt tcgttttcag agcaagagat tacgcgcaga ccaaaacgat ctcaagaaga 12180 tcatcttatt aaggggtctg acgctcagtg gaacgaaaac tcacgttaag ggattttggt 12240 catgagatta tcaaaaagga tcttcaccta gatcctttta aattaaaaat gaagttttaa 12300 atcaatctaa agtatatatg agtaaacttg gtctgacagt taccaatgct taatcagtga 12360 ggcacctatc tcagcgatct gtctatttcg ttcatccata gttgcctgac tccccgtcgt 12420 gtagataact acgatacggg agggcttacc atctggcccc agtgctgcaa tgataccgcg 12480 agacccacgc tcaccggctc cagatttatc agcaataaac cagccagccg gaagggccga 12540 gcgcagaagt ggtcctgcaa ctttatccgc ctccatccag tctattaatt gttgccggga 12600 agctagagta agtagttcgc cagttaatag tttgcgcaac gttgttgcca ttgctgcagg 12660 catcgtggtg tcacgctcgt cgtttggtat ggcttcattc agctccggtt cccaacgatc 12720 aaggcgagtt acatgatccc ccatgttgtg caaaaaagcg gttagctcct tcggtcctcc 12780 gatcgttgtc agaagtaagt tggccgcagt gttatcactc atggttatgg cagcactgca 12840 taattctctt actgtcatgc catccgtaag atgcttttct gtgactggtg agtactcaac 12900 caagtcattc tgagaatagt gtatgcggcg accgagttgc tcttgcccgg cgtcaacacg 12960 ggataatacc gcgccacata gcagaacttt aaaagtgctc atcattggaa aacgttcttc 13020 ggggcgaaaa ctctcaagga tcttaccgct gttgagatcc agttcgatgt aacccactcg 13080 tgcacccaac tgatcttcag catcttttac tttcaccagc gtttctgggt gagcaaaaac 13140 aggaaggcaa aatgccgcaa aaaagggaat aagggcgaca cggaaatgtt gaatactcat 13200 actcttcctt tttcaatatt attgaagcat ttatcagggt tattgtctca tgagcggata 13260 catatttgaa tgtatttaga aaaataaaca aataggggtt ccgcgcacat ttccccgaaa 13320 agtgccacct gacgtgtcga gacgcgtaat acgactcact atag 13364 <210> 84 <211> 13283 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 84 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgacgcc 7560 accatgaggc ctggcctgcc ctcctacctg atcatcctgg ccgtgtgcct gttcagccac 7620 ctgctgtcca gcagatacgg cgccgaggcc gtgagcgagc ccctggacaa ggctttccac 7680 ctgctgctga acacctacgg cagacccatc cggtttctgc gggagaacac cacccagtgc 7740 acctacaaca gcagcctgcg gaacagcacc gtcgtgagag agaacgccat cagcttcaac 7800 tttttccaga gctacaacca gtactacgtg ttccacatgc ccagatgcct gtttgccggc 7860 cctctggccg agcagttcct gaaccaggtg gacctgaccg agacactgga aagataccag 7920 cagcggctga atacctacgc cctggtgtcc aaggacctgg ccagctaccg gtcctttagc 7980 cagcagctca aggctcagga tagcctcggc gagcagccta ccaccgtgcc ccctcccatc 8040 gacctgagca tcccccacgt gtggatgcct ccccagacca cccctcacgg ctggaccgag 8100 agccacacca cctccggcct gcacagaccc cacttcaacc agacctgcat cctgttcgac 8160 ggccacgacc tgctgtttag caccgtgacc ccctgcctgc accagggctt ctacctgatc 8220 gacgagctga gatacgtgaa gatcaccctg accgaggatt tcttcgtggt caccgtgtcc 8280 atcgacgacg acacccccat gctgctgatc ttcggccacc tgcccagagt gctgttcaag 8340 gccccctacc agcgggacaa cttcatcctg cggcagaccg agaagcacga gctgctggtg 8400 ctggtcaaga aggaccagct gaaccggcac tcctacctga aggaccccga cttcctggac 8460 gccgccctgg acttcaacta cctggacctg agcgccctgc tgagaaacag cttccacaga 8520 tacgccgtgg acgtgctgaa gtccggacgg tgccagatgc tcgatcggcg gaccgtggag 8580 atggccttcg cctatgccct cgccctgttc gccgctgcca gacaggaaga ggctggcgcc 8640 caggtgtcag tgcccagagc cctggataga caggccgccc tgctgcagat ccaggaattc 8700 atgatcacct gcctgagcca gaccccccct agaaccaccc tgctgctgta ccccacagcc 8760 gtggatctgg ccaagagggc cctgtggacc cccaaccaga tcaccgacat cacaagcctc 8820 gtgcggctcg tgtacatcct gagcaagcag aaccagcagc acctgatccc ccagtgggcc 8880 ctgagacaga tcgccgactt cgccctgaag ctgcacaaga cccatctggc cagctttctg 8940 agcgccttcg ccaggcagga actgtacctg atgggcagcc tggtccacag catgctggtg 9000 cataccaccg agcggcggga gatcttcatc gtggagacag gcctgtgtag cctggccgag 9060 ctgtcccact ttacccagct gctggcccac cctcaccacg agtacctgag cgacctgtac 9120 accccctgca gcagcagcgg cagacgggac cacagcctgg aacggctgac cagactgttc 9180 cccgatgcca ccgtgcctgc tacagtgcct gccgccctgt ccatcctgtc caccatgcag 9240 cccagcaccc tggaaacctt ccccgacctg ttctgcctgc ccctgggcga gagctttagc 9300 gccctgaccg tgtccgagca cgtgtcctac atcgtgacca atcagtacct gatcaagggc 9360 atcagctacc ccgtgtccac cacagtcgtg ggccagagcc tgatcatcac ccagaccgac 9420 agccagacca agtgcgagct gacccggaac atgcacacca cacacagcat caccgtggcc 9480 ctgaacatca gcctggaaaa ctgcgctttc tgtcagtctg ccctgctgga atacgacgat 9540 acccagggcg tgatcaacat catgtacatg cacgacagcg acgacgtgct gttcgccctg 9600 gacccctaca acgaggtggt ggtgtccagc ccccggaccc actacctgat gctgctgaag 9660 aacggcaccg tgctggaagt gaccgacgtg gtggtggacg ccaccgactg ataatctaga 9720 cggcgcgccc acccagcggc cgcctataac tctctacggc taacctgaat ggactacgac 9780 atagtctagt cgacgccacc atgtgcagaa ggcccgactg cggcttcagc ttcagccctg 9840 gacccgtgat cctgctgtgg tgctgcctgc tgctgcctat cgtgtcctct gccgccgtgt 9900 ctgtggcccc tacagccgcc gagaaggtgc cagccgagtg ccccgagctg accagaagat 9960 gcctgctggg cgaggtgttc gagggcgaca agtacgagag ctggctgcgg cccctggtca 10020 acgtgaccgg cagagatggc cccctgagcc agctgatccg gtacagaccc gtgacccccg 10080 aggccgccaa tagcgtgctg ctggacgagg ccttcctgga taccctggcc ctgctgtaca 10140 acaaccccga ccagctgaga gccctgctga ccctgctgtc cagcgacacc gcccccagat 10200 ggatgaccgt gatgcggggc tacagcgagt gtggagatgg cagccctgcc gtgtacacct 10260 gcgtggacga cctgtgcaga ggctacgacc tgaccagact gagctacggc cggtccatct 10320 tcacagagca cgtgctgggc ttcgagctgg tgccccccag cctgttcaac gtggtggtgg 10380 ccatccggaa cgaggccacc agaaccaaca gagccgtgcg gctgcctgtg tctacagccg 10440 ctgcacctga gggcatcaca ctgttctacg gcctgtacaa cgccgtgaaa gagttctgcc 10500 tccggcacca gctggatccc cccctgctga gacacctgga caagtactac gccggcctgc 10560 ccccagagct gaagcagacc agagtgaacc tgcccgccca cagcagatat ggccctcagg 10620 ccgtggacgc cagatgataa tctagacggc gcgcccaccc acctgcagga tacagcagca 10680 attggcaagc tgcttacata gaactcgcgg cgattggcat gccgccttaa aatttttatt 10740 ttatttttct tttcttttcc gaatcggatt ttgtttttaa tatttcaaaa aaaaaaaaaa 10800 aaaaaaaaaa aaaaaaaaaa agggtcggca tggcatctcc acctcctcgc ggtccgacct 10860 gggcatccga aggaggacgc acgtccactc ggatggctaa gggagagcca cgtttaaacg 10920 ctagagcaag acgtttcccg ttgaatatgg ctcataacac cccttgtatt actgtttatg 10980 taagcagaca gttttattgt tcatgatgat atatttttat cttgtgcaat gtaacatcag 11040 agattttgag acacaacgtg gctttgttga ataaatcgaa cttttgctga gttgaaggat 11100 cagatcacgc atcttcccga caacgcagac cgttccgtgg caaagcaaaa gttcaaaatc 11160 accaactggt ccacctacaa caaagctctc atcaaccgtg gctccctcac tttctggctg 11220 gatgatgggg cgattcaggc ctggtatgag tcagcaacac cttcttcacg aggcagacct 11280 cagcgctagc ggagtgtata ctggcttact atgttggcac tgatgagggt gtcagtgaag 11340 tgcttcatgt ggcaggagaa aaaaggctgc accggtgcgt cagcagaata tgtgatacag 11400 gatatattcc gcttcctcgc tcactgactc gctacgctcg gtcgttcgac tgcggcgagc 11460 ggaaatggct tacgaacggg gcggagattt cctggaagat gccaggaaga tacttaacag 11520 ggaagtgaga gggccgcggc aaagccgttt ttccataggc tccgcccccc tgacaagcat 11580 cacgaaatct gacgctcaaa tcagtggtgg cgaaacccga caggactata aagataccag 11640 gcgtttcccc tggcggctcc ctcgtgcgct ctcctgttcc tgcctttcgg tttaccggtg 11700 tcattccgct gttatggccg cgtttgtctc attccacgcc tgacactcag ttccgggtag 11760 gcagttcgct ccaagctgga ctgtatgcac gaaccccccg ttcagtccga ccgctgcgcc 11820 ttatccggta actatcgtct tgagtccaac ccggaaagac atgcaaaagc accactggca 11880 gcagccactg gtaattgatt tagaggagtt agtcttgaag tcatgcgccg gttaaggcta 11940 aactgaaagg acaagttttg gtgactgcgc tcctccaagc cagttacctc ggttcaaaga 12000 gttggtagct cagagaacct tcgaaaaacc gccctgcaag gcggtttttt cgttttcaga 12060 gcaagagatt acgcgcagac caaaacgatc tcaagaagat catcttatta aggggtctga 12120 cgctcagtgg aacgaaaact cacgttaagg gattttggtc atgagattat caaaaaggat 12180 cttcacctag atccttttaa attaaaaatg aagttttaaa tcaatctaaa gtatatatga 12240 gtaaacttgg tctgacagtt accaatgctt aatcagtgag gcacctatct cagcgatctg 12300 tctatttcgt tcatccatag ttgcctgact ccccgtcgtg tagataacta cgatacggga 12360 gggcttacca tctggcccca gtgctgcaat gataccgcga gacccacgct caccggctcc 12420 agatttatca gcaataaacc agccagccgg aagggccgag cgcagaagtg gtcctgcaac 12480 tttatccgcc tccatccagt ctattaattg ttgccgggaa gctagagtaa gtagttcgcc 12540 agttaatagt ttgcgcaacg ttgttgccat tgctgcaggc atcgtggtgt cacgctcgtc 12600 gtttggtatg gcttcattca