KR20180117122A - 인간화 tmprss 유전자를 갖는 설치류 - Google Patents
인간화 tmprss 유전자를 갖는 설치류 Download PDFInfo
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- KR20180117122A KR20180117122A KR1020187026552A KR20187026552A KR20180117122A KR 20180117122 A KR20180117122 A KR 20180117122A KR 1020187026552 A KR1020187026552 A KR 1020187026552A KR 20187026552 A KR20187026552 A KR 20187026552A KR 20180117122 A KR20180117122 A KR 20180117122A
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Abstract
유전자 변형된 마우스 및 랫트와 같은 설치류, 및 이를 만들고 사용하기 위한 방법 및 조성물이 제공된다. 설치류는 내인성 설치류 Tmprss2, Tmprss4, 또는 Tmprss11d 유전자와 같은 적어도 하나의 내인성 설치류 Tmprss 유전자의 인간화를 포함한다.
Description
관련 출원에 대한 상호 참조
본 출원은 그 내용 전체가 참조로서 본원에 통합되는 2016년 2월 29일에 출원된 미국 가출원 번호 제62/301,023호의 우선권의 이익을 주장한다.
참조로서 서열 목록 포함
2017년 2월 13일에 생성되고, EFS-Web을 통해 미국 특허 상표청에 제출된 33093_10234US01_SequenceListing.txt로 명명된 275 KB의 ASCII 텍스트 파일 내 서열 목록이 참조로써 본원에 통합된다.
II형 막관통 세린 프로테아제는 N 말단 막관통 도메인을 특징으로 하는 프로테아제 계열이다(Bugge 외의 J. Biol. Chem. 284 (35): 23177-23181, 2009; Hooper 외의 J. Biol. Chem. 272(2): 857-860, 2001). 본 계열의 모든 구성원은 단쇄 지모겐(single-chain zymogen)으로서 발현되고 고도로 보존된 R/(IV)VGG 모티프 내에서의 절단에 의해 단백질 분해 방식으로 활성화된다. 본 계열의 일 구성원으로, 막관통 프로테아제인 세린 4형(TMPRSS4)은 상피를 가로지르는 나트륨과 물의 흐름을 조절하는 상피 나트륨 채널(ENaC)를 활성화시키는 것으로 나타났다(Guipponi 외의 2002 Hum. Mol. Genet. 11:2829; Vuagniaux 외의 2002 J. Gen. Physiol. 120:191). TMPRSS4의 단백질 분해 활성자는 알려져 있지 않지만; 현재까지 이용 가능한 데이터는 단백질이 자체 활성화됨을 암시한다. 활성화될 때, TMPRSS4의 촉매 도메인은 이황화 결합을 통해 단백질의 N 말단에 결합된 채로 유지된다. TMPRSS4, TMPRSS2 및 TMPRSS11D (또는 인간 기도 트립신 유사 프로테아제; Human Airway Trypsin-like protease; "HAT")는 바이러스 생명 주기의 제1 필수 단계인 인플루엔자 A 혈구 응집소(hemagglutinin; HA)를 시험관 내에서 절단하는 것으로 나타났다. 이러한 절단은, 단백질이 전구체 단백질(HA0)로서 합성되고 활성을 위해 HA1 및 HA2로의 절단을 필요로 하므로 HA의 활성에 필수적이다. Caco-2 세포에서 TMPRSS4의 RNAi 녹다운은 바이러스의 확산을 감소시켰다. 또한, TMPRSS4는 인플루엔자로 감염된 마우스의 폐에서 강하게 상향 조절되는 것으로 나타났다( 외의 2006 J. Virol. 80:9896; 외의 2009 Vaccine 27: 6324; 외의 2010 J. Virol. 84: 5604; Bertam 외의 2010 J. Virol. 84:10016; Bertam 외의 2010 J. Virol. 84:10016; 외의 2011 J. Virol. 85: 1554; Bahgat 외의 2011 Virol. J. 8:27).
바이러스 감염 및 다른 질병의 치료 및 예방을 위해 인간 II형 막관통 세린 프로테아제를 특이적으로 표적화하는 항체를 포함하는 화합물을 식별하고 시험하기 위해 생체 내 시스템, 예를 들어 감염의 설치류 모델을 개발하는 것이 필요하다.
본 발명은 새로운 치료제를 확인하고 개발하기 생체 내 시스템을 제공하기 위해 설치류 동물을 조작하는 것이 바람직하다는 인식을 포함한다. 예를 들어, 본 발명은 인간화 Tmprss 유전자를 갖는 설치류가 바이러스 감염의 치료 및 예방을 위한 치료제의 식별과 개발에 사용하기에 바람직하다는 인식을 포함한다.
일 양태에서, 본 발명은 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss 유전자를 함유하는 게놈을 가진 설치류를 제공하되, 상기 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 유전자의 5' 조절 서열(들), 예컨대 프로모터 및/또는 증강자(들)에 의해 조절된다.
일부 구현예에서, 본원에 개시된 설치류 내의 인간화 Tmprss 유전자는 인간 TMPRSS 단백질의 세포외 도메인(ectodomain)과 실질적으로 동일한 (예: 서열이 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유하는 인간화 Tmprss 단백질을 암호화한다. 일부 구현예에서, 인간화 Tmprss 단백질은 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 (예: 서열이 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포질 및 막관통 부분을 함유한다.
일부 구현예에서, 본원에 개시된 설치류는 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss 유전자를 함유하되, 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열은 동족 인간 TMPRSS 유전자에 의해 암호화된 인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한 (예: 서열이 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 폴리펩티드를 암호화한다. 일부 구현예에서, 본원에 개시된 설치류는 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss 유전자를 함유하되, 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss 유전자에 의해 암호화된 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부붕과 실질적으로 동일한 (예: 서열이 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 폴리펩티드를 암호화한다.
일부 구현예에서, 본원에 개시된 설치류는 내인성 설치류 Tmprss 유전자의 인접 게놈 서열을 동족 인간 TMPRSS 유전자의 인접 게놈 서열과 대체함으로써 생성된 내인성 설치류 Tmprss 유전자좌에 위치한 인간화 Tmprss 유전자를 함유한다. 특정 구현예에서, 삽입되는 동족 인간 TMPRSS 유전자의 인접 게놈 서열은 인간 TMPRSS 유전자에 의해 암호화된 인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는 엑손 서열을 포함한다. 일부 구현예에서, 동족 인간 TMPRSS 유전자의 인접 게놈 서열은 또한 동족 인간 TMPRSS 유전자의 3' UTR을 포함한다.
일부 구현예에서, 본원에 개시된 설치류는 내인성 설치류 Tmprss 유전자좌에서 인간화 Tmprss 유전자에 대해 이형접합체이다. 다른 구현예에서, 설치류는 내인성 설치류 Tmprss 유전자좌에서 인간화 Tmprss 유전자에 대해 동형접합체이다.
또 다른 구현예에서, 설치류는 둘 이상의 인간화 Tmprss 유전자(예를 들어, 인간화 Tmprss2, 인간화 Tmprss4, 및 인간화 Tmprss11d 유전자 중 둘 이상)를 상이한 내인성 설치류 Tmprss 유전자좌에 (각각의 내인성 설치류 Tmprss 유전자좌는 각각 동족 인간 TMPRSS 유전자로 인간화됨) 함유한다.
일부 구현예에서, 본원에 개시된 설치류는 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열 및 인간 TMPRSS2 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss2 유전자를 함유하되, 인간화 Tmprss2 유전자는 내인성 설치류 Tmprss2 유전자의 프로모터에 의해 조절된다.
일부 구현예에서, 인간화 Tmprss2 유전자는 인간화에 사용된 인간 TMPRSS2 유전자에 의해 암호화된 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 (예: 서열이 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유하는 인간화 Tmprss2 단백질을 암호화한다. 인간 TMPRSS2 단백질은, 일부 구현예에서, 서열 번호 4에 명시된 바와 같은 아미노산 서열과 적어도 85% 동일한 (예: 적어도 90%, 95%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 함유한다. 일부 구현예에서, 인간화 Tmprss2 단백질은 예를 들어 서열 번호 4에 명시된 바와 같은 인간 TMPRSS2 단백질의 잔기 W106 내지 G492 또는 C 말단 387 아미노산으로 이루어진 아미노산 서열과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유한다. 일부 구현예에서, 인간화 Tmprss2 유전자는 인간화되는 내인성 설치류 Tmprss2 유전자에 의해 암호화된 설치류 Tmprss2 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포질 및 막관통 부분을 추가로 함유하는 인간화 Tmprss2 단백질을 암호화한다. 예시적인 내인성 설치류 Tmprss2 단백질은 서열 번호 2에 명시된다.
일부 구현예에서, 설치류는 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열 및 인간 TMPRSS2 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss2 유전자를 함유하되, 인간 TMPRSS2 유전자의 뉴클레오티드 서열은 인간 TMPRSS2 유전자에 의해 암호화된 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 암호화한다. 특정 구현예에서, 인간 TMPRSS2 유전자의 뉴클레오티드 서열은 인간 TMPRSS2 유전자의 코딩 엑손 13에 코딩 엑손 4 내지 정지 코돈을 함유하는 인간 TMPRSS2 유전자의 인접 게놈 서열이다. 특정 구현예에서, 인간 TMPRSS2 유전자의 인접 게놈 서열은 인간 TMPRSS2 유전자의 3' UTR을 추가로 함유한다. 일부 구현예에서, 인간화 Tmprss2 유전자에 포함된 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss2 유전자에 의해 암호화된 내인성 설치류 Tmprss2 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포질 및 막관통 부분을 암호화한다.
특정 구현예에서, 인간화 Tmprss2 유전자는 내인성 설치류 Tmprss2 유전자의 코딩 엑손 1 내지 2 및 인간 TMPRSS2 유전자의 코딩 엑손 4 내지 코딩 엑손 13을 포함하되, 인간화 Tmprss2 유전자는 내인성 설치류 Tmprss2 유전자에 의해 암호화된 설치류 Tmprss2 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 포함하는 인간화 Tmprss2 단백질, 및 인간 TMPRSS2 유전자에 의해 암호화된 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화한다. 인간화 Tmprss2 유전자는 엑손 3을 일부 구현예에서는 인간 TMPRSS2 유전자의 코딩 엑손 3에 함유하고, 다른 구현예에서는 내인성 설치류 Tmprss2 유전자의 코딩 엑손 3에 함유한다. 일부 구현예에서, 인간화 Tmprss2 유전자는 내인성 설치류 Tmprss2 유전자의 코딩 엑손 3의 5' 부분 및 인간 TMPRSS2 유전자의 코딩 엑손 3의 3' 부분을 포함하는 엑손 3을 함유한다.
일부 구현예에서, 본원에 개시된 설치류는 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열 및 인간 TMPRSS4 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss4 유전자를 함유하되, 인간화 Tmprss4 유전자는 내인성 설치류 Tmprss4 유전자의 프로모터에 의해 조절된다.
일부 구현예에서, 인간화 Tmprss4 유전자는 인간화에 사용된 인간 TMPRSS4 유전자에 의해 암호화된 인간 TMPRSS4 단백질의 세포외 도메인과 실질적으로 동일한 (예: 서열이 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유하는 인간화 Tmprss4 단백질을 암호화한다. 인간 TMPRSS4 단백질은, 일부 구현예에서, 서열 번호 11에 명시된 바와 같은 아미노산 서열과 적어도 85% 동일한 (예: 적어도 90%, 95%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 함유한다. 일부 구현예에서, 인간화 Tmprss4 단백질은 서열 번호 11에 명시된 바와 같은 인간 TMPRSS4 단백질의 잔기 K54 내지 L437 또는 C 말단 384 아미노산으로 이루어진 아미노산 서열과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유한다. 일부 구현예에서, 인간화 Tmprss4 유전자는 인간화되는 내인성 설치류 Tmprss4 유전자에 의해 암호화된 설치류 Tmprss4 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포질 및 막관통 부분을 추가로 함유하는 인간화 Tmprss4 단백질을 암호화한다. 예시적인 내인성 설치류 Tmprss4 단백질은 서열 번호 9에 명시된다.
일부 구현예에서, 설치류는 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열 및 인간 TMPRSS4 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss4 유전자를 함유하되, 인간 TMPRSS4 유전자의 뉴클레오티드 서열은 인간 TMPRSS4 유전자에 의해 암호화된 인간 TMPRSS4 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화한다. 특정 구현예에서, 인간 TMPRSS4 유전자의 뉴클레오티드 서열은 인간 TMPRSS4 유전자의 코딩 엑손 13에 코딩 엑손 4 내지 정지 코돈을 함유하는 인접 게놈 서열이다. 일부 구현예에서, 인간화 Tmprss4 유전자에 포함된 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss4 유전자에 의해 암호화된 내인성 설치류 Tmprss4 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화한다.
특정 구현예에서, 인간화 Tmprss4 유전자는 내인성 설치류 Tmprss4 유전자의 코딩 엑손 1 내지 3 및 인간 TMPRSS4 유전자의 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 함유한다.
일부 구현예에서, 본원에 개시된 설치류는 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열 및 인간 TMPRSS11D 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss11d 유전자를 함유하되, 인간화 Tmprss11d 유전자는 내인성 설치류 Tmprss11d 유전자의 프로모터에 의해 조절된다.
일부 구현예에서, 인간화 Tmprss11d 유전자는 인간화에 사용된 인간 TMPRSS11D 유전자에 의해 암호화된 인간 TMPRSS11D 단백질의 세포외 도메인과 실질적으로 동일한 (예: 서열이 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유하는 인간화 Tmprss11d 단백질을 암호화한다. 인간 TMPRSS11D 단백질은, 일부 구현예에서, 서열 번호 18에 명시된 바와 같은 아미노산 서열과 적어도 85% 동일한 (예: 적어도 90%, 95%, 98%, 99% 또는 100% 동일한) 아미노산 서열을 함유한다. 일부 구현예에서, 인간화 Tmprss11d 단백질은 예를 들어 서열 번호 18에 명시된 바와 같은 인간 TMPRSS11D 단백질의 잔기 A42 내지 I418 또는 C 말단 377 아미노산으로 이루어진 아미노산 서열과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유한다. 일부 구현예에서, 인간화 Tmprss11d 유전자는 인간화되는 내인성 설치류 Tmprss11d 유전자에 의해 암호화된 설치류 Tmprss11d 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 (예: 적어도 85%, 90%, 95%, 98%, 99% 또는 100% 동일한) 세포질 및 막관통 부분을 추가로 함유하는 인간화 Tmprss11d 단백질을 암호화한다. 예시적인 내인성 설치류 Tmprss11d 단백질은 서열 번호 16에 명시된다.
일부 구현예에서, 설치류는 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열 및 인간 TMPRSS11D 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss11d 유전자를 함유하되, 인간 TMPRSS11D 유전자의 뉴클레오티드 서열은 인간 TMPRSS11D 유전자에 의해 암호화된 인간 TMPRSS11D 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화한다. 특정 구현예에서, 인간 TMPRSS11d 유전자의 뉴클레오티드 서열은 인간 TMPRSS11D 유전자의 코딩 엑손 3에 내지 코딩 엑손 10 내의 정지 코돈을 함유하는 인접 게놈 서열이다. 특정 구현예에서, 인간 TMPRSS11D 유전자의 인접 게놈 서열은 인간 TMPRSS11D 유전자의 3' UTR을 추가로 함유한다. 일부 구현예에서, 인간화 Tmprss11d 유전자에 포함된 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss11d 유전자에 의해 암호화된 내인성 설치류 Tmprss11d 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화한다.
특정 구현예에서, 인간화 Tmprss11d 유전자는 내인성 설치류 Tmprss11d 유전자의 코딩 엑손 1 내지 2 및 인간 TMPRSS11D 유전자의 코딩 엑손 3 내지 코딩 엑손 13을 함유한다.
또 다른 양태에서, 본 발명은 본원에 기술된 바와 같은 인간화 Tmprss 유전자를 함유하는 게놈을 가진 단리된 설치류 세포 또는 조직을 제공한다. 특정 구현예에서, 인간화 Tmprss 유전자는 인간화 Tmprss2 유전자, 인간화 Tmprss4 유전자, 및 인간화 Tmprss11d 유전자로 이루어지는 군으로부터 선택된다.