gctccggttc ccaacgatca aggcgagtta catgatcccc 12660 catgttgtgc aaaaaagcgg ttagctcctt cggtcctccg atcgttgtca gaagtaagtt 12720 ggccgcagtg ttatcactca tggttatggc agcactgcat aattctctta ctgtcatgcc 12780 atccgtaaga tgcttttctg tgactggtga gtactcaacc aagtcattct gagaatagtg 12840 tatgcggcga ccgagttgct cttgcccggc gtcaacacgg gataataccg cgccacatag 12900 cagaacttta aaagtgctca tcattggaaa acgttcttcg gggcgaaaac tctcaaggat 12960 cttaccgctg ttgagatcca gttcgatgta acccactcgt gcacccaact gatcttcagc 13020 atcttttact ttcaccagcg tttctgggtg agcaaaaaca ggaaggcaaa atgccgcaaa 13080 aaagggaata agggcgacac ggaaatgttg aatactcata ctcttccttt ttcaatatta 13140 ttgaagcatt tatcagggtt attgtctcat gagcggatac atatttgaat gtatttagaa 13200 aaataaacaa ataggggttc cgcgcacatt tccccgaaaa gtgccacctg acgtgtcgag 13260 acgcgtaata cgactcacta tag 13283 <210> 85 <211> 13463 <212> DNA <213> Artificial Sequence <220> <221> source <223> /note="Description of Artificial Sequence: Synthetic polynucleotide" <400> 85 ataggcggcg catgagagaa gcccagacca attacctacc caaaatggag aaagttcacg 60 ttgacatcga ggaagacagc ccattcctca gagctttgca gcggagcttc ccgcagtttg 120 aggtagaagc caagcaggtc actgataatg accatgctaa tgccagagcg ttttcgcatc 180 tggcttcaaa actgatcgaa acggaggtgg acccatccga cacgatcctt gacattggaa 240 gtgcgcccgc ccgcagaatg tattctaagc acaagtatca ttgtatctgt ccgatgagat 300 gtgcggaaga tccggacaga ttgtataagt atgcaactaa gctgaagaaa aactgtaagg 360 aaataactga taaggaattg gacaagaaaa tgaaggagct cgccgccgtc atgagcgacc 420 ctgacctgga aactgagact atgtgcctcc acgacgacga gtcgtgtcgc tacgaagggc 480 aagtcgctgt ttaccaggat gtatacgcgg ttgacggacc gacaagtctc tatcaccaag 540 ccaataaggg agttagagtc gcctactgga taggctttga caccacccct tttatgttta 600 agaacttggc tggagcatat ccatcatact ctaccaactg ggccgacgaa accgtgttaa 660 cggctcgtaa cataggccta tgcagctctg acgttatgga gcggtcacgt agagggatgt 720 ccattcttag aaagaagtat ttgaaaccat ccaacaatgt tctattctct gttggctcga 780 ccatctacca cgagaagagg gacttactga ggagctggca cctgccgtct gtatttcact 840 tacgtggcaa gcaaaattac acatgtcggt gtgagactat agttagttgc gacgggtacg 900 tcgttaaaag aatagctatc agtccaggcc tgtatgggaa gccttcaggc tatgctgcta 960 cgatgcaccg cgagggattc ttgtgctgca aagtgacaga cacattgaac ggggagaggg 1020 tctcttttcc cgtgtgcacg tatgtgccag ctacattgtg tgaccaaatg actggcatac 1080 tggcaacaga tgtcagtgcg gacgacgcgc aaaaactgct ggttgggctc aaccagcgta 1140 tagtcgtcaa cggtcgcacc cagagaaaca ccaataccat gaaaaattac cttttgcccg 1200 tagtggccca ggcatttgct aggtgggcaa aggaatataa ggaagatcaa gaagatgaaa 1260 ggccactagg actacgagat agacagttag tcatggggtg ttgttgggct tttagaaggc 1320 acaagataac atctatttat aagcgcccgg atacccaaac catcatcaaa gtgaacagcg 1380 atttccactc attcgtgctg cccaggatag gcagtaacac attggagatc gggctgagaa 1440 caagaatcag gaaaatgtta gaggagcaca aggagccgtc acctctcatt accgccgagg 1500 acgtacaaga agctaagtgc gcagccgatg aggctaagga ggtgcgtgaa gccgaggagt 1560 tgcgcgcagc tctaccacct ttggcagctg atgttgagga gcccactctg gaagccgatg 1620 tagacttgat gttacaagag gctggggccg gctcagtgga gacacctcgt ggcttgataa 1680 aggttaccag ctacgatggc gaggacaaga tcggctctta cgctgtgctt tctccgcagg 1740 ctgtactcaa gagtgaaaaa ttatcttgca tccaccctct cgctgaacaa gtcatagtga 1800 taacacactc tggccgaaaa gggcgttatg ccgtggaacc ataccatggt aaagtagtgg 1860 tgccagaggg acatgcaata cccgtccagg actttcaagc tctgagtgaa agtgccacca 1920 ttgtgtacaa cgaacgtgag ttcgtaaaca ggtacctgca ccatattgcc acacatggag 1980 gagcgctgaa cactgatgaa gaatattaca aaactgtcaa gcccagcgag cacgacggcg 2040 aatacctgta cgacatcgac aggaaacagt gcgtcaagaa agaactagtc actgggctag 2100 ggctcacagg cgagctggtg gatcctccct tccatgaatt cgcctacgag agtctgagaa 2160 cacgaccagc cgctccttac caagtaccaa ccataggggt gtatggcgtg ccaggatcag 2220 gcaagtctgg catcattaaa agcgcagtca ccaaaaaaga tctagtggtg agcgccaaga 2280 aagaaaactg tgcagaaatt ataagggacg tcaagaaaat gaaagggctg gacgtcaatg 2340 ccagaactgt ggactcagtg ctcttgaatg gatgcaaaca ccccgtagag accctgtata 2400 ttgacgaagc ttttgcttgt catgcaggta ctctcagagc gctcatagcc attataagac 2460 ctaaaaaggc agtgctctgc ggggatccca aacagtgcgg tttttttaac atgatgtgcc 2520 tgaaagtgca ttttaaccac gagatttgca cacaagtctt ccacaaaagc atctctcgcc 2580 gttgcactaa atctgtgact tcggtcgtct caaccttgtt ttacgacaaa aaaatgagaa 2640 cgacgaatcc gaaagagact aagattgtga ttgacactac cggcagtacc aaacctaagc 2700 aggacgatct cattctcact tgtttcagag ggtgggtgaa gcagttgcaa atagattaca 2760 aaggcaacga aataatgacg gcagctgcct ctcaagggct gacccgtaaa ggtgtgtatg 2820 ccgttcggta caaggtgaat gaaaatcctc tgtacgcacc cacctcagaa catgtgaacg 2880 tcctactgac ccgcacggag gaccgcatcg tgtggaaaac actagccggc gacccatgga 2940 taaaaacact gactgccaag taccctggga atttcactgc cacgatagag gagtggcaag 3000 cagagcatga tgccatcatg aggcacatct tggagagacc ggaccctacc gacgtcttcc 3060 agaataaggc aaacgtgtgt tgggccaagg ctttagtgcc ggtgctgaag accgctggca 3120 tagacatgac cactgaacaa tggaacactg tggattattt tgaaacggac aaagctcact 3180 cagcagagat agtattgaac caactatgcg tgaggttctt tggactcgat ctggactccg 3240 gtctattttc tgcacccact gttccgttat ccattaggaa taatcactgg gataactccc 3300 cgtcgcctaa catgtacggg ctgaataaag aagtggtccg tcagctctct cgcaggtacc 3360 cacaactgcc tcgggcagtt gccactggaa gagtctatga catgaacact ggtacactgc 3420 gcaattatga tccgcgcata aacctagtac ctgtaaacag aagactgcct catgctttag 3480 tcctccacca taatgaacac ccacagagtg acttttcttc attcgtcagc aaattgaagg 3540 gcagaactgt cctggtggtc ggggaaaagt tgtccgtccc aggcaaaatg gttgactggt 3600 tgtcagaccg gcctgaggct accttcagag ctcggctgga tttaggcatc ccaggtgatg 3660 tgcccaaata tgacataata tttgttaatg tgaggacccc atataaatac catcactatc 3720 agcagtgtga agaccatgcc attaagctta gcatgttgac caagaaagct tgtctgcatc 3780 tgaatcccgg cggaacctgt gtcagcatag gttatggtta cgctgacagg gccagcgaaa 3840 gcatcattgg tgctatagcg cggcagttca agttttcccg ggtatgcaaa ccgaaatcct 3900 cacttgaaga gacggaagtt ctgtttgtat tcattgggta cgatcgcaag gcccgtacgc 3960 acaatcctta caagctttca tcaaccttga ccaacattta tacaggttcc agactccacg 4020 aagccggatg tgcaccctca tatcatgtgg tgcgagggga tattgccacg gccaccgaag 4080 gagtgattat aaatgctgct aacagcaaag gacaacctgg cggaggggtg tgcggagcgc 4140 tgtataagaa attcccggaa agcttcgatt tacagccgat cgaagtagga aaagcgcgac 4200 tggtcaaagg tgcagctaaa catatcattc atgccgtagg accaaacttc aacaaagttt 4260 cggaggttga aggtgacaaa cagttggcag aggcttatga gtccatcgct aagattgtca 4320 acgataacaa ttacaagtca gtagcgattc cactgttgtc caccggcatc ttttccggga 4380 acaaagatcg actaacccaa tcattgaacc atttgctgac agctttagac accactgatg 4440 cagatgtagc catatactgc agggacaaga aatgggaaat gactctcaag gaagcagtgg 4500 ctaggagaga agcagtggag gagatatgca tatccgacga ctcttcagtg acagaacctg 4560 atgcagagct ggtgagggtg catccgaaga gttctttggc tggaaggaag ggctacagca 4620 caagcgatgg caaaactttc tcatatttgg aagggaccaa gtttcaccag gcggccaagg 4680 atatagcaga aattaatgcc atgtggcccg ttgcaacgga ggccaatgag caggtatgca 4740 tgtatatcct cggagaaagc atgagcagta ttaggtcgaa atgccccgtc gaagagtcgg 4800 aagcctccac accacctagc acgctgcctt gcttgtgcat ccatgccatg actccagaaa 4860 gagtacagcg cctaaaagcc tcacgtccag aacaaattac tgtgtgctca tcctttccat 4920 tgccgaagta tagaatcact ggtgtgcaga agatccaatg ctcccagcct atattgttct 4980 caccgaaagt gcctgcgtat attcatccaa ggaagtatct cgtggaaaca ccaccggtag 5040 acgagactcc ggagccatcg gcagagaacc aatccacaga ggggacacct gaacaaccac 5100 cacttataac cgaggatgag accaggacta gaacgcctga gccgatcatc atcgaagagg 5160 aagaagagga tagcataagt ttgctgtcag atggcccgac ccaccaggtg ctgcaagtcg 5220 aggcagacat tcacgggccg ccctctgtat ctagctcatc ctggtccatt cctcatgcat 5280 ccgactttga tgtggacagt ttatccatac ttgacaccct ggagggagct agcgtgacca 5340 gcggggcaac gtcagccgag actaactctt acttcgcaaa gagtatggag tttctggcgc 5400 gaccggtgcc tgcgcctcga acagtattca ggaaccctcc acatcccgct ccgcgcacaa 5460 gaacaccgtc acttgcaccc agcagggcct gctcgagaac cagcctagtt tccaccccgc 5520 caggcgtgaa tagggtgatc actagagagg agctcgaggc gcttaccccg tcacgcactc 5580 ctagcaggtc ggtctcgaga accagcctgg tctccaaccc gccaggcgta aatagggtga 5640 ttacaagaga ggagtttgag gcgttcgtag cacaacaaca