또 다른 양태에서, 본 발명은 본원에 기술된 바와 같은 인간화 Tmprss 유전자를 함유하는 게놈을 가진 설치류 배주 줄기 세포를 제공한다. 특정 구현예에서, 인간화 Tmprss 유전자는 인간화 Tmprss2 유전자, 인간화 Tmprss4 유전자, 및 인간화 Tmprss11d 유전자로 이루어지는 군으로부터 선택된다.
또 다른 양태에서, 본원에 기술된 설치류 배아 줄기 세포로부터 생성된 설치류 배아가 또한 제공된다.
일 양태에서, 본 발명은 설치류 내에서 내인성 Tmprss 유전자의 인간화에 사용하기에 적합한 핵산 벡터를 제공한다. 일부 구현예에서, 핵산 벡터는 5' 상동 아암 및 3' 상동 아암이 측면에 위치한 인간 Tmprss 핵산 서열(예: 인간 TMPRSS 단백질의 세포외 도메인을 암호화하는 인간 게놈 DNA)을 포함한다. 5' 및 3' 상동 아암은 인간 Tmprss 핵산 서열에 대해 5' 및 3'에 각각 위치하는 핵산 서열이며, 동족 설치류 Tmprss 단백질의 세포외 도메인을 암호화하는 설치류 게놈 DNA의 측면에 위치하는 설치류의 내인성 Tmprss 유전자좌에서 게놈 DNA 서열에 대해 상동성이다. 따라서, 5' 및 3' 상동 아암은 동족 설치류 Tmprss 단백질의 세포외 도메인을 암호화하는 설치류 게놈 DNA의 상동성 재조합 및 인간 Tmprss 핵산 서열과의 대체를 매개하여 본원에 기술된 바와 같은 인간화 Tmprss 유전자를 형성할 수 있다.
추가적인 양태에서, 본 발명은 인간화 Tmprss 유전자를 함유하는 게놈을 가진 설치류를 제공하는 방법에 관한 것이다. 상기 방법은 내인성 설치류 Tmprss 유전자의 게놈 서열을 동족 인간 TMPRSS 유전자의 게놈 서열로 대체시켜 인간화 Tmprss 유전자를 형성하기 위해 설치류의 게놈을 변형시키는 것을 포함한다.
일부 구현예에서, 본 발명은 인간화 Tmprss 유전자를 갖는 설치류(예: 마우스 또는 랫트)를 만드는 방법으로서, (a) 설치류 배아 줄기 세포의 내인성 설치류 Tmprss 유전자좌에 동족 TMPRSS 유전자의 뉴클레오티드 서열을 함유하는 게놈 단편을 삽입하여 (본원에 기술된 것들과 같은) 인간화 Tmprss 유전자를 형성하는 단계; (b) (a) 단계의 인간화 Tmprss 유전자를 포함하는 설치류 배아 줄기 세포를 수득하는 단계; 및 (c) (b) 단계의 설치류 배아 줄기 세포를 이용하여 설치류를 생성하는 단계를 포함하는 방법을 제공한다.
일부 구현예에서, 인간화 Tmprss 유전자는 인간화 Tmprss2 유전자, 인간화 Tmprss4 유전자, 및 인간화 Tmprss11d 유전자로 이루어지는 군으로부터 선택된다. 다양한 구현예에서, 인간화 Tmprss 유전자는 인간화에 사용된 인간 TMPRSS 유전자에 의해 암호화된 인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한 (예: 서열이 적어도 90%, 95%, 98%, 99% 또는 100% 동일한) 세포외 도메인을 함유하는 인간화 Tmprss 단백질을 암호화한다. 특정 구현예에서, 인간화 Tmprss 단백질은 인간 TMPRSS2 단밸질, 인간 TMPRSS4 단백질, 및 인간 TMPRSS11D 단백질로 이루어지는 군으로부터 선택된 인간 TMPRSS 단백질의 세포외 도메인을 함유한다. 특정 구현예에서, 인간화 Tmprss 단백질은 인간화되는 내인성 설치류 Tmprss 유전자에 의해 암호화된 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 함유한다.
또 다른 양태에서, 본 발명은 인플루엔자 바이러스 감염에 있어서 화합물(예: 인간 TMPRSS 단백질을 특이적으로 표적화하는 후보 억제제)의 치료 효능을 평가하기 위해 본원에 기술된 설치류를 사용하는 방법을 제공한다. 상기 방법은, 본원에 기술된 설치류를 제공하는 단계; 설치류에 인플루엔자 바이러스와 후보 화합물을 투여하는 단계; 및 설치류에서 인플루엔자 바이러스 감염의 존재 및 중증도를 모니터링하여 후보 약물의 치료 효능을 알아내는 단계를 포함할 수 있다.
일부 구현예에서, 인플루엔자 바이러스는 화합물 이전에 설치류에 투여된다. 일부 구현예에서, 인플루엔자 바이러스는 화합물 이후에 설치류에 투여된다.
일부 구현예에서, 후보 화합물은 인간 TMPRSS 단백질에 대해 특이적인 항체 또는 이의 항원 결합 단편이다. 특정 구현예에서, 후보 화합물은 인간 TMPRSS2 단백질, 인간 TMPRSS4 단백질, 및 인간 TMPRSS11D 단백질로 이루어지는 군으로부터 선택된 인간 TMPRSS 단백질에 대해 특이적인 항체 또는 이의 항원 결합 단편이다.
본 발명의 다른 특징, 목적 및 장점은 다음의 상세한 설명에서 명백해진다. 그러나, 상세한 설명은 본 발명의 특정한 구현예를 나타내지만, 단지 예시로서 제공될 뿐 제한하고자 함이 아닌 것으로 이해해야 한다. 본 발명의 범주 내 다양한 변형예들 및 수정예들이 상세한 설명으로부터 당업자에게 명백해질 것이다.
다음의 도면들로 구성된 본원에 포함된 도면은 단지 예시적인 목적이며 제한하고자 하는 것이 아니다.
도 1a 내지 1d. 마우스 Tmprss2의 인간화를 위한 예시적 전략
도 1a는 마우스 Tmprss2 및 인간 TMPRSS2 유전자의 게놈 조직의 도면을 도시하며, 축척에 비례하지는 않는다. 엑손은 게놈 서열 전체에 걸쳐 삽입된 가는 막대로 표시되며, 두 가지 유전자 모두에 대한 첫 번째 코딩 엑손은 엑손 위에 시작 코돈 "ATG"로 표시되고, 마지막 코딩 엑손은 엑손 위에 "정지" 코돈으로 표시되어 있다. 결실할 약 25,291 bp의 마우스 게놈 단편과 삽입할 약 25,091 bp의 인간 게놈 단편이 표시되어 있다. 실시예 1에 기재된 검정에 사용된 프로브의 위치가 표시되어 있다. TM: 막관통 도메인; SRCR: 스캐빈저 수용체 시스테인-리치 유사 도메인; LDLRa: 저밀도 리포단백질 수용체 클래스 A.
도 1b는 내인성 마우스 Tmprss2 유전자의 인간화를 위한 예시적인 변형된 BAC 벡터를 접합 서열(서열 번호 22, 23 및 24)과 함께 도시하며, 축척에 비례하지는 않는다.
도 1c는 네오마이신 카세트가 결실된 후의 인간화 Tmprss2 대립유전자를 접합 서열(서열 번호 22 및 25)과 함께 도시하며, 축척에 비례하지는 않는다.
도 1d는 인간 TMPRSS2 단백질(서열 번호 4), 마우스 Tmprss2 단백질(서열 번호 2), 및 인간화 Tmprss2 단백질("7010 돌연변이 단백질")(서열 번호 7)의 서열 배열을 제시한다.
도 2a 내지 2d 마우스 Tmprss4의 인간화를 위한 예시적 전략
도 2a는 마우스 Tmprss4 및 인간 TMPRSS4 유전자의 게놈 조직의 도면을 도시하며, 축척에 비례하지는 않는다. 엑손은 게놈 서열 전체에 걸쳐 삽입된 가는 막대로 표시되며, 두 가지 유전자 모두에 대한 첫 번째 엑손(및 첫 번째 코딩 엑손)은 엑손 위에 시작 코돈 "ATG"로 표시되고, 마지막 코딩 엑손은 엑손 위에 "정지" 코돈으로 표시되어 있다. 결실할 약 11,074 bp의 마우스 게놈 단편과 삽입할 약 14,963 bp의 인간 게놈 단편이 표시되어 있다. 실시예 2에 기재된 검정에 사용된 프로브의 위치가 표시되어 있다. TM: 막관통 도메인; SRCR: 스캐빈저 수용체 시스테인-리치 유사 도메인; LDLRa: 저밀도 리포단백질 수용체 클래스 A.
도 2b는 내인성 마우스 Tmprss4 유전자의 인간화를 위한 예시적인 변형된 BAC 벡터를 접합 서열(서열 번호 38, 39 및 40)과 함께 도시하며, 축척에 비례하지는 않는다.
도 2c는 네오마이신 카세트가 결실된 후의 인간화 Tmprss4 대립유전자를 접합 서열(서열 번호 41 및 40)과 함께 도시하며, 축척에 비례하지는 않는다.
도 2d는 인간 TMPRSS4 단백질(서열 번호 11), 마우스 Tmprss4 단백질(서열 번호 9), 및 인간화 Tmprss4 단백질("7224 돌연변이 단백질")(서열 번호 14)의 서열 배열을 제시한다.
도 3a 내지 3d 마우스 Tmprss11d의 인간화를 위한 예시적 전략
도 3a는 마우스 Tmprss11d 및 인간 TMPRSS11D 유전자의 게놈 조직의 도면을 도시하며, 축척에 비례하지는 않는다. 엑손은 게놈 서열 전체에 걸쳐 삽입된 가는 막대로 표시되며, 두 가지 유전자 모두에 대한 첫 번째 엑손(및 첫 번째 코돈 엑손)은 엑손 위에 시작 코돈 "ATG"로 표시되고, 마지막 코딩 엑손은 엑손 위에 "정지" 코돈으로 표시되어 있다. 결실할 약 35,667 bp의 마우스 게놈 단편과 삽입할 약 33,927 bp의 인간 게놈 단편이 표시되어 있다. 실시예 3에 기재된 검정에 사용된 프로브의 위치가 표시되어 있다. TM: 막관통 도메인; SEA: 성게 정자 단백질, 엔테로키나아제(enterokinase) 및 아그린(agrin)에서 발견된 도메인.
도 3b는 내인성 마우스 Tmprss11d 유전자의 인간화를 위한 예시적인 변형된 BAC 벡터를 접합 서열(서열 번호 57, 58 및 59)과 함께 도시하며, 축척에 비례하지는 않는다.
도 3c는 네오마이신 카세트가 결실된 후의 인간화 Tmprss11 대립유전자를 접합 서열(서열 번호 57 및 60)과 함께 도시하며, 축척에 비례하지는 않는다.
도 3d는 인간 TMPRSS11D 단백질(서열 번호 18), 마우스 Tmprss11d 단백질(서열 번호 16), 및 인간화 Tmprss11d 단백질("7226 돌연변이 단백질")(서열 번호 21)의 서열 배열을 제시한다.
도 4는, MAID7225 HumInTMPRSS4 마우스가 고 용량의 중증 인플루엔자 A H1N1이나 중증 마우스 적응형 H3N2의 투여에 대해 민감성에 있어 차이가 없음을 나타내는 실험 결과를 도시한다. A/Puerto Rico/08/1934(H1N1)(연회색 원, 점선)를 투여한 MAID7225 HumIn TMRPSS4 마우스는 야생형 마우스(연회색 사각형, 점선)와 비교하여 유사한 생존율을 보였다. 마찬가지로, A/Aichi/02/1968-X31(H3N2)(진회색 삼각형, 점선)을 투여한 MAID7225 HumIn TMRPSS4 마우스는 야생형 마우스(연회색 역삼각형, 파선)와 비교하여 유사한 생존율을 보였다. 0일 차에 1150 PFU의 A/Puerto Rico/08/1934(H1N1) 또는 10,000 PFU의 A/Aichi/02/1968-X31(H3N2)로 감염시켰다. 감염되지 않는 음성 대조 MAID7225 HumIn TMPRSS4 및 야생형 마우스(검은 다이아몬드, 실선)를 대조군에 포함시켰다.
도 1a 내지 1d. 마우스 Tmprss2의 인간화를 위한 예시적 전략
도 1a는 마우스 Tmprss2 및 인간 TMPRSS2 유전자의 게놈 조직의 도면을 도시하며, 축척에 비례하지는 않는다. 엑손은 게놈 서열 전체에 걸쳐 삽입된 가는 막대로 표시되며, 두 가지 유전자 모두에 대한 첫 번째 코딩 엑손은 엑손 위에 시작 코돈 "ATG"로 표시되고, 마지막 코딩 엑손은 엑손 위에 "정지" 코돈으로 표시되어 있다. 결실할 약 25,291 bp의 마우스 게놈 단편과 삽입할 약 25,091 bp의 인간 게놈 단편이 표시되어 있다. 실시예 1에 기재된 검정에 사용된 프로브의 위치가 표시되어 있다. TM: 막관통 도메인; SRCR: 스캐빈저 수용체 시스테인-리치 유사 도메인; LDLRa: 저밀도 리포단백질 수용체 클래스 A.
도 1b는 내인성 마우스 Tmprss2 유전자의 인간화를 위한 예시적인 변형된 BAC 벡터를 접합 서열(서열 번호 22, 23 및 24)과 함께 도시하며, 축척에 비례하지는 않는다.
도 1c는 네오마이신 카세트가 결실된 후의 인간화 Tmprss2 대립유전자를 접합 서열(서열 번호 22 및 25)과 함께 도시하며, 축척에 비례하지는 않는다.
도 1d는 인간 TMPRSS2 단백질(서열 번호 4), 마우스 Tmprss2 단백질(서열 번호 2), 및 인간화 Tmprss2 단백질("7010 돌연변이 단백질")(서열 번호 7)의 서열 배열을 제시한다.
도 2a 내지 2d 마우스 Tmprss4의 인간화를 위한 예시적 전략
도 2a는 마우스 Tmprss4 및 인간 TMPRSS4 유전자의 게놈 조직의 도면을 도시하며, 축척에 비례하지는 않는다. 엑손은 게놈 서열 전체에 걸쳐 삽입된 가는 막대로 표시되며, 두 가지 유전자 모두에 대한 첫 번째 엑손(및 첫 번째 코딩 엑손)은 엑손 위에 시작 코돈 "ATG"로 표시되고, 마지막 코딩 엑손은 엑손 위에 "정지" 코돈으로 표시되어 있다. 결실할 약 11,074 bp의 마우스 게놈 단편과 삽입할 약 14,963 bp의 인간 게놈 단편이 표시되어 있다. 실시예 2에 기재된 검정에 사용된 프로브의 위치가 표시되어 있다. TM: 막관통 도메인; SRCR: 스캐빈저 수용체 시스테인-리치 유사 도메인; LDLRa: 저밀도 리포단백질 수용체 클래스 A.
도 2b는 내인성 마우스 Tmprss4 유전자의 인간화를 위한 예시적인 변형된 BAC 벡터를 접합 서열(서열 번호 38, 39 및 40)과 함께 도시하며, 축척에 비례하지는 않는다.
도 2c는 네오마이신 카세트가 결실된 후의 인간화 Tmprss4 대립유전자를 접합 서열(서열 번호 41 및 40)과 함께 도시하며, 축척에 비례하지는 않는다.
도 2d는 인간 TMPRSS4 단백질(서열 번호 11), 마우스 Tmprss4 단백질(서열 번호 9), 및 인간화 Tmprss4 단백질("7224 돌연변이 단백질")(서열 번호 14)의 서열 배열을 제시한다.