atgacggttt gatgcgggtg 5700 catacatctt ttcctccgac accggtcaag ggcatttaca acaaaaatca gtaaggcaaa 5760 cggtgctatc cgaagtggtg ttggagagga ccgaattgga gatttcgtat gccccgcgcc 5820 tcgaccaaga aaaagaagaa ttactacgca agaaattaca gttaaatccc acacctgcta 5880 acagaagcag ataccagtcc aggaaggtgg agaacatgaa agccataaca gctagacgta 5940 ttctgcaagg cctagggcat tatttgaagg cagaaggaaa agtggagtgc taccgaaccc 6000 tgcatcctgt tcctttgtat tcatctagtg tgaaccgtgc cttttcaagc cccaaggtcg 6060 cagtggaagc ctgtaacgcc atgttgaaag agaactttcc gactgtggct tcttactgta 6120 ttattccaga gtacgatgcc tatttggaca tggttgacgg agcttcatgc tgcttagaca 6180 ctgccagttt ttgccctgca aagctgcgca gctttccaaa gaaacactcc tatttggaac 6240 ccacaatacg atcggcagtg ccttcagcga tccagaacac gctccagaac gtcctggcag 6300 ctgccacaaa aagaaattgc aatgtcacgc aaatgagaga attgcccgta ttggattcgg 6360 cggcctttaa tgtggaatgc ttcaagaaat atgcgtgtaa taatgaatat tgggaaacgt 6420 ttaaagaaaa ccccatcagg cttactgaag aaaacgtggt aaattacatt accaaattaa 6480 aaggaccaaa agctgctgct ctttttgcga agacacataa tttgaatatg ttgcaggaca 6540 taccaatgga caggtttgta atggacttaa agagagacgt gaaagtgact ccaggaacaa 6600 aacatactga agaacggccc aaggtacagg tgatccaggc tgccgatccg ctagcaacag 6660 cgtatctgtg cggaatccac cgagagctgg ttaggagatt aaatgcggtc ctgcttccga 6720 acattcatac actgtttgat atgtcggctg aagactttga cgctattata gccgagcact 6780 tccagcctgg ggattgtgtt ctggaaactg acatcgcgtc gtttgataaa agtgaggacg 6840 acgccatggc tctgaccgcg ttaatgattc tggaagactt aggtgtggac gcagagctgt 6900 tgacgctgat tgaggcggct ttcggcgaaa tttcatcaat acatttgccc actaaaacta 6960 aatttaaatt cggagccatg atgaaatctg gaatgttcct cacactgttt gtgaacacag 7020 tcattaacat tgtaatcgca agcagagtgt tgagagaacg gctaaccgga tcaccatgtg 7080 cagcattcat tggagatgac aatatcgtga aaggagtcaa atcggacaaa ttaatggcag 7140 acaggtgcgc cacctggttg aatatggaag tcaagattat agatgctgtg gtgggcgaga 7200 aagcgcctta tttctgtgga gggtttattt tgtgtgactc cgtgaccggc acagcgtgcc 7260 gtgtggcaga ccccctaaaa aggctgttta agcttggcaa acctctggca gcagacgatg 7320 aacatgatga tgacaggaga agggcattgc atgaagagtc aacacgctgg aaccgagtgg 7380 gtattctttc agagctgtgc aaggcagtag aatcaaggta tgaaaccgta ggaacttcca 7440 tcatagttat ggccatgact actctagcta gcagtgttaa atcattcagc tacctgagag 7500 gggcccctat aactctctac ggctaacctg aatggactac gacatagtct agtcgacgcc 7560 accatggaaa gccggatctg gtgcctggtc gtgtgcgtga acctgtgcat cgtgtgcctg 7620 ggagccgccg tgagcagcag cagcaccaga ggcaccagcg ccacacacag ccaccacagc 7680 agccacacca cctctgccgc ccacagcaga tccggcagcg tgtcccagag agtgaccagc 7740 agccagaccg tgtcccacgg cgtgaacgag acaatctaca acaccaccct gaagtacggc 7800 gacgtcgtgg gcgtgaatac caccaagtac ccctacagag tgtgcagcat ggcccagggc 7860 accgacctga tcagattcga gcggaacatc gtgtgcacca gcatgaagcc catcaacgag 7920 gacctggacg agggcatcat ggtggtgtac aagagaaaca tcgtggccca caccttcaaa 7980 gtgcgggtgt accagaaggt gctgaccttc cggcggagct acgcctacat ccacaccaca 8040 tacctgctgg gcagcaacac cgagtacgtg gcccctccca tgtgggagat ccaccacatc 8100 aacagccaca gccagtgcta cagcagctac agccgcgtga tcgccggcac agtgttcgtg 8160 gcctaccacc gggacagcta cgagaacaag accatgcagc tgatgcccga cgactacagc 8220 aacacccaca gcaccagata cgtgaccgtg aaggaccagt ggcacagcag aggcagcacc 8280 tggctgtacc gggagacatg caacctgaac tgcatggtca ccatcaccac cgccagaagc 8340 aagtaccctt accacttctt cgccacctcc accggcgacg tggtggacat cagccccttc 8400 tacaacggca ccaaccggaa cgccagctac ttcggcgaga acgccgacaa gttcttcatc 8460 ttccccaact acaccatcgt gtccgacttc ggcagaccca acagcgctct ggaaacccac 8520 agactggtgg cctttctgga acgggccgac agcgtgatca gctgggacat ccaggacgag 8580 aagaacgtga cctgccagct gaccttctgg gaggcctctg agagaaccat cagaagcgag 8640 gccgaggaca gctaccactt cagcagcgcc aagatgaccg ccaccttcct gagcaagaaa 8700 caggaagtga acatgagcga ctccgccctg gactgcgtga gggacgaggc catcaacaag 8760 ctgcagcaga tcttcaacac cagctacaac cagacctacg agaagtatgg caatgtgtcc 8820 gtgttcgaga caacaggcgg cctggtggtg ttctggcagg gcatcaagca gaaaagcctg 8880 gtggagctgg aacggctcgc caaccggtcc agcctgaacc tgacccacaa ccggaccaag 8940 cggagcaccg acggcaacaa cgcaacccac ctgtccaaca tggaaagcgt gcacaacctg 9000 gtgtacgcac agctgcagtt cacctacgac accctgcggg gctacatcaa cagagccctg 9060 gcccagatcg ccgaggcttg gtgcgtggac cagcggcgga ccctggaagt gttcaaagag 9120 ctgtccaaga tcaaccccag cgccatcctg agcgccatct acaacaagcc tatcgccgcc 9180 agattcatgg gcgacgtgct gggcctggcc agctgcgtga ccatcaacca gaccagcgtg 9240 aaggtgctgc gggacatgaa cgtgaaagag agcccaggcc gctgctactc cagacccgtg 9300 gtcatcttca acttcgccaa cagctcctac gtgcagtacg gccagctggg cgaggacaac 9360 gagatcctgc tggggaacca ccggaccgag gaatgccagc tgcccagcct gaagatcttt 9420 atcgccggca acagcgccta cgagtatgtg gactacctgt tcaagcggat gatcgacctg 9480 agcagcatct ccaccgtgga cagcatgatc gccctggaca tcgaccccct ggaaaacacc 9540 gacttccggg tgctggaact gtacagccag aaagagctgc ggagcagcaa cgtgttcgac 9600 ctggaagaga tcatgcggga gttcaacagc tacaagcagc gcgtgaaata cgtggaggac 9660 aaggtggtgg accccctgcc tccttacctg aagggcctgg acgacctgat gagcggactg 9720 ggcgctgccg gaaaagccgt gggagtggcc attggagctg tgggcggagc tgtggcctct 9780 gtcgtggaag gcgtcgccac ctttctgaag aaccccttcg gcgccttcac catcatcctg 9840 gtggccattg ccgtcgtgat catcacctac ctgatctaca cccggcagcg gagactgtgt 9900 acccagcccc tgcagaacct gttcccctac ctggtgtccg ccgatggcac cacagtgacc 9960 agcggctcca ccaaggatac cagcctgcag gccccaccca gctacgaaga gagcgtgtac 10020 aacagcggca gaaagggccc tggccctccc agctctgatg ccagcacagc cgcccctccc 10080 tacaccaacg agcaggccta ccagatgctg ctggccctgg ctagactgga tgccgagcag 10140 agggcccagc agaacggcac cgacagcctg gatggcagaa ccggcaccca ggacaagggc 10200 cagaagccca acctgctgga ccggctgcgg caccggaaga acggctaccg gcacctgaag 10260 gacagcgacg aggaagagaa cgtctgataa tctagacggc gcgcccaccc agcggccgca 10320 tacagcagca attggcaagc tgcttacata gaactcgcgg cgattggcat gccgccttaa 10380 aatttttatt ttatttttct tttcttttcc gaatcggatt ttgtttttaa tatttcaaaa 10440 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa agggtcggca tggcatctcc acctcctcgc 10500 ggtccgacct gggcatccga aggaggacgc acgtccactc ggatggctaa gggagagcca 10560 cgtttaaacc agctccaatt cgccctatag tgagtcgtat tacgcgcgct cactggccgt 10620 cgttttacaa cgtcgtgact gggaaaaccc tggcgttacc caacttaatc gccttgcagc 10680 acatccccct ttcgccagct ggcgtaatag cgaagaggcc cgcaccgatc gcccttccca 10740 acagttgcgc agcctgaatg gcgaatggga cgcgccctgt agcggcgcat taagcgcggc 10800 gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag cgcccgctcc 10860 tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc aagctctaaa 10920 tcgggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc ccaaaaaact 10980 tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt ttcgcccttt 11040 gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa caacactcaa 11100 ccctatctcg gtctattctt ttgatttata agggattttg ccgatttcgg cctattggtt 11160 aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat taacgcttac 11220 aatttaggtg gcacttttcg gggaaatgtg cgcggaaccc ctatttgttt atttttctaa 11280 atacattcaa atatgtatcc gctcatgaga caataaccct gataaatgct tcaataatat 11340 tgaaaaagga agagtatgag tattcaacat ttccgtgtcg cccttattcc cttttttgcg 11400 gcattttgcc ttcctgtttt tgctcaccca gaaacgctgg tgaaagtaaa agatgctgaa 11460 gatcagttgg gtgcacgagt gggttacatc gaactggatc tcaacagcgg taagatcctt 11520 gagagttttc gccccgaaga acgttttcca atgatgagca cttttaaagt tctgctatgt 11580 ggcgcggtat tatcccgtat tgacgccggg caagagcaac tcggtcgccg catacactat 11640 tctcagaatg acttggttga gtactcacca gtcacagaaa agcatcttac ggatggcatg 11700 acagtaagag aattatgcag tgctgccata accatgagtg ataacactgc ggccaactta 11760 cttctgacaa cgatcggagg accgaaggag ctaaccgctt ttttgcacaa catgggggat 11820 catgtaactc gccttgatcg ttgggaaccg gagctgaatg aagccatacc aaacgacgag 11880 cgtgacacca cgatgcctgt agcaatggca acaacgttgc gcaaactatt aactggcgaa 11940 ctacttactc tagcttcccg gcaacaatta atagactgga tggaggcgga taaagttgca 12000 ggaccacttc tgcgctcggc ccttccggct ggctggttta ttgctgataa atctggagcc 12060 ggtgagcgtg ggtctcgcgg tatcattgca gcactggggc cagatggtaa gccctcccgt 12120 atcgtagtta tctacacgac ggggagtcag gcaactatgg atgaacgaaa tagacagatc 12180 gctgagatag gtgcctcact gattaagcat tggtaactgt cagaccaagt ttactcatat 12240 atactttaga ttgatttaaa acttcatttt taatttaaaa ggatctaggt gaagatcctt 12300 tttgataatc tcatgaccaa aatcccttaa cgtgagtttt cgttccactg agcgtcagac 12360 cccgtagaaa agatcaaagg atcttcttga gatccttttt ttctgcgcgt aatctgctgc 12420 ttgcaaacaa aaaaaccacc gctaccagcg gtggtttgtt tgccggatca agagctacca 12480 actctttttc cgaaggtaac tggcttcagc agagcgcaga taccaaatac tgttcttcta 12540 gtgtagccgt agttaggcca ccacttcaag aactctgtag caccgcctac atacctcgct 12600 ctgctaatcc tgttaccagt ggctgctgcc agtggcgata agtcgtgtct taccgggttg 12660 gactcaagac gatagttacc ggataaggcg cagcggtcgg gctgaacggg gggttcgtgc 12720 acacagccca gcttggagcg aacgacctac accgaactga gatacctaca gcgtgagcta 12780 tgagaaagcg ccacgcttcc cgaagggaga aaggcggaca ggtatccggt aagcggcagg 12840 gtcggaacag gagagcgcac gagggagctt ccagggggaa acgcctggta tctttatagt 12900 cctgtcgggt ttcgccacct ctgacttgag cgtcgatttt tgtgatgctc gtcagggggg 12960 cggagcctat ggaaaaacgc cagcaacgcg gcctttttac ggttcctggc cttttgctgg 13020 ccttttgctc acatgttctt tcctgcgtta tcccctgatt ctgtggataa ccgtattacc 13080 gcctttgagt gagctgatac cgctcgccgc agccgaacga ccgagcgcag cgagtcagtg 13140 agcgaggaag cggaagagcg cccaatacgc aaaccgcctc tccccgcgcg ttggccgatt 13200 cattaatgca gctggcacga caggtttccc gactggaaag cgggcagtga gcgcaacgca 13260 attaatgtga gttagctcac tcattaggca ccccaggctt tacactttat gctcccggct 13320 cgtatgttgt gtggaattgt gagcggataa caatttcaca caggaaacag ctatgaccat 13380 gattacgcca agcgcgcaat taaccctcac taaagggaac aaaagctggg taccgggccc 13440 acgcgtaata cgactcacta tag 13463

Claims (46)

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  29. 세포에 알파바이러스 레플리콘을 포함하는 알파바이러스 레플리콘 입자 (VRP)를 전달하는 단계, 및 알파바이러스 레플리콘의 발현에 적합한 조건 하에 세포를 유지하는 단계를 포함하는 단백질 복합체를 형성하는 방법으로서,
    단백질 복합체는 형성되고,
    세포는 시험관 내 또는 비-사람 대상체의 생체 내에 있고,
    알파바이러스 레플리콘은:
    a. MRPGLPSYLIILAVCLFSHLLSSRYGAEAVSEPLDKAFHLLLNTYGRPIRFLRENTTQCTYNSSLRNSTVVRENAISFNFFQSYNQYYVFHMPRCLFAGPLAEQFLNQVDLTETLERYQQRLNTYALVSKDLASYRSFSQQLKAQDSLGEQPTTVPPPIDLSIPHVWMPPQTTPHGWTESHTTSGLHRPHFNQTCILFDGHDLLFSTVTPCLHQGFYLIDELRYVKITLTEDFFVVTVSIDDDTPMLLIFGHLPRVLFKAPYQRDNFILRQTEKHELLVLVKKDQLNRHSYLKDPDFLDAALDFNYLDLSALLRNSFHRYAVDVLKSGRCQMLDRRTVEMAFAYALALFAAARQEEAGAQVSVPRALDRQAALLQIQEFMITCLSQTPPRTTLLLYPTAVDLAKRALWTPNQITDITSLVRLVYILSKQNQQHLIPQWALRQIADFALKLHKTHLASFLSAFARQELYLMGSLVHSMLVHTTERREIFIVETGLCSLAELSHFTQLLAHPHHEYLSDLYTPCSSSGRRDHSLERLTRLFPDATVPATVPAALSILSTMQPSTLETFPDLFCLPLGESFSALTVSEHVSYIVTNQYLIKGISYPVSTTVVGQSLIITQTDSQTKCELTRNMHTTHSITVALNISLENCAFCQSALLEYDDTQGVINIMYMHDSDDVLFALDPYNEVVVSSPRTHYLMLLKNGTVLEVTDVVVDATDSRLLMMSVYALSAIIGIYLLYRMLKTC-- 또는 MRPGLPSYLIILAVCLFSHLLSSRYGAEAVSEPLDKAFHLLLNTYGRPIRFLRENTTQCTYNSSLRNSTVVRENAISFNFFQSYNQYYVFHMPRCLFAGPLAEQFLNQVDLTETLERYQQRLNTYALVSKDLASYRSFSQQLKAQDSLGEQPTTVPPPIDLSIPHVWMPPQTTPHGWTESHTTSGLHRPHFNQTCILFDGHDLLFSTVTPCLHQGFYLIDELRYVKITLTEDFFVVTVSIDDDTPMLLIFGHLPRVLFKAPYQRDNFILRQTEKHELLVLVKKDQLNRHSYLKDPDFLDAALDFNYLDLSALLRNSFHRYAVDVLKSGRCQMLDRRTVEMAFAYALALFAAARQEEAGAQVSVPRALDRQAALLQIQEFMITCLSQTPPRTTLLLYPTAVDLAKRALWTPNQITDITSLVRLVYILSKQNQQHLIPQWALRQIADFALKLHKTHLASFLSAFARQELYLMGSLVHSMLVHTTERREIFIVETGLCSLAELSHFTQLLAHPHHEYLSDLYTPCSSSGRRDHSLERLTRLFPDATVPATVPAALSILSTMQPSTLETFPDLFCLPLGESFSALTVSEHVSYIVTNQYLIKGISYPVSTTVVGQSLIITQTDSQTKCELTRNMHTTHSITVALNISLENCAFCQSALLEYDDTQGVINIMYMHDSDDVLFALDPYNEVVVSSPRTHYLMLLKNGTVLEVTDVVVDATD--의 서열로 구성되는 CMV gH 단백질을 암호화하는 첫 번째 뉴클레오티드 서열;
    b. MCRRPDCGFSFSPGPVILLWCCLLLPIVSSAAVSVAPTAAEKVPAECPELTRRCLLGEVFEGDKYESWLRPLVNVTGRDGPLSQLIRYRPVTPEAANSVLLDEAFLDTLALLYNNPDQLRALLTLLSSDTAPRWMTVMRGYSECGDGSPAVYTCVDDLCRGYDLTRLSYGRSIFTEHVLGFELVPPSLFNVVVAIRNEATRTNRAVRLPVSTAAAPEGITLFYGLYNAVKEFCLRHQLDPPLLRHLDKYYAGLPPELKQTRVNLPAHSRYGPQAVDAR--의 서열로 구성되는 CMV gL 단백질을 암호화하는 두 번째 뉴클레오티드 서열;
    c. MSPKDLTPFLTTLWLLLGHSRVPRVRAEECCEFINVNHPPERCYDFKMCNRFTVALRCPDGEVCYSPEKTAEIRGIVTTMTHSLTRQVVHNKLTSCNYNPLYLEADGRIRCGKVNDKAQYLLGAAGSVPYRWINLEYDKITRIVGLDQYLESVKKHKRLDVCRAKMGYMLQ--의 서열로 구성되는 CMV UL128 단백질을 암호화하는 세 번째 뉴클레오티드 서열;
    d. MLRLLLRHHFHCLLLCAVWATPCLASPWSTLTANQNPSPPWSKLTYSKPHDAATFYCPFLYPSPPRSPLQFSGFQRVSTGPECRNETLYLLYNREGQTLVERSSTWVKKVIWYLSGRNQTILQRMPRTASKPSDGNVQISVEDAKIFGAHMVPKQTKLLRFVVNDGTRYQMCVMKLESWAHVFRDYSVSFQVRLTFTEANNQTYTFCTHPNLIV--의 서열로 구성되는 CMV UL130 단백질을 암호화하는 네 번째 뉴클레오티드 서열; 및
    e. MRLCRVWLSVCLCAVVLGQCQRETAEKNDYYRVPHYWDACSRALPDQTRYKYVEQLVDLTLNYHYDASHGLDNFDVLKRINVTEVSLLISDFRRQNRRGGTNKRTTFNAAGSLAPHARSLEFSVRLFAN--의 서열로 구성되는 CMV UL131 단백질을 암호화하는 다섯 번째 뉴클레오티드 서열
    을 포함하는 폴리뉴클레오티드를 포함하는 자가 복제 RNA 분자를 포함하며,
    첫 번째, 두 번째, 세 번째, 네 번째 및 다섯 번째 뉴클레오티드 서열들은 프로모터, 바이러스 2A 부위 및 IRES로부터 선택된 조절 요소와 각각 작동 가능하게 연결되는, 방법.
  30. 제 29항에 있어서, 세포는 비-사람 대상체의 생체 내에 있는 것을 특징으로 하는 방법.
  31. 세포에 제29 항의 자가 복제 RNA 분자를 전달하는 단계, 및 상기 자가 복제 RNA의 발현에 적합한 조건 하에 세포를 유지하는 단계를 포함하는 단백질 복합체를 형성하는 방법으로서, 단백질 복합체는 형성되고, 세포는 시험관 내 또는 비-사람 대상체의 생체 내에 있는, 방법.
  32. 제 31항에 있어서, 세포는 비-사람 대상체의 생체 내에 있는 것을 특징으로 하는 방법.
  33. 제29 항의 자가 복제 RNA 분자와 세포를 접촉시키는 단계를 포함하는, 세포 내로 헤르페스바이러스 유입을 억제하는 방법으로서, 세포는 시험관 내 또는 비-사람 대상체의 생체 내에 있는, 방법.
  34. 제29 항의 VRP와 세포를 접촉시키는 단계를 포함하는 세포 내로 헤르페스바이러스 유입을 억제하는 방법으로서, 세포는 시험관 내 또는 비-사람 대상체의 생체 내에 있는, 방법.
  35. 제 33항 또는 제 34항에 있어서, 세포는 상피 세포, 내피 세포, 및 섬유아세포 내로 구성된 그룹으로부터 선택되는 것을 특징으로 하는 방법.
  36. 제 35항에 있어서, 세포는 상피 세포인 것을 특징으로 하는 방법.
  37. 제 33항에 있어서, 세포는 비- 사람 대상체의 생체 내에 있는 것을 특징으로 하는 방법.
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Publication number Priority date Publication date Assignee Title
US8580276B2 (en) 2009-06-05 2013-11-12 City Of Hope Genetically stable recombinant modified vaccinia ankara (rMVA) vaccines and methods of preparation thereof
SI2591114T1 (sl) 2010-07-06 2016-10-28 Glaxosmithkline Biologicals S.A. Imunizacija velikih sesalcev z majhnimi odmerki RNA
HUE047796T2 (hu) 2010-07-06 2020-05-28 Glaxosmithkline Biologicals Sa RNS bevitele több immunútvonal bekapcsolására
HUE026646T2 (en) 2010-07-06 2016-07-28 Glaxosmithkline Biologicals Sa Preferred liposomes containing lipids of PKA value for delivery of RNA
EP3578205A1 (en) 2010-08-06 2019-12-11 ModernaTX, Inc. A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof
HUE060524T2 (hu) 2010-08-31 2023-03-28 Glaxosmithkline Biologicals Sa Pegilált liposzómák immunogén kódoló RNS beszállítására
RU2013120302A (ru) 2010-10-01 2014-11-20 Модерна Терапьютикс, Инк. Сконструированные нуклеиновые кислоты и способы их применения
EP3520813B1 (en) 2010-10-11 2023-04-19 GlaxoSmithKline Biologicals S.A. Antigen delivery platforms
JP2014511687A (ja) 2011-03-31 2014-05-19 モデルナ セラピューティクス インコーポレイテッド 工学操作された核酸の送達および製剤
EP3854413A1 (en) * 2011-07-06 2021-07-28 GlaxoSmithKline Biologicals SA Immunogenic combination compositions and uses thereof
CA2872033A1 (en) * 2011-10-11 2013-04-18 Novartis Ag Recombinant self-replicating polycistronic rna molecules
LT2791160T (lt) 2011-12-16 2022-06-10 Modernatx, Inc. Modifikuotos mrnr sudėtys
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9254311B2 (en) 2012-04-02 2016-02-09 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins
US9192651B2 (en) 2012-04-02 2015-11-24 Moderna Therapeutics, Inc. Modified polynucleotides for the production of secreted proteins
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
CN104853771A (zh) * 2012-07-06 2015-08-19 诺华股份有限公司 巨细胞病毒蛋白的复合物
DK2877580T3 (en) 2012-07-27 2019-04-23 Hope City VAT VACCINE TO DELIVER A UL128 COMPLEX AND PREVENT CMV INFECTION
WO2014028429A2 (en) 2012-08-14 2014-02-20 Moderna Therapeutics, Inc. Enzymes and polymerases for the synthesis of rna
WO2014081507A1 (en) 2012-11-26 2014-05-30 Moderna Therapeutics, Inc. Terminally modified rna
MX2015008847A (es) * 2013-01-10 2015-10-30 Novartis Ag Composiciones inmunogenicas de virus de influenza y usos de las mismas.