도 3a 내지 3d 마우스 Tmprss11d의 인간화를 위한 예시적 전략
도 3a는 마우스 Tmprss11d 및 인간 TMPRSS11D 유전자의 게놈 조직의 도면을 도시하며, 축척에 비례하지는 않는다. 엑손은 게놈 서열 전체에 걸쳐 삽입된 가는 막대로 표시되며, 두 가지 유전자 모두에 대한 첫 번째 엑손(및 첫 번째 코돈 엑손)은 엑손 위에 시작 코돈 "ATG"로 표시되고, 마지막 코딩 엑손은 엑손 위에 "정지" 코돈으로 표시되어 있다. 결실할 약 35,667 bp의 마우스 게놈 단편과 삽입할 약 33,927 bp의 인간 게놈 단편이 표시되어 있다. 실시예 3에 기재된 검정에 사용된 프로브의 위치가 표시되어 있다. TM: 막관통 도메인; SEA: 성게 정자 단백질, 엔테로키나아제(enterokinase) 및 아그린(agrin)에서 발견된 도메인.
도 3b는 내인성 마우스 Tmprss11d 유전자의 인간화를 위한 예시적인 변형된 BAC 벡터를 접합 서열(서열 번호 57, 58 및 59)과 함께 도시하며, 축척에 비례하지는 않는다.
도 3c는 네오마이신 카세트가 결실된 후의 인간화 Tmprss11 대립유전자를 접합 서열(서열 번호 57 및 60)과 함께 도시하며, 축척에 비례하지는 않는다.
도 3d는 인간 TMPRSS11D 단백질(서열 번호 18), 마우스 Tmprss11d 단백질(서열 번호 16), 및 인간화 Tmprss11d 단백질("7226 돌연변이 단백질")(서열 번호 21)의 서열 배열을 제시한다.
도 4는, MAID7225 HumInTMPRSS4 마우스가 고 용량의 중증 인플루엔자 A H1N1이나 중증 마우스 적응형 H3N2의 투여에 대해 민감성에 있어 차이가 없음을 나타내는 실험 결과를 도시한다. A/Puerto Rico/08/1934(H1N1)(연회색 원, 점선)를 투여한 MAID7225 HumIn TMRPSS4 마우스는 야생형 마우스(연회색 사각형, 점선)와 비교하여 유사한 생존율을 보였다. 마찬가지로, A/Aichi/02/1968-X31(H3N2)(진회색 삼각형, 점선)을 투여한 MAID7225 HumIn TMRPSS4 마우스는 야생형 마우스(연회색 역삼각형, 파선)와 비교하여 유사한 생존율을 보였다. 0일 차에 1150 PFU의 A/Puerto Rico/08/1934(H1N1) 또는 10,000 PFU의 A/Aichi/02/1968-X31(H3N2)로 감염시켰다. 감염되지 않는 음성 대조 MAID7225 HumIn TMPRSS4 및 야생형 마우스(검은 다이아몬드, 실선)를 대조군에 포함시켰다.
본 발명은 II 형 막관통 세린 프로테아제(또는 transmembrane protease/serine을 지칭하는 "Tmprss")를 암호화하는 인간화 유전자를 갖는 유전자 변형된 설치류(예: 마우스 및 랫트)에 관한 것이다. 유전자 변형된 설치류는, 인플루엔자 바이러스 감염과 같은 질병의 치료 및 예방을 위해 인간 TMPRSS 분자를 특이적으로 표적화하는 후보 화합물에 대한 스크리닝에 사용하기에 적합하다. 따라서, 본 발명은 인간화 Tmprss 유전자를 갖는 유전자 변형된 설치류, 유전자 변형된 설치류로부터 단리된 세포 및 조직, 유전자 변형된 설치류를 만드는 방법 및 조성물, 및 치료 화합물의 스크리닝 및 시험을 위한 유전자 변형된 설치류의 용도를 제공한다. 본 발명의 다양한 구현예가 아래에 더 기술된다.
II 형 막관통 세린 프로테아제("Tmprss")
비인간 분자의 경우 "Tmprss"로 지칭되고 인간 분자의 경우 "TMPRSS"("transmembrane protease/serine")로도 본원에서 지칭되는 II 형 막관통 세린 프로테아제는 N 말단 막관통 도메인 및 C 말단 세포외 세린 프로테아제 도메인을 특징으로 하는 단백질 집단이다. 상기 집단에서 적어도 18개의 구성원을 식별하였는데, 이들은 4개의 하위 집단으로 그룹화된다(전술한 Bugge 외의 (2009) 내용 참조). 모든 구성원은 (i) 짧은 N 말단 세포질 도메인, (ii) 막관통 도메인, 및 (iii) 프로테아제 도메인 및 막관통 도메인을 프로테아제 도메인과 연결시키는 줄기 영역을 함유하는 세포외 도메인 등을 포함하여, 집단을 정의하는 몇 개의 공통적인 구조적 특징을 공유한다. 줄기 영역은 다음의 6가지 상이한 유형의 모듈 구조 도메인의 조합을 함유한다: SEA (sea urchin sperm protein/enteropeptidase/agrin) 도메인, 그룹 A 스캐빈저 수용체 도메인 (group A scavenger receptor domain), LDLA (low-density lipoprotein receptor class A) 도메인, CUB (Cls/Clr urchin embryonic growth factor, bone morphogenetic protein-1) 도메인, MAM (meprin/A5 antigen/receptor protein phosphatase mu) 도메인, 및 프리즐 도메인(frizzled domain). Bugge 외의 전술한 (2009) 리뷰 참조. 예를 들어, 둘 다 헵신(hepsin)/TMPRSS 하위 집단에 속하는 TMPRSS2 및 TMPRSS4는 줄기 영역에서 단일 LDLA 도메인이 선행하는 그룹 A 스캐빈저 수용체 도메인을 갖는다. HAT/DESC 하위 집단에 속하고 human airway trypsin-like protease를 지칭하는 "HAT"로도 알려진 TMPRSS11D는 단일 SEA 도메인을 갖는다. 전술한 Bugge 외의 (2009)의 도 1 참조.
II 형 막관통 세린 프로테아제는 초기에 비활성 효소 전구체로서 생성되는데, 이는 프로테아제 도메인 전의 컨센서스 활성화 모티프에서 염기성 아미노산 잔기를 따르는 절단에 의한 활성화를 필요로한다. 활성화된 프로테아제의 일부는 프로도메인(prodomain)과 프로테아제 도메인 사이에서의 이황화 결합의 결과로서 막 결합을 유지한다. 세포외 도메인은 세포 국지화, 활성화, 억제 및/또는 이들 프로테아제의 기질 특이성에 대해 중요한 것으로 여겨진다(전술한 Bugge 외의 (2009); Szabo 외의 Int. J. Biochem. Cell Biol. 40: 1297-1316 (2008) 참조).
II 형 막관통 세린 프로테아제의 구성원에 대한 다양한 생화학적 및 병태생리학적 정보가 문서화되었다. TMPRSS2, TMPRSS4 및 TMPRSS11D는 바이러스 생명 주기의 제1 필수 단계인 인플루엔자 A 혈구 응집소(hemagglutinin; HA)를 시험관 내에서 절단하는 것으로 나타났다. 본원에 기술된 인간화 Tmprss 유전자를 갖는 유전자 변형된 설치류 동물은 TMPRSS 분자의 생물학적 기능에 대한 철저한 이해는 물론이고 인간 TMPRSS 분자를 특이적으로 표적화하는 치료 화합물의 스크리닝을 가능하게 하는 유용한 생체 내 시스템을 제공한다.
마우스, 인간 및 인간화 Tmprss 핵산 및 단백질 서열을 포함하는 예시적인 Tmprss 서열이 본 출원에 제공되며 다음의 표에 요약되어 있다. 실시예 섹션에서의 분석에 사용된 프라이머와 프로브 서열 및 예시적인 인간화 Tmprss 대립유전자의 삽입 접합 서열 또한 표에 포함된다.
서열의 요약 설명
인간화 Tmprss 설치류 동물
일 양태에서, 본 발명은 인간화 Tmprss 단백질을 암호화하는 인간화 Tmprss 유전자를 생식계열에 함유하는 설치류 동물을 제공한다.
"인간화"라는 용어가 핵산 또는 단백질의 맥락에서 사용될 때, 이는 자연에서 설치류 동물에서 발견되는 특정한 유전자 또는 단백질의 구조와 실질적으로 또는 동일하게 상응하는 부분을 포함하는 구조(즉, 뉴클레오티드 또는 아미노산 서열)를 가진 핵산 또는 단백질을 포함하고, 관련된 설치류 유전자 또는 단백질에서 발견되는 것과 상이한 대신에 상응하는 인간 유전자 또는 단백질에서 발견되는 구조와 밀접하게 또는 동일하게 상응하는 부분도 포함한다. 인간화 유전자를 함유하거나 인간화 단백질을 발현하는 설치류는 "인간화" 설치류이다.
일부 구현예에서, 본 발명의 설치류는 마우스, 랫트, 및 햄스터로부터 선택된다. 일부 구현예에서, 본 발명의 설치류는 쥐상목 상과(superfamily Muroidea)로부터 선택된다. 일부 구현예에서, 본 발명의 유전자 변형된 설치류는 칼로미스쿠스과(Calomyscidae)(예를 들어, 마우스 유사 햄스터), 비단털쥐과(Cricetidae)(예를 들어, 햄스터, 미국 랫트 및 마우스, 들쥐), 쥐과(Muridae(트루 마우스 및 랫트, 게르빌루스쥐, 아프리카가시쥐, 크레스티드 랫트), 네소미스과(Nesomyidae)(클라이밍 마우스, 락 마우스(rock mice), 흰꼬리 랫트, 말라가시 랫트 및 마우스), 가시겨울잠쥐과(Platacanthomyidae)(예를 들어, 가시겨울잠쥐), 및 소경쥐과(Spalacidae)(예를 들어, 두더쥐쥐, 대나무쥐, 및 동북)로부터 선택되는 과로부터 유래한다. 일부 특정 구현예에서, 본 발명의 유전자 변형된 설치류는 트루 마우스 또는 랫트(패밀리 쥐과), 게르빌루스쥐, 아프리카가시쥐, 크레스티드 랫트로부터 선택된다. 일부 특정 구현예에서, 본 발명의 유전자 변형된 마우스는 쥐과(family Muridae)의 구성원으로부터 선택된다.
일부 구현예에서, 본원에 기술된 설치류는 내인성 설치류 Tmprss 유전자의 뉴클레오티드 및 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하는 게놈 내에 인간화 Tmprss 유전자를 함유하되, 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 인간 TMPRSS 유전자의 뉴클레오티드 서열은 인간화 Tmprss 유전자가 Tmprss 단백질을 암호화하고, 프로모터 및/또는 증강자(들)와 같은 내인성 설치류 Tmprss 유전자의 5' 조절 요소(들)에 의해 조절되도록 서로 작동 가능하게 연결된다.
본 발명은 특히 대등한 (like-for-like) 인간화에 관한 것인데, 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열이 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열에 작동 가능하게 연결되어 인간화 유전자를 형성한다. 예를 들어, 일부 구현예에서, 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열은 인간 TMPRSS2 유전자의 뉴클레오티드 서열에 작동 가능하게 연결되어 인간화 Tmprss2 유전자를 형성한다. 다른 구현예에서, 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열은 인간 TMPRSS4 유전자의 뉴클레오티드 서열에 작동 가능하게 연결되어 인간화 Tmprss4 유전자를 형성한다. 또 다른 구현예에서, 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열은 인간 TMPRSS11D 유전자의 뉴클레오티드 서열에 작동 가능하게 연결되어 인간화 Tmprss11d 유전자를 형성한다.
일부 구현예에서, 본 발명의 유전자 변형된 설치류는 그의 게놈에 인간화 Tmprss 유전자를 함유하되, 인간화 Tmprss 유전자는 인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 함유하는 인간화 Tmprss 단백질을 암호화한다. 용어 "세포외 도메인(ectodomain)"은 세포막의 외부로 연장되는 막관통 단백질의 부분, 즉 막관통 단백질의 세포외 부분을 지칭한다. TMPRSS 분자의 세포외 도메인은 프로테아제 도메인 및 막관통 도메인을 프로테아제 도메인과 연결시키는 줄기 영역을 포함한다. 세포외 도메인 또는 "인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한" 폴리펩티드라는 말은, 일부 구현예에서 인간 TMPRSS 단백질의 세포외 도메인과 서열이 적어도 85%, 90%, 95%, 95%, 99% 또는 100% 동일한 폴리펩티드; 일부 구현예에서, 10, 9, 8, 7, 6, 5, 4, 3, 2 또는 1개 이하의 아미노산(들)만큼 인간 TMPRSS 단백질의 세포외 도메인과 상이한 폴리펩티드; 일부 구현예에서, 예를 들어 세포외 도메인의 N 말단 또는 C 말단에서 아미노산을 결여하거나 추가적인 아미노산을 가짐으로써 세포외 도메인의 N 말단 또는 C 말단에서 인간 TMPRSS 단백질의 세포외 도메인과 상이한 폴리펩티드; 및 일부 구현예에서, 인간 TMPRSS 단백질의 실질적으로 세포외 도메인인 폴리펩티드를 의미한다. 인간 TMPRSS 단백질의 "실질적으로 세포외 도메인"이라는 말은, 세포외 도메인과 동일하거나, N 말단 또는 C 말단에서 1~5개(즉, 1, 2, 3, 4, 또는 5개)의 아미노산의 결여하거나 추가적인 1~5개의 아미노산을 가짐으로써 세포외 도메인과 상이한 폴리펩티드를 의미한다.
일부 구현예에서, 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 함유하는 인간화 Tmprss 단백질을 암호화한다. 세포질 및 막관통 부분 또는 "내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한" 폴리펩티드라는 말은, 일부 구현예에서, 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 서열이 적어도 85%, 90%, 95%, 95%, 99% 또는 100% 동일한 폴리펩티드; 일부 구현예에서, 10, 9, 8, 7, 6, 5, 4, 3, 2 또는 1개 이하의 아미노산(들)만큼 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 상이한 폴리펩티드; 일부 구현예에서, 막관통 도메인의 C 말단에서 아미노산을 결여하거나 추가적인 아미노산을 가짐으로써 C 말단에서만 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 상이한 폴리펩티드; 및 일부 구현예에서, 내인성 설치류 Tmprss 단백질의 세포질 도메인 및 실질적으로 막관통 도메인으로 이루어진 폴리펩티드를 의미한다. 내인성 설치류 Tmprss 단백질의 "실질적으로 막관통 도메인"이라는 말은, 막관통 도메인과 동일하거나, C 말단에서 1~5개의 아미노산을 결여하거나 추가적인 1~5개의 아미노산을 가짐으로써 막관통 도메인과 상이한 폴리펩티드를 의미한다.
일부 구현예에서, 유전자 변형된 설치류에서의 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하되, 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열은 인간 TMPRSS 유전자에 의해 암호화된 인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한 폴리펩티드를 암호화한다. 특정 구현예에서, 인간화 Tmprss 유전자에서의 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열은 인간 TMPRSS 유전자에 의해 암호화된 인간 TMPRSS 단백질의 세포외 도메인을 암호화한다.
일부 구현예에서, 유전자 변형된 설치류의 게놈 내의 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하되, 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열은 설치류 Tmprss 유전자에 의해 암호화된 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 폴리펩티드를 암호화한다. 특정 구현예에서, 인간화 Tmprss 유전자 내에 존재하는 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss 유전자에 의해 암호화된 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 도메인을 암호화한다.
일부 구현예에서, 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 유전자좌에서 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열을 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열과 대체함으로써 생성된다.
일부 구현예에서, 내인성 설치류 Tmprss 유전자좌에서의 설치류 Tmprss 유전자의 인접 게놈 서열은 인간화 Tmprss 유전자를 형성하기 위해 동족 인간 TMPRSS 유전자의 인접 게놈 서열과 대체되었다.
특정 구현예에서, 내인성 설치류 Tmprss 유전자에 삽입된 인간 TMPRSS 유전자의 인접 게놈 서열은 인간 TMPRSS 유전자에 의해 암호화된 인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는 인간 TMPRSS 유전자의 엑손을 전체적으로 또는 부분적으로 포함한다.