WO2014159813A1 (en) 2013-03-13 2014-10-02 Moderna Therapeutics, Inc. Long-lived polynucleotide molecules
EP2971010B1 (en) 2013-03-14 2020-06-10 ModernaTX, Inc. Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions
EP3052106A4 (en) 2013-09-30 2017-07-19 ModernaTX, Inc. Polynucleotides encoding immune modulating polypeptides
CN106659803A (zh) 2014-04-23 2017-05-10 摩登纳特斯有限公司 核酸疫苗
RU2016147987A (ru) * 2014-05-08 2018-06-13 Пфайзер Инк. Средства и способы лечения cmv
EP3015475A1 (en) * 2014-10-31 2016-05-04 Novartis AG Mammalian cells expressing cytomegalovirus antigens
EP3048114A1 (en) 2015-01-22 2016-07-27 Novartis AG Cytomegalovirus antigens and uses thereof
WO2017044895A2 (en) 2015-09-10 2017-03-16 City Of Hope MVA-gH/gL-PC VACCINE DERIVED ANTIBODIES NEUTRALIZING HUMAN CYTOMEGALOVIRUS INFECTIVITY AND METHODS THEREOF
US10849920B2 (en) 2015-10-05 2020-12-01 Modernatx, Inc. Methods for therapeutic administration of messenger ribonucleic acid drugs
WO2017070613A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Human cytomegalovirus vaccine
US20180303929A1 (en) * 2015-10-22 2018-10-25 Moderna TX, Inc. Herpes simplex virus vaccine
CA3002912A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Nucleic acid vaccines for varicella zoster virus (vzv)
CN108778365B (zh) 2016-01-11 2021-05-25 沃达瑞公司 微针组合物及其使用方法
US10611800B2 (en) 2016-03-11 2020-04-07 Pfizer Inc. Human cytomegalovirus gB polypeptide
WO2017162265A1 (en) * 2016-03-21 2017-09-28 Biontech Rna Pharmaceuticals Gmbh Trans-replicating rna
WO2017162266A1 (en) 2016-03-21 2017-09-28 Biontech Rna Pharmaceuticals Gmbh Rna replicon for versatile and efficient gene expression
CA3041307A1 (en) 2016-10-21 2018-04-26 Giuseppe Ciaramella Human cytomegalovirus vaccine
CA3050914A1 (en) * 2017-01-27 2018-08-02 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Vaccine compositions of herpesvirus envelope protein combinations to induce immune response
WO2018170256A1 (en) * 2017-03-15 2018-09-20 Modernatx, Inc. Herpes simplex virus vaccine
US11045540B2 (en) * 2017-03-15 2021-06-29 Modernatx, Inc. Varicella zoster virus (VZV) vaccine
US20200054737A1 (en) * 2017-04-26 2020-02-20 Modema TX, Inc. Herpes simplex virus vaccine
US11389529B2 (en) * 2017-07-13 2022-07-19 City Of Hope Expression system for expressing herpesvirus glycoprotein complexes
JP7355731B2 (ja) 2017-08-16 2023-10-03 アクイタス セラピューティクス インコーポレイテッド 脂質ナノ粒子製剤における使用のための脂質
US11524069B2 (en) * 2017-09-13 2022-12-13 Sanofi Pasteur Human cytomegalovirus immunogenic composition
CA3094216A1 (en) * 2018-06-08 2019-12-12 Vakzine Projekt Management Gmbh Viral particle - based vaccine
US20210363543A1 (en) * 2018-10-30 2021-11-25 Nantbio, Inc. Self Replicating RNA System
US11629172B2 (en) 2018-12-21 2023-04-18 Pfizer Inc. Human cytomegalovirus gB polypeptide
EP4004018A1 (en) 2019-07-24 2022-06-01 GlaxoSmithKline Biologicals SA Modified human cytomegalovirus proteins
MX2022007905A (es) 2019-12-31 2022-08-25 Elixirgen Therapeutics Inc Administracion transitoria basada en temperatura de acidos nucleicos y proteinas a celulas y tejidos.
JP2023524860A (ja) * 2020-05-11 2023-06-13 ヤンセン ファーマシューティカルズ，インコーポレーテッド ＳＡＲＳ－ＣｏＶ－２ワクチン
US20230234992A1 (en) 2020-06-05 2023-07-27 Glaxosmithkline Biologicals Sa Modified betacoronavirus spike proteins
TWI810589B (zh) 2020-06-21 2023-08-01 美商輝瑞股份有限公司 人巨細胞病毒糖蛋白Ｂ（ｇＢ）多肽
US11406703B2 (en) 2020-08-25 2022-08-09 Modernatx, Inc. Human cytomegalovirus vaccine
WO2022236008A1 (en) * 2021-05-07 2022-11-10 Board Of Regents, The University Of Texas System Methods and compositions for transport, storage, and delivery of adeno-associated viral vector and other molecules
WO2023104114A2 (en) * 2021-12-07 2023-06-15 Immorna (hangzhou) Biotechnology Co., Ltd. Rna formulations and lipids
WO2023144665A1 (en) 2022-01-28 2023-08-03 Glaxosmithkline Biologicals Sa Modified human cytomegalovirus proteins

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076645A2 (en) 2003-02-27 2004-09-10 University Of Massachusetts Compositions and methods for cytomegalovirus treatment
WO2005007689A1 (en) 2003-07-11 2005-01-27 Alphavax, Inc. Alphavirus-based cytomegalovirus vaccines
WO2007146024A2 (en) 2006-06-07 2007-12-21 The Trustees Of Princeton University Cytomegalovirus surface protein complex for use in vaccines and as a drug target

Family Cites Families (278)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186745A (en) 1976-07-30 1980-02-05 Kauzlarich James J Porous catheters
US4458066A (en) 1980-02-29 1984-07-03 University Patents, Inc. Process for preparing polynucleotides
US5132418A (en) 1980-02-29 1992-07-21 University Patents, Inc. Process for preparing polynucleotides
US4500707A (en) 1980-02-29 1985-02-19 University Patents, Inc. Nucleosides useful in the preparation of polynucleotides
US4973679A (en) 1981-03-27 1990-11-27 University Patents, Inc. Process for oligonucleo tide synthesis using phosphormidite intermediates
US4668777A (en) 1981-03-27 1987-05-26 University Patents, Inc. Phosphoramidite nucleoside compounds
US4373071A (en) 1981-04-30 1983-02-08 City Of Hope Research Institute Solid-phase synthesis of polynucleotides
US6090406A (en) 1984-04-12 2000-07-18 The Liposome Company, Inc. Potentiation of immune responses with liposomal adjuvants
US4797368A (en) 1985-03-15 1989-01-10 The United States Of America As Represented By The Department Of Health And Human Services Adeno-associated virus as eukaryotic expression vector
US5153319A (en) 1986-03-31 1992-10-06 University Patents, Inc. Process for preparing polynucleotides
US4853228A (en) 1987-07-28 1989-08-01 Micro-Pak, Inc. Method of manufacturing unilamellar lipid vesicles
US5047524A (en) 1988-12-21 1991-09-10 Applied Biosystems, Inc. Automated system for polynucleotide synthesis and purification
US5262530A (en) 1988-12-21 1993-11-16 Applied Biosystems, Inc. Automated system for polynucleotide synthesis and purification
US6867195B1 (en) 1989-03-21 2005-03-15 Vical Incorporated Lipid-mediated polynucleotide administration to reduce likelihood of subject's becoming infected
CA2425745C (en) 1989-03-21 2005-03-29 Philip L. Felgner Expression of exogenous polynucleotide sequences in a vertebrate
HU212924B (en) 1989-05-25 1996-12-30 Chiron Corp Adjuvant formulation comprising a submicron oil droplet emulsion
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
ATE157012T1 (de) 1989-11-03 1997-09-15 Univ Vanderbilt Verfahren zur in vivo-verabreichung von funktionsfähigen fremden genen
US5674192A (en) 1990-12-28 1997-10-07 Boston Scientific Corporation Drug delivery
US5279833A (en) 1990-04-04 1994-01-18 Yale University Liposomal transfection of nucleic acids into animal cells
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
US5173414A (en) 1990-10-30 1992-12-22 Applied Immune Sciences, Inc. Production of recombinant adeno-associated virus vectors
KR100242671B1 (ko) 1991-03-07 2000-03-02 고돈 에릭 유전학적으로 처리한 백신 균주
FR2676072B1 (fr) * 1991-05-03 1994-11-18 Transgene Sa Vecteur de delivrance d'arn.
US5693535A (en) 1992-05-14 1997-12-02 Ribozyme Pharmaceuticals, Inc. HIV targeted ribozymes
US5750390A (en) 1992-08-26 1998-05-12 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of diseases caused by expression of the bcl-2 gene
US5587308A (en) 1992-06-02 1996-12-24 The United States Of America As Represented By The Department Of Health & Human Services Modified adeno-associated virus vector capable of expression from a novel promoter
JP3285355B2 (ja) 1992-06-04 2002-05-27 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア ｉｎｖｉｖｏ遺伝子治療のための方法及び組成物
AU4769893A (en) 1992-07-17 1994-02-14 Ribozyme Pharmaceuticals, Inc. Method and reagent for treatment of animal diseases
US5474914A (en) 1992-07-29 1995-12-12 Chiron Corporation Method of producing secreted CMV glycoprotein H
US20020102273A1 (en) 1995-08-08 2002-08-01 Robert B. Grieve Use of alphavirus expression vectors to produce parasite anitgens
EP1624068A1 (en) 1993-06-01 2006-02-08 Life Technologies Inc. Genetic immunization with cationic lipids
US6015686A (en) 1993-09-15 2000-01-18 Chiron Viagene, Inc. Eukaryotic layered vector initiation systems
US5397307A (en) 1993-12-07 1995-03-14 Schneider (Usa) Inc. Drug delivery PTCA catheter and method for drug delivery
JP3403233B2 (ja) 1994-01-20 2003-05-06 テルモ株式会社 バルーンカテーテル
IL112820A0 (en) * 1994-03-07 1995-05-26 Merck & Co Inc Coordinate in vivo gene expression
JPH08511956A (ja) 1994-04-07 1996-12-17 アクゾ・ノベル・エヌ・ベー Ｒｎａを含む凍結乾燥組成物
US5993850A (en) 1994-09-13 1999-11-30 Skyepharma Inc. Preparation of multivesicular liposomes for controlled release of encapsulated biologically active substances
US5885613A (en) 1994-09-30 1999-03-23 The University Of British Columbia Bilayer stabilizing components and their use in forming programmable fusogenic liposomes
CA2204254C (en) 1994-11-17 2010-02-16 Stephen Lewis Hart Internalisation of dna, using conjugates of poly-l-lysine and an integrin receptor ligand
JPH11504802A (ja) * 1994-11-30 1999-05-11 カイロン コーポレイション 組換えアルファウイルスベクター
WO1996017072A2 (en) 1994-11-30 1996-06-06 Chiron Viagene, Inc. Recombinant alphavirus vectors
US6071890A (en) 1994-12-09 2000-06-06 Genzyme Corporation Organ-specific targeting of cationic amphiphile/DNA complexes for gene therapy
US5965434A (en) 1994-12-29 1999-10-12 Wolff; Jon A. Amphipathic PH sensitive compounds and delivery systems for delivering biologically active compounds
US5664701A (en) 1995-01-25 1997-09-09 Uniplast, Inc. Glue gun system with removable cartridges
US5700642A (en) 1995-05-22 1997-12-23 Sri International Oligonucleotide sizing using immobilized cleavable primers
US5792462A (en) 1995-05-23 1998-08-11 University Of North Carolina At Chapel Hill Alphavirus RNA replicon systems
US5981501A (en) 1995-06-07 1999-11-09 Inex Pharmaceuticals Corp. Methods for encapsulating plasmids in lipid bilayers
US7422902B1 (en) 1995-06-07 2008-09-09 The University Of British Columbia Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer
JPH11512609A (ja) 1995-09-27 1999-11-02 アメリカ合衆国 クローン化されたヌクレオチド配列からの感染性ＲＳウイルス（ｒｅｓｐｉｒａｔｏｒｙ ｓｙｎｃｙｔｉａｌ ｖｉｒｕｓ）の生産
ATE234362T1 (de) * 1995-11-28 2003-03-15 Univ Johns Hopkins Med Konditionell-replizierende virale vektoren und ihre verwendung.
AU724716B2 (en) 1996-02-12 2000-09-28 Ml Laboratories Plc Novel methods of vaccination and vaccines therefore comprising a nucleic acid encoding a first epitope and a peptide containing a second epitope
DE19605548A1 (de) 1996-02-15 1997-09-04 Boehringer Ingelheim Int Zusammensetzung für die Transfektion höherer eukaryotischer Zellen
DE19612967A1 (de) 1996-04-01 1997-10-02 Behringwerke Ag Verfahren zur Vermehrung von Influenzaviren in Zellkultur, sowie die durch das Verfahren erhältlichen Influenzaviren
US6451592B1 (en) 1996-04-05 2002-09-17 Chiron Corporation Recombinant alphavirus-based vectors with reduced inhibition of cellular macromolecular synthesis
JP2001503735A (ja) 1996-07-03 2001-03-21 ユニバーシティ オブ ピッツバーグ 親水性活性試薬のためのエマルジョン処方物
US7384923B2 (en) 1999-05-14 2008-06-10 Lipoxen Technologies Limited Liposomes
CN1138533C (zh) 1996-09-13 2004-02-18 利普森有限公司 脂质体
US6395302B1 (en) 1996-11-19 2002-05-28 Octoplus B.V. Method for the preparation of microspheres which contain colloidal systems
WO1998051278A2 (en) 1997-05-14 1998-11-19 Inex Pharmaceuticals Corporation High efficiency encapsulation of charged therapeutic agents in lipid vesicles
US6048546A (en) 1997-07-31 2000-04-11 Sandia Corporation Immobilized lipid-bilayer materials
US6060308A (en) 1997-09-04 2000-05-09 Connaught Laboratories Limited RNA respiratory syncytial virus vaccines
US6090619A (en) 1997-09-08 2000-07-18 University Of Florida Materials and methods for intracellular delivery of biologically active molecules
US6129705A (en) 1997-10-01 2000-10-10 Medtronic Ave, Inc. Drug delivery and gene therapy delivery system
JP2002500003A (ja) 1997-11-28 2002-01-08 ザ・クラウン・イン・ザ・ライト・オヴ・ザ・クイーンズランド・デパートメント・オヴ・ヘルス フラビウイルスの発現および送達のシステム
US6009406A (en) 1997-12-05 1999-12-28 Square D Company Methodology and computer-based tools for re-engineering a custom-engineered product line
GB9726555D0 (en) 1997-12-16 1998-02-11 Smithkline Beecham Plc Vaccine
WO1999055310A1 (en) 1998-04-27 1999-11-04 Altus Biologics Inc. Stabilized protein crystals, formulations containing them and methods of making them
US6432925B1 (en) 1998-04-16 2002-08-13 John Wayne Cancer Institute RNA cancer vaccine and methods for its use
US6517842B1 (en) 1998-06-29 2003-02-11 The United States Of America As Represented By The Secretary Of The Army Marburg virus vaccines
CA2335393C (en) 1998-07-20 2008-09-23 Inex Pharmaceuticals Corporation Liposomal encapsulated nucleic acid-complexes
EP1980617A1 (en) * 1998-12-31 2008-10-15 Novartis Vaccines and Diagnostics, Inc. Improved expression of HIV polypeptides and production of virus-like particles
US6492169B1 (en) 1999-05-18 2002-12-10 Crucell Holland, B.V. Complementing cell lines
ATE289630T1 (de) 1999-09-09 2005-03-15 Curevac Gmbh Transfer von mrnas unter verwendung von polykationischen verbindungen
CN1411512A (zh) 1999-10-20 2003-04-16 约翰霍普金斯大学医学院 嵌合的免疫原性组合物及其编码核酸
US8541008B2 (en) 1999-11-19 2013-09-24 Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center Pharmaceutical compositions and methods to vaccinate against candidiasis
EP1103610A1 (en) 1999-11-26 2001-05-30 Introgene B.V. Production of vaccines from immortalised mammalian cell lines
US20030212022A1 (en) 2001-03-23 2003-11-13 Jean-Marie Vogel Compositions and methods for gene therapy
EP1287015A1 (en) 2000-04-18 2003-03-05 Human Genome Sciences, Inc. Extracellular matrix polynucleotides, polypeptides, and antibodies
AU2001275423B2 (en) 2000-06-09 2007-01-11 Regulon, Inc. Encapsulation of polynucleotides and drugs into targeted liposomes
WO2002002606A2 (en) 2000-07-03 2002-01-10 Chiron S.P.A. Immunisation against chlamydia pneumoniae
AU2001290520A1 (en) 2000-08-01 2002-02-13 The Johns Hokpins University Intercellular transport protein linked to an antigen as a molecular vaccine
US20040142474A1 (en) 2000-09-14 2004-07-22 Expression Genetics, Inc. Novel cationic lipopolymer as a biocompatible gene delivery agent
DK1322287T3 (da) 2000-09-28 2006-07-24 Chiron Corp Mikropartikler til administration af heterologe nukleinsyrer
EP2284181A1 (en) 2000-10-27 2011-02-16 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A and B
US7445924B2 (en) 2000-11-23 2008-11-04 Bavarian Nordic A/S Modified Vaccinia Ankara virus variant and cultivation method
US7731975B2 (en) 2001-01-31 2010-06-08 The United States Of America As Represented By The Secretary Of The Army Chimeric filovirus glycoprotein
EP1363660A4 (en) 2001-02-01 2006-06-21 Univ Johns Hopkins HIGHER MOLECULAR VACCINE BASED ON AUTOMPLICATIVE RNA, SUICIDE DNA OR UNDNA DNA VECTOR, WHICH LINKS ANTIGEN WITH A POLYPEPTIDE WHICH PROMOTES THE PRESENTATION OF THE ANTIGEN
AU2002306709A1 (en) 2001-03-14 2002-09-24 Replicon Technologies, Inc. Oncolytic rna replicons
AU2002306736A1 (en) 2001-03-16 2002-10-03 Johns Hopkins University A replication-defective alphavirus vaccine linking antigen with an immunogenicity-potentiating polypeptide and a method of delivery the same
CA2445947A1 (en) 2001-04-30 2002-11-07 Targeted Genetics Corporation Lipid-comprising drug delivery complexes and methods for their production
US20030077251A1 (en) 2001-05-23 2003-04-24 Nicolas Escriou Replicons derived from positive strand RNA virus genomes useful for the production of heterologous proteins
EP2842964A1 (de) 2001-06-05 2015-03-04 Curevac GmbH Virtuelles Verfahren zur Ermittlung einer modifzierten mRNA-Sequenz
US20050175629A1 (en) 2001-08-31 2005-08-11 Giuseppe Del Giudice Helicobacter pylori vaccination
JP4790984B2 (ja) 2001-09-06 2011-10-12 アルファヴァックス，インコーポレイテッド アルファウイルスレプリコンベクター系
WO2003068190A1 (en) 2002-02-13 2003-08-21 Northeastern University Intracellular delivery of therapeutic agents
DE10207177A1 (de) 2002-02-19 2003-09-04 Novosom Ag Fakultativ kationische Lipide
US6861410B1 (en) 2002-03-21 2005-03-01 Chiron Corporation Immunological adjuvant compositions
DE60328481D1 (de) 2002-05-14 2009-09-03 Novartis Vaccines & Diagnostic Schleimhautapplizierter impfstoff, der das adjuvanz chitosan und menigokokkenantigene enthält
DE60334618D1 (de) 2002-06-28 2010-12-02 Protiva Biotherapeutics Inc Verfahren und vorrichtung zur herstellung von liposomen
CN100340289C (zh) 2002-07-05 2007-10-03 利普生技术有限公司 增强核酸接种免疫应答的方法
US20060251620A1 (en) 2002-08-22 2006-11-09 Lidia Ivanova Inducible alphaviral/orip based gene expression system
BR0314236A (pt) 2002-09-13 2005-08-09 Replicor Inc Formulação de oligonucleotìdeo, composição farmacêutica, kit, composto antiviral, preparação de oligonucleotìdeo e métodos para seleção de um oligonucleotìdeo antiviral para uso como um agente antiviral, para profilaxia ou tratamento de uma infecção viral em um paciente, para tratamento profilático de câncer causado por oncovìrus, para identificação de um composto que altera a ligação de um oligonucleotìdeo a pelo menos um componente viral, para purificação da ligação de oligonucleotìdeos a pelo menos um componente viral e para enriquecimento de oligonucleotìdeos a partir de um agrupamento de oligonucleotìdeos
ES2618309T3 (es) * 2002-12-13 2017-06-21 Alphavax, Inc. Partículas de replicón de alfavirus multi-antigénico y métodos
ATE471335T1 (de) 2002-12-23 2010-07-15 Vical Inc Impfstoffe gegen infektionen mit dem humanen zytomegalivirus auf grundlage von codonoptimierten polynukleotiden
WO2004069148A2 (en) 2003-02-04 2004-08-19 Bar-Ilan University Snornai-small nucleolar rna degradation by rna interference in trypanosomatids
CN1791678A (zh) 2003-03-20 2006-06-21 阿尔法瓦克斯公司 改进的甲病毒复制子和辅助构建体
CA2520386A1 (en) 2003-03-27 2004-10-14 Children's Hospital, Inc. Nontypeable haemophilus influenzae virulence factors
US7731967B2 (en) 2003-04-30 2010-06-08 Novartis Vaccines And Diagnostics, Inc. Compositions for inducing immune responses
KR20060063788A (ko) 2003-05-30 2006-06-12 니뽄 신야쿠 가부시키가이샤 올리고 핵산 담지 복합체, 이 복합체를 함유하는 의약조성물
MXPA05013260A (es) 2003-06-26 2006-03-09 Chiron Corp Composiciones inmunogenicas para chlamydia trachomatis.