특정 구현예에서, 인간화 대체 이후 내인성 설치류 Tmprss 유전자좌에 남아있고 삽입된 인접 인간 TMPRSS 게놈 서열에 작동 가능하게 연결된 내인성 설치류 Tmprss 유전자의 게놈 서열은 내인성 설치류 Tmprss 유전자에 의해 암호화된 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화한다.
내인성 Tmprss 단백질 및 인간 TMPRSS 단백질이 막관통 도메인과 세포외 도메인 사이의 접합부 근처에서 공통 아미노산을 공유하는 상황에서, 인간 TMPRSS 단백질의 세포외 도메인을 정교하게 암호화하는 인간 TMPRSS 게놈 서열을 삽입하는 것은 필요하지 않을 수 있다. 생성된 인간화 Tmprss 유전자에 의해 암호화된 인간화 Tmprss 단백질이 인간 TMPRSS 단백질의 세포외 도메인과 동일한 세포외 도메인 및 내인성 설치류 Tmprss 단백질의 막관통 도메인과 동일한 막관통 도메인을 포함하도록, 내인성 설치류 Tmprss 단백질의 세포질 도메인과 실질적으로 막관통 도메인을 암호화하는 내인성 설치류 Tmprss 유전자의 게놈 서열에 작동 가능하게 연결된 인간 TMPRSS 단백질의 실질적으로 세포외 도메인을 암호화하는 인간 TMPRSS 유전자의 약간 길거나 짧은 게놈 서열을 삽입하는 것이 가능하다.
일부 구현예에서, 인간화 Tmprss 유전자에 포함된 인간 TMPRSS 유전자의 뉴클레오티드 서열은 인간 TMPRSS 유전자의 3' 미번역 영역("UTR")을 또한 포함한다. 특정 구현예에서, 인간화 Tmprss 유전자는 또한, 인간 TMPRSS 유전자의 3' UTR에 추가하여 인간 TMPRSS 유전자좌로부터 추가적인 인간 게놈 서열을 인간 TMPRSS 3' UTR 다음에 포함한다. 추가적인 인간 게놈 서열은 인간 TMPRSS 유전자의 3' UTR의 바로 하류의 인간 TMPRSS 유전자좌에서 발견되는 적어도 10~200 bp, 예컨대 50 bp, 75 bp, 100 bp, 125 bp, 150 bp, 175 bp, 200 bp 또는 그 이상으로 이루어질 수 있다. 다른 구현예에서, 인간화 Tmprss 유전자 내에 존재하는 인간 TMPRSS 유전자의 뉴클레오티드 서열은 인간 3' UTR을 포함하지 않고; 대신에, 내인성 설치류 Tmprss 유전자의 3' UTR이 포함되고 인간화 Tmprss 유전자의 정지 코돈의 바로 뒤에 위치한다. 예를 들어, 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 도메인을 암호화하는 엑손 서열을 함유하는 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열을 포함할 수 있는데, 인간 TMPRSS 단백질의 세포외 도메인 내지 정지 코돈을 암호화하는 엑손을 함유하는 인간 TMPRSS 유전자의 뉴클레오티드 서열이 이를 따르고, 내인성 설치류 Tmprss 유전자의 3' UTR은 정지 코돈의 바로 뒤에 위치한다.
일부 구현예에서, 인간화 Tmprss 유전자는 설치류 내에서 암호화된 인간화 Tmprss 단백질을 발현시킨다. 일부 구현예에서, 인간화 Tmprss 단백질은 대조군 설치류(예: 인간화 Tmprss 유전자가 없는 설치류)에서의 대응 설치류 Tmprss 단백질과 필적하거나 실질적으로 동일한 패턴으로 발현된다. 일부 구현예에서, 인간화 Tmprss 단백질은 대조군 설치류(예: 인간화 Tmprss 유전자가 없는 설치류)에서의 대응 설치류 Tmprss 단백질과 필적하거나 실질적으로 동일한 레벨로 발현된다. 특정 구현예에서, 인간화 Tmprss 단백질은 세포 표면에서 발현되고 검출된다. 특정 구현예에서, 인간화 Tmprss 단백질 또는 가용성 형태(예: 제거된 세포외 도메인 형태)는 설치류의 혈청에서, 예컨대 대조군 설치류에서의 대응 설치류 Tmprss 단백질 또는 이의 가용성 형태에 필적하거나 실질적으로 동일한 레벨로 발현되고 검출된다. 인간화 설치류에서의 인간화 유전자 또는 단백질을 대조군 설치류의 내인성 설치류 유전자 또는 단백질과 비교하는 맥락에서, 용어 "필적하는(comparable)"은 비교되는 분자 또는 레벨이 서로 동일하지 않을 수 있지만, 관찰된 차이점 또는 유사성에 기초하여 결론이 합리적으로 도출될 수 있도록 이들 사이의 비교를 허용하기에 충분히 유사함을 의미하며; 발현 레벨을 지칭할 때의 용어 "실질적으로 동일한(substantially the same)"은 비교되는 레벨이 서로 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 또는 1%보다 더 크게 상이하지 않음을 의미한다.
일부 구현예에서, 본 발명은 본원에 기술된 비인간 바와 같은 설치류 동물로부터 단리된 세포 또는 조직을 제공한다. 일부 구현예에서, 세포는 수상세포, 림프구(예컨대, B 또는 T 세포), 대식세포 및 단핵구로부터 선택된다. 일부 구현예에서, 조직은 지방, 방광, 뇌, 가슴, 골수, 눈, 심장, 장, 신장, 간, 폐, 림프절, 근육, 췌장, 혈장, 혈청, 피부, 비장, 위, 흉선, 고환, 난자, 및 이의 조합으로부터 선택된다.
일부 구현예에서, 본 발명은 본원에 기술된 바와 같은 인간화 Tmprss 유전자를 함유하는 게놈을 가진 설치류 배아 줄기 세포를 제공한다. 일부 구현예에서, 설치류 배아 줄기 세포는 마우스 배아 줄기 세포이다. 일부 구현예에서, 설치류 배아 줄기 세포는 랫트 배아 줄기 세포이다. 인간화 Tmprss 유전자를 게놈에 함유하는 설치류 배아 줄기 세포는 아래에 후술하는 바와 같이 인간화 설치류를 만드는 데 사용될 수 있다.
일부 구현예에서, 본원에서 제공된 설치류는 그의 게놈 내의 인간화 Tmprss 유전자에 대해 이형접합체이다. 다른 구현예에서, 본원에서 제공된 설치류는 그의 게놈 내의 인간화 Tmprss 유전자에 대해 동형접합체이다.
특정 구현예에서, 설치류는 그의 게놈 내에 다수의, 즉 둘 이상의 인간화 Tmprss 유전자를 포함한다. 즉, 설치류 내의 둘 이상의 상이한 내인성 Tmprss 유전자좌가 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 사용하여 인간화되었다. 예를 들어, 설치류가 다음으로부터 선택된 둘 이상의 유전자좌에서 인간화되었다: Tmprss2, Tmprss4, 및 Tmprss11d.
(마우스와 같은) 예시적인 인간화 Tmprss2 설치류, (마우스와 같은) 인간화 Tmprss4 설치류, 및 (마우스와 같은) 인간화 Tmprss11d 설치류가 아래에 더 기술된다.
인간화 Tmprss2 설치류
일부 구현예에서, 본 발명은 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열 및 인간 TMPRSS2 유전자의 뉴클레오티드 서열을 포함하고, 프로모터 및/또는 증강자(들)과 같은 내인성 설치류 Tmprss2 유전자의 5' 조절 요소(들)에 의해 조절되는 인간화 Tmprss2 유전자를 함유하는 게놈을 가진 설치류를 제공한다. 예시적인 설치류는 마우스와 랫트를 포함한다.
일부 구현예에서, 인간화 Tmprss2 유전자는 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 함유하는 인간화 Tmprss2 단백질을 암호화한다.
특정 구현예에서, 인간 TMPRSS2 단백질은 서열 번호 4에 명시된 바와 같은 아미노산 서열과 적어도 85%, 90%, 95%, 98%, 99% 또는 100%의 동일성을 갖는 아미노산 서열을 갖는다.