US7368537B2 (en) 2003-07-15 2008-05-06 Id Biomedical Corporation Of Quebec Subunit vaccine against respiratory syncytial virus infection
EP1648519B1 (en) 2003-07-16 2014-10-08 Protiva Biotherapeutics Inc. Lipid encapsulated interfering rna
PT1648500E (pt) 2003-07-31 2014-10-10 Novartis Vaccines & Diagnostic Composições imunogénicas para estreptococos piogenes
EP1512393A1 (de) 2003-09-08 2005-03-09 BOEHRINGER INGELHEIM PHARMA GMBH &amp; CO. KG Verfahren zur Herstellung von homogenen Liposomen und Lipoplexen
EP1528101A1 (en) 2003-11-03 2005-05-04 ProBioGen AG Immortalized avian cell lines for virus production
WO2005046621A2 (en) 2003-11-12 2005-05-26 The United States Of America As Represented By The Secretary Of The Navy Enhancement of vaccine-induced immune responses and protection by heterologous boosting with alphavirus replicon vaccines
US7303881B2 (en) 2004-04-30 2007-12-04 Pds Biotechnology Corporation Antigen delivery compositions and methods of use
GB0410866D0 (en) 2004-05-14 2004-06-16 Chiron Srl Haemophilius influenzae
ATE420965T1 (de) * 2004-05-18 2009-01-15 Alphavax Inc Von tc-83 abgeleitete alphavirus-vektoren, partikel und verfahren
WO2005116270A2 (en) 2004-05-18 2005-12-08 Vical Incorporated Influenza virus vaccine composition and method of use
GB0411428D0 (en) 2004-05-21 2004-06-23 Got A Gene Ab Vectors
WO2006078294A2 (en) 2004-05-21 2006-07-27 Novartis Vaccines And Diagnostics Inc. Alphavirus vectors for respiratory pathogen vaccines
WO2005120152A2 (en) 2004-06-07 2005-12-22 Protiva Biotherapeutics, Inc. Cationic lipids and methods of use
ATE536418T1 (de) 2004-06-07 2011-12-15 Protiva Biotherapeutics Inc Lipidverkapselte interferenz-rna
AU2005327198B2 (en) 2004-07-09 2011-03-31 University Of North Carolina At Chapel Hill Viral adjuvants
WO2006007712A1 (en) 2004-07-19 2006-01-26 Protiva Biotherapeutics, Inc. Methods comprising polyethylene glycol-lipid conjugates for delivery of therapeutic agents
EP1794183A2 (en) 2004-10-01 2007-06-13 Novartis Vaccines and Diagnostics S.r.l. Hepatitis c virus replication system
WO2006053646A2 (en) 2004-11-19 2006-05-26 Novosom Ag Improvements in or relating to pharmaceutical compositions for local administration
GB2421025A (en) 2004-12-09 2006-06-14 Oxxon Therapeutics Ltd HSV vaccination vectors
JP5042863B2 (ja) 2005-02-14 2012-10-03 サーナ・セラピューティクス・インコーポレイテッド 生物学的に活性な分子をデリバリーするための脂質ナノ粒子系組成物および方法
US7404969B2 (en) 2005-02-14 2008-07-29 Sirna Therapeutics, Inc. Lipid nanoparticle based compositions and methods for the delivery of biologically active molecules
DK2351772T3 (en) 2005-02-18 2016-09-05 Glaxosmithkline Biologicals Sa Proteins and nucleic acids from meningitis / sepsis-associated Escherichia coli
US8062644B2 (en) 2005-02-18 2011-11-22 Novartis Vaccines & Diagnostics Srl. Immunogens from uropathogenic Escherichia coli
DE602006008278D1 (de) 2005-03-02 2009-09-17 Pharmazeutische zusammensetzung
GB0504436D0 (en) 2005-03-03 2005-04-06 Glaxosmithkline Biolog Sa Vaccine
CN101687025A (zh) 2005-03-30 2010-03-31 诺华疫苗和诊断公司 B型流感嗜血杆菌
CN101193655A (zh) * 2005-04-11 2008-06-04 美国政府健康及人类服务部，疾病控制和预防中心 抗大流行性流感病毒株的疫苗
US7618393B2 (en) 2005-05-03 2009-11-17 Pharmajet, Inc. Needle-less injector and method of fluid delivery
AU2006259858A1 (en) 2005-05-12 2006-12-28 Novartis Vaccines And Diagnostics S.R.L. Immunogenic compositions for Chlamydia trachomatis
US8703095B2 (en) 2005-07-07 2014-04-22 Sanofi Pasteur S.A. Immuno-adjuvant emulsion
EP1909758A1 (en) 2005-08-02 2008-04-16 I.D.M. Immuno-Designed Molecules Process for the preparation of liposomal formulations
US7951384B2 (en) 2005-08-05 2011-05-31 University Of Massachusetts Virus-like particles as vaccines for paramyxovirus
EP3611266B1 (en) 2005-08-23 2022-11-09 The Trustees of the University of Pennsylvania Rna containing modified nucleosides and methods of use thereof
EP1764089A1 (en) 2005-09-15 2007-03-21 Novosom AG Serum stable liposomes comprising amphoter II lipid mixtures
DE102005046490A1 (de) 2005-09-28 2007-03-29 Johannes-Gutenberg-Universität Mainz Modifikationen von RNA, die zu einer erhöhten Transkriptstabilität und Translationseffizienz führen
DK1940826T3 (da) 2005-09-29 2011-04-18 Elan Pharm Inc Pyrimidinylamidforbindelser, der inhiberer leukocytadhæsion medieret gennem BLA-4
CN101355960A (zh) 2005-10-18 2009-01-28 诺华疫苗和诊断公司 使用α病毒复制子颗粒进行粘膜和全身免疫
JP2007112768A (ja) 2005-10-24 2007-05-10 Kyoto Univ 肝指向性リポソーム組成物
US7776336B2 (en) 2005-10-25 2010-08-17 Novartis Vaccines And Diagnostics Srl Compositions comprising Yersinia pestis antigens
CA2630220C (en) 2005-11-22 2020-10-13 Doris Coit Norovirus and sapovirus antigens
US9393215B2 (en) 2005-12-02 2016-07-19 Novartis Ag Nanoparticles for use in immunogenic compositions
EP2004141A2 (en) 2006-03-17 2008-12-24 Novosom AG An efficient method for loading amphoteric liposomes with nucleic acid active substances
US7915399B2 (en) 2006-06-09 2011-03-29 Protiva Biotherapeutics, Inc. Modified siRNA molecules and uses thereof
CN101506381B (zh) 2006-06-21 2012-09-05 斯克里普斯研究学院 针对肿瘤基质抗原fap的dna组合物及其使用方法
EP2049559B1 (en) * 2006-07-28 2012-12-19 The Trustees of the University of Pennsylvania Improved hpv vaccines
CA2659552A1 (en) 2006-08-16 2008-02-21 Novartis Ag Immunogens from uropathogenic escherichia coli
NZ575901A (en) 2006-09-12 2012-04-27 Alphavax Inc Alphavirus replicon particles matched to protein antigens as immunological adjuvants
DE102007001370A1 (de) 2007-01-09 2008-07-10 Curevac Gmbh RNA-kodierte Antikörper
JP2010519203A (ja) 2007-02-16 2010-06-03 メルク・シャープ・エンド・ドーム・コーポレイション 生物活性分子の活性を強化するための組成物及び方法
WO2008109806A2 (en) 2007-03-08 2008-09-12 Massachusetts Institute Of Technology Electrostatic coating of particles for drug delivery
US8877206B2 (en) 2007-03-22 2014-11-04 Pds Biotechnology Corporation Stimulation of an immune response by cationic lipids
CA2682161A1 (en) 2007-03-29 2008-10-09 Alnylam Pharmaceuticals, Inc. Compositions and methods for inhibiting expression of a gene from ebola virus
US8748591B2 (en) 2007-04-17 2014-06-10 The Board Of Regents Of The University Of Texas System Chimeric sindbis-western equine encephalitis virus and uses thereof
DK2494993T3 (en) 2007-05-04 2018-11-12 Marina Biotech Inc Amino acid lipids and uses thereof
CA2688061A1 (en) * 2007-05-23 2008-12-04 Mannkind Corporation Multicistronic vectors and methods for their design
DE102007029471A1 (de) 2007-06-20 2008-12-24 Novosom Ag Neue fakultativ kationische Sterole
JP5602624B2 (ja) * 2007-06-21 2014-10-08 アルファバックス， インコーポレイテッド αウイルス構造タンパク質の発現のためのプロモーターレスカセット
WO2009003975A1 (en) 2007-07-04 2009-01-08 Ribovax Biotechnologies Sa Antibodies against human cytomegalovirus (hcmv)
GB0714963D0 (en) 2007-08-01 2007-09-12 Novartis Ag Compositions comprising antigens
US20110177155A1 (en) 2007-08-21 2011-07-21 Immune Disease Institute, Inc. Methods of delivery of agents to leukocytes and endothelial cells
GB0717187D0 (en) 2007-09-04 2007-10-17 Novartis Ag Compositions comprising yersinia pestis antigens
US20090162395A1 (en) 2007-09-26 2009-06-25 Crowe Jr James E Vaccine for rsv and mpv
EP2042193A1 (en) 2007-09-28 2009-04-01 Biomay AG RNA Vaccines
AU2008338803B2 (en) 2007-11-26 2015-02-05 Glaxosmithkline Biologicals S.A. Methods of generating alphavirus particles
EP2067749A1 (en) 2007-11-29 2009-06-10 Total Petrochemicals France Process for purification of an aqueous phase containing polyaromatics
WO2009074861A2 (en) 2007-12-10 2009-06-18 Powderject Research Limited Improved vaccine
WO2009111088A2 (en) 2008-01-02 2009-09-11 The Johns Hopkins University Antitumor immunization by liposomal delivery of vaccine to the spleen
CA2709875C (en) 2008-01-02 2019-07-16 Tekmira Pharmaceuticals Corporation Improved compositions and methods for the delivery of nucleic acids
ITMI20081249A1 (it) 2008-07-09 2010-01-09 Novartis Vaccines & Diagnostic Immunogeni di escherichia coli con solubilità migliorata.
US20110110857A1 (en) 2008-03-06 2011-05-12 Roberto Petracca Mutant forms of chlamydia htra
HUE034483T2 (en) 2008-04-15 2018-02-28 Protiva Biotherapeutics Inc New lipid preparations for introducing a nucleic acid
WO2009127230A1 (en) 2008-04-16 2009-10-22 Curevac Gmbh MODIFIED (m)RNA FOR SUPPRESSING OR AVOIDING AN IMMUNOSTIMULATORY RESPONSE AND IMMUNOSUPPRESSIVE COMPOSITION
WO2009132131A1 (en) 2008-04-22 2009-10-29 Alnylam Pharmaceuticals, Inc. Amino lipid based improved lipid formulation
WO2009132206A1 (en) 2008-04-25 2009-10-29 Liquidia Technologies, Inc. Compositions and methods for intracellular delivery and release of cargo
US20100040650A1 (en) 2008-05-30 2010-02-18 Crowe Jr James E Virus-Like paramyxovirus particles and vaccines
EP2130912A1 (en) 2008-06-04 2009-12-09 Institut für Viruskrankeiten und Immunprophylaxe Pestivirus replicons providing an RNA-based viral vector system
WO2009156852A1 (en) 2008-06-25 2009-12-30 Novartis Ag Rapid responses to delayed booster immunisations
US20110229969A1 (en) * 2008-06-25 2011-09-22 Volker Sandig Cell Line for Propagation of Highly Attenuated AlphaViruses
JP5475774B2 (ja) * 2008-07-16 2014-04-16 インスティテュート フォー リサーチ イン バイオメディシン ヒトサイトメガロウイルス中和抗体およびその使用
JP2010025644A (ja) 2008-07-16 2010-02-04 Kochi Univ Of Technology 硝酸イオンの呈色試薬並びにこれを用いた硝酸イオンの検出及び定量方法
PT2352759T (pt) * 2008-07-16 2018-01-08 Inst Res Biomedicine Anticorpos neutralizantes de citomegalovírus humano e utilização destes
EP2328614A1 (en) 2008-08-06 2011-06-08 Novartis AG Microparticles for use in immunogenic compositions
CL2008002322A1 (es) 2008-08-07 2009-06-05 Univ Concepcion Formulacion farmaceutica veterinaria que comprende un sistema vectorial viral constituido por una particula recombinante de arn que codifica una cu/zn superoxido dismutasa de la bacteria patogena de bovinos brucella abortus, y al menos un alfavirus arn perteneciente a la familia del virus semliki forest (sfv), util como vacuna.
ES2915692T3 (es) 2008-08-13 2022-06-24 California Inst Of Techn Nanopartículas portadoras y composiciones, métodos y sistemas relacionados
EP2331557B1 (en) 2008-08-15 2013-12-18 Novartis AG Alphavirus packaging cell lines
US20110177122A1 (en) 2008-09-26 2011-07-21 The United States Of America, As Represented By The Secretary, Dept. Of Health & Human Services Dna prime/activated vaccine boost immunization to influenza virus
CA2984026C (en) 2008-10-09 2020-02-11 Arbutus Biopharma Corporation Improved amino lipids and methods for the delivery of nucleic acids
JP6087504B2 (ja) 2008-11-07 2017-03-01 マサチューセッツ インスティテュート オブ テクノロジー アミノアルコールリピドイドおよびその使用
JP5747282B2 (ja) 2008-11-10 2015-07-15 テクミラ ファーマシューティカルズ コーポレイションＴｅｋｍｉｒａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏｒｐｏｒａｔｉｏｎ 治療薬を送達するための新規な脂質及び組成物
AU2009316680B2 (en) 2008-11-18 2016-03-24 Takeda Vaccines, Inc. RSV F VLPs and methods of manufacture and use thereof
EP3243504A1 (en) 2009-01-29 2017-11-15 Arbutus Biopharma Corporation Improved lipid formulation
ES2565377T3 (es) 2009-04-14 2016-04-04 Glaxosmithkline Biologicals Sa Composiciones para inmunización contra Staphylococcus aureus
EP2416652B1 (en) 2009-05-05 2018-11-07 Arbutus Biopharma Corporation Methods of delivering oligonucleotides to immune cells
PT3431076T (pt) 2009-06-10 2021-10-26 Arbutus Biopharma Corp Formulação lipídica melhorada
IL292615B2 (en) 2009-07-01 2023-11-01 Protiva Biotherapeutics Inc Nucleic acid-lipid particles, preparations containing them and their uses
EP2450031B1 (en) 2009-07-02 2018-08-29 Konica Minolta Holdings, Inc. Method for producing liposomes by two-stage emulsification method using outer aqueous phase containing specific dispersing agent, method for producing liposome dispersion or dry powder thereof using the method for producing liposomes, and liposome dispersion or dry powder thereof produced thereby
US20110300205A1 (en) 2009-07-06 2011-12-08 Novartis Ag Self replicating rna molecules and uses thereof
HRP20220756T1 (hr) 2009-07-15 2022-09-02 Glaxosmithkline Biologicals S.A. Proteinski pripravci rsv f i postupci za izradu istih
DK2453914T3 (en) 2009-07-16 2018-10-08 Vaxil Biotherapeutics Ltd ANTIGEN-SPECIFIC MULTIPLE PIT-BASED ANTI-INFECTIOUS VACCINES
DK2459231T3 (en) 2009-07-31 2016-09-05 Ethris Gmbh RNA with a combination of unmodified and modified nucleotides for protein expression
TWI445708B (zh) 2009-09-02 2014-07-21 Irm Llc 作為ｔｌｒ活性調節劑之化合物及組合物
JP5988492B2 (ja) 2009-09-02 2016-09-07 ノバルティス アーゲー Ｔｌｒ活性モジュレーターを含む免疫原性組成物
US20110070260A1 (en) 2009-09-09 2011-03-24 Baric Ralph S Multivalent Immunogenic Compositions Against Noroviruses and Methods of Use
CN102712935B (zh) 2009-11-04 2017-04-26 不列颠哥伦比亚大学 含有核酸的脂质粒子及相关的方法
US20110112353A1 (en) 2009-11-09 2011-05-12 Circulite, Inc. Bifurcated outflow cannulae
SI2506857T1 (en) 2009-12-01 2018-08-31 Translate Bio, Inc. Delivery of mRNA for the enrichment of proteins and enzymes in human genetic diseases
US9687550B2 (en) 2009-12-07 2017-06-27 Arbutus Biopharma Corporation Compositions for nucleic acid delivery
WO2011071936A2 (en) 2009-12-07 2011-06-16 Gary Dahl Compositions and methods for reprogramming eukaryotic cells
EP3494963A1 (en) 2009-12-18 2019-06-12 The University of British Columbia Methods and compositions for delivery of nucleic acids
CA2785492C (en) 2009-12-23 2018-07-24 Novartis Ag Lipids, lipid compositions, and methods of using them
EP2525815B1 (en) 2010-01-24 2015-02-25 Novartis AG Irradiated biodegradable polymer microparticles
CA2792679C (en) 2010-03-09 2019-11-12 Biomedical Research Models, Inc. A novel mucosal vaccination approach for herpes simplex virus type-2
WO2011127316A1 (en) 2010-04-07 2011-10-13 Novartis Ag Method for generating a parvovirus b19 virus-like particle
HUE026646T2 (en) 2010-07-06 2016-07-28 Glaxosmithkline Biologicals Sa Preferred liposomes containing lipids of PKA value for delivery of RNA
HUE047796T2 (hu) 2010-07-06 2020-05-28 Glaxosmithkline Biologicals Sa RNS bevitele több immunútvonal bekapcsolására
CN103154242B (zh) 2010-07-06 2015-09-30 诺华股份有限公司 诺如病毒衍生的免疫原性组合物和方法
SI2591114T1 (sl) 2010-07-06 2016-10-28 Glaxosmithkline Biologicals S.A. Imunizacija velikih sesalcev z majhnimi odmerki RNA
SI2590676T1 (sl) 2010-07-06 2016-11-30 Glaxosmithkline Biologicals, S.A. Virionu podobni delci za dajanje za samorepliciranje RNA molekul
US9192661B2 (en) 2010-07-06 2015-11-24 Novartis Ag Delivery of self-replicating RNA using biodegradable polymer particles
MX343410B (es) 2010-07-06 2016-11-04 Novartis Ag * Emulsiones cationicas de agua en aceite.
US9770463B2 (en) 2010-07-06 2017-09-26 Glaxosmithkline Biologicals Sa Delivery of RNA to different cell types
US8898852B2 (en) 2010-08-04 2014-12-02 Honeywell International Inc. Air burst to clear detection window
EP3578205A1 (en) 2010-08-06 2019-12-11 ModernaTX, Inc. A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof
AU2011295938B2 (en) 2010-08-31 2016-01-14 Glaxosmithkline Biologicals S.A. Lipids suitable for liposomal delivery of protein-coding RNA
SI4008357T1 (sl) * 2010-08-31 2023-04-28 Glaxosmithkline Biologicals Sa Mali liposomi za dostavo imunogen-kodirajoče RNA
HUE060524T2 (hu) 2010-08-31 2023-03-28 Glaxosmithkline Biologicals Sa Pegilált liposzómák immunogén kódoló RNS beszállítására
EP2614072A4 (en) 2010-09-09 2014-03-19 Univ Virginia Commonwealth VACCINE AGAINST THE HUMAN CYTOMEGALOVIRUS
RU2013120302A (ru) 2010-10-01 2014-11-20 Модерна Терапьютикс, Инк. Сконструированные нуклеиновые кислоты и способы их применения
EP3520813B1 (en) 2010-10-11 2023-04-19 GlaxoSmithKline Biologicals S.A. Antigen delivery platforms
AR083548A1 (es) 2010-10-25 2013-03-06 Stepan Co Composiciones de amonio cuaternario, betaina, o sulfobetainas
US9405700B2 (en) 2010-11-04 2016-08-02 Sonics, Inc. Methods and apparatus for virtualization in an integrated circuit
EP2667892B1 (en) 2011-01-26 2019-03-27 GlaxoSmithKline Biologicals SA Rsv immunization regimen
KR20140007404A (ko) 2011-01-31 2014-01-17 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 신규 허피스 항원을 암호화하는 핵산 분자, 이것을 포함하는 백신 및 이것의 사용 방법
WO2012116714A1 (en) 2011-03-02 2012-09-07 Curevac Gmbh Vaccination in elderly patients
JP2014511687A (ja) 2011-03-31 2014-05-19 モデルナ セラピューティクス インコーポレイテッド 工学操作された核酸の送達および製剤
SG194755A1 (en) 2011-05-13 2013-12-30 Novartis Ag Pre-fusion rsv f antigens
CA2835428A1 (en) 2011-05-17 2012-11-22 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof for non-human vertebrates
EP3998064A1 (en) 2011-06-08 2022-05-18 Translate Bio, Inc. Cleavable lipids
BR112014000235A8 (pt) 2011-07-06 2018-03-06 Novartis Ag emulsões de óleo em água catiônicas
JP2014520807A (ja) 2011-07-06 2014-08-25 ノバルティス アーゲー 免疫原性組成物およびその使用
EP3854413A1 (en) 2011-07-06 2021-07-28 GlaxoSmithKline Biologicals SA Immunogenic combination compositions and uses thereof
AU2012280901B2 (en) 2011-07-06 2016-11-10 Glaxosmithkline Biologicals S.A. Oil-in-water emulsions that contain nucleic acids
RU2014104090A (ru) 2011-07-06 2015-08-20 Новартис Аг Липосомы с эффективным соотношением n:p для доставки молекул phk
CA2846043A1 (en) 2011-08-31 2013-03-07 Novartis Ag Pegylated liposomes for delivery of immunogen-encoding rna
EP2755693A4 (en) 2011-09-12 2015-05-20 Moderna Therapeutics Inc MODIFIED NUCLEIC ACIDS AND METHODS OF USE
US9428535B2 (en) 2011-10-03 2016-08-30 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
CA2872033A1 (en) 2011-10-11 2013-04-18 Novartis Ag Recombinant self-replicating polycistronic rna molecules
US20140348863A1 (en) 2011-10-12 2014-11-27 Alessia Bianchi Cmv antigens and uses thereof
EP2791364A4 (en) 2011-12-14 2015-11-11 Moderna Therapeutics Inc METHODS OF RESPONSE TO A BIOLOGICAL THREAT
LT2791160T (lt) 2011-12-16 2022-06-10 Modernatx, Inc. Modifikuotos mrnr sudėtys
US20130165504A1 (en) 2011-12-21 2013-06-27 modeRNA Therapeutics Methods of increasing the viability or longevity of an organ or organ explant
CA2868391A1 (en) 2012-04-02 2013-10-10 Stephane Bancel Polynucleotides comprising n1-methyl-pseudouridine and methods for preparing the same
US9192651B2 (en) 2012-04-02 2015-11-24 Moderna Therapeutics, Inc. Modified polynucleotides for the production of secreted proteins
WO2014081507A1 (en) 2012-11-26 2014-05-30 Moderna Therapeutics, Inc. Terminally modified rna
MX2015008847A (es) 2013-01-10 2015-10-30 Novartis Ag Composiciones inmunogenicas de virus de influenza y usos de las mismas.
US9504747B2 (en) 2013-03-08 2016-11-29 Novartis Ag Lipids and lipid compositions for the delivery of active agents
EP2971010B1 (en) 2013-03-14 2020-06-10 ModernaTX, Inc. Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions
WO2014160243A1 (en) 2013-03-14 2014-10-02 The Trustees Of The University Of Pennsylvania Purification and purity assessment of rna molecules synthesized with modified nucleosides
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
PL3083556T3 (pl) 2013-12-19 2020-06-29 Novartis Ag Lipidy i kompozycje lipidowe dla dostarczania środków czynnych
ES2910425T3 (es) 2015-09-17 2022-05-12 Modernatx Inc Compuestos y composiciones para la administración intracelular de agentes terapéuticos
HRP20230209T1 (hr) 2015-10-28 2023-04-14 Acuitas Therapeutics Inc. Novi lipidi i lipidne formulacije nanočestica za isporuku nukleinskih kiselina
CN116549671A (zh) 2016-11-10 2023-08-08 川斯勒佰尔公司 用于递送mrna的改进的基于ice的脂质纳米颗粒制剂
US11045540B2 (en) 2017-03-15 2021-06-29 Modernatx, Inc. Varicella zoster virus (VZV) vaccine
AU2019384557A1 (en) 2018-11-21 2021-06-10 Translate Bio, Inc. Treatment of cystic fibrosis by delivery of nebulized mRNA encoding CFTR
WO2021038508A1 (en) 2019-08-30 2021-03-04 Glaxosmithkline Biologicals Sa Jet mixing lipid nanoparticle manufacturing process
WO2022137133A1 (en) 2020-12-22 2022-06-30 Curevac Ag Rna vaccine against sars-cov-2 variants

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076645A2 (en) 2003-02-27 2004-09-10 University Of Massachusetts Compositions and methods for cytomegalovirus treatment
WO2005007689A1 (en) 2003-07-11 2005-01-27 Alphavax, Inc. Alphavirus-based cytomegalovirus vaccines
WO2007146024A2 (en) 2006-06-07 2007-12-21 The Trustees Of Princeton University Cytomegalovirus surface protein complex for use in vaccines and as a drug target

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