일부 구현예에서, 인간화 Tmprss2 단백질은 인간 TMPRSS2 단백질의 C 말단 387 아미노산, 예를 들어, 인간 TMPRSS2 단백질의 아미노산 106 내지 492를 함유한다. 일부 구현예에서, 인간화 Tmprss2 단백질은 서열 번호 4의 W106 내지 G492로 이루어진 아미노산 서열과 실질적으로 동일한 세포외 도메인을 함유한다. 특정 구현예에서, 인간화 Tmprss2 단백질은, 서열 번호 4의 W106 내지 G492로 이루어진 아미노산 서열과 적어도 85%, 90%, 95%, 98%, 99% 또는 100%의 동일성을 갖는 세포외 도메인; 서열 번호 4의 W106 내지 G492로 이루어진 아미노산 서열과 10, 9, 8, 7, 6, 5, 4, 3, 2 또는 1개 이하의 아미노산(들)만큼 상이한 세포외 도메인; 또는, 예를 들어, N 말단 또는 C 말단에서 1~5개의 아미노산을 결여하거나 추가적인 1~5개의 아미노산을 가짐으로써 서열 번호 4의 W106 내지 G492로 이루어진 아미노산 서열과 N 말단 또는 C 말단에서만 상이한 세포외 도메인을 함유한다.
일부 구현예에서, 인간화 Tmprss2 단백질은 내인성 설치류 Tmprss2 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 함유한다. 일부 구현예에서, 인간화 Tmprss2 단백질은 내인성 설치류 Tmprss2 단백질의 막관통 도메인 및 세포질 도메인을 추가로 포함한다.
특정 구현예에서, 인간화 Tmprss2 단백질은 내인성 설치류 Tmprss2 단백질의 막관통 도메인과 세포질 도메인, 및 인간 TMPRSS2 단백질의 세포외 도메인을 함유한다. 특정 구현예에서, 인간화 Tmprss2 유전자는 서열 번호 7에 명시된 바와 같은 아미노산 서열을 갖는 인간화 Tmprss2 단백질을 암호화한다.
일부 구현예에서, 인간화 Tmprss2 유전자는 내인성 설치류 Tmprss2 유전자좌에서 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열을 인간 TMPRSS2 유전자의 뉴클레오티드 서열과 대체함으로써 생성된다.
일부 구현예에서, 내인성 설치류 Tmprss2 유전자좌에서의 설치류 Tmprss2 유전자의 인접 게놈 서열은 인간화 Tmprss2 유전자를 형성하기 위해 인간 TMPRSS2 유전자의 인접 게놈 서열과 대체되었다.
특정 구현예에서, 내인성 설치류 Tmprss2 유전자에 삽입된 인간 TMPRSS2 유전자의 인접 게놈 서열은 인간 TMPRSS2 유전자에 의해 암호화된 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는 인간 TMPRSS2 유전자의 엑손 서열, 즉 엑손을 전체적으로 또는 부분적으로 포함한다. 내인성 Tmprss2 단백질 및 인간 TMPRSS2 단백질이 막관통 도메인 및 세포외 도메인의 접합부 근처에서 공통 아미노산을 공유하는 상황에서, 인간 TMPRSS2 단백질의 세포외 도메인을 정교하게 암호화하는 인간 TMPRSS2 게놈 서열을 삽입하는 것은 필요하지 않을 수 있고, 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 갖는 인간화 Tmprss2 단백질을 만들기 위해 인간 TMPRSS2 단백질의 실질적으로 세포외 도메인을 암호화하는 약간 길거나 짧은 인간 TMPRSS2 게놈 서열을 사용하는 것이 가능하다.
특정 구현예에서, 내인성 설치류 Tmprss2 유전자에 삽입되는 인간 TMPRSS2 유전자의 인접 게놈 서열은 인간 TMPRSS2 유전자의 적어도 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 함유한다.
특정 구현예에서, 내인성 설치류 Tmprss2 유전자에 삽입되는 인간 TMPRSS2 유전자의 인접 게놈 서열은 인간 TMPRSS2 유전자의 인트론 3 및 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 함유한다. 특정 구현예에서, 내인성 설치류 Tmprss2 유전자에 삽입되는 인간 TMPRSS2 유전자의 인접 게놈 서열은 인간 TMPRSS2 유전자의 코딩 엑손 3의 3' 부분, 인트론 3, 및 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 함유한다. 특정 구현예에서, 인간화에 포함된 인간 TMPRSS2 유전자의 코딩 엑손 3의 3' 부분은 5~10 염기쌍의 길이, 즉 코딩 엑손 3의 3' 말단의 약 5, 6, 7, 8, 9 또는 10 염기쌍의 길이이다.
일부 구현예에서, 내인성 설치류 Tmprss2 유전자에 삽입되는 인간 TMPRSS2 유전자의 인접 게놈 서열은 인간 TMPRSS2 유전자의 3' UTR을 또한 함유한다. 특정 구현예에서, 인간화를 위해 인간 TMPRSS2 유전자의 전체 코딩 엑손 13은 인간 TMPRSS2 유전자의 3' UTR을 포함하는 인접 인간 TMPRSS2 게놈 서열에 포함된다. 특정 구현예에서, 인간 TMPRSS2 유전자의 인접 게놈 서열은 인간 TMPRSS2 유전자의 3' UTR의 하류에서 추가적인 인간 게놈 서열을 포함한다. 추가적인 인간 게놈 서열은 인간 TMPRSS2 유전자좌에서 인간 TMPRSS2 유전자의 3' UTR의 바로 하류에서 발견되는 적어도 10~200 bp, 또는 적어도 10, 20, 30, 40, 50, 75, 100, 125, 150, 175, 또는 200 bp의 서열일 수 있다.
일부 구현예에서, 인간화 Tmprss2 유전자좌에 남아 있는 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss2 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화한다. 내인성 Tmprss2 단백질 및 인간 TMPRSS2 단백질이 막관통 도메인 및 세포외 도메인의 접합부 근처에서 공통 아미노산을 공유하는 상황에서, 내인성 설치류 Tmprss2 단백질의 막관통 도메인을 정교하게 암호화하는 내인성 설치류 Tmprss2 게놈 서열을 유지시키는 것은 필요하지 않을 수 있고, 내인성 설치류 Tmprss2 단백질과 동일한 막관통 도메인을 갖는 인간화 Tmprss2 단백질을 암호화하기 위해 인간화 대체에서 내인성 설치류 Tmprss2 단백질의 실질적으로 막관통 도메인을 암호화하는 약간 길거나 짧은 설치류 Tmprss2 게놈 서열을 유지시키는 것이 가능하다. 일부 구현예에서, 인간화 Tmprss2 유전자좌에 남아 있는 내인성 설치류 Tmprss2 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss2 유전자의 엑손 1~2 및 코딩 엑손 3의 5' 부분을 포함하되, 코딩 엑손 3의 5' 부분은 코돈 엑손 3의 실질적인 부분, 즉, 코딩 엑손 3의 3' 말단에서 5~10 염기쌍을 제외한 전체 코딩 엑손 3이다.
특정 구현예에서, 인간화 Tmprss2 유전자는 내인성 설치류 Tmprss2 유전자의 코딩 엑손 1 내지 2 및 코딩 엑손 3의 5' 부분, 및 인간 TMPRSS2 유전자의 코딩 엑손 3의 3' 부분 및 코딩 엑손 4 내지 코딩 엑손 13을 포함하되, 인간화 Tmprss2 유전자는 설치류 Tmprss2 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 함유하는 인간화 Tmprss2 단백질, 및 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화한다. 특정 구현예에서, 인간화 Tmprss2 유전자는 내인성 설치류 Tmprss2 유전자에 의해 암호화된 설치류 Tmprss2 단백질의 세포질 도메인 및 막관통 도메인, 및 인간 TMPRSS2 유전자에 의해 암호화된 인간 TMPRSS2 단백질의 세포외 도메인을 함유하는 인간화 Tmprss2 단백질을 암호화한다. 특정 구현예에서, 인간화 Tmprss2 유전자는 서열 번호 7에 명시된 바와 같은 아미노산 서열을 갖는 인간화 Tmprss2 단백질을 암호화한다.
일부 구현예에서, 인간화에 사용된 인간 TMPRSS2 유전자 및 설치류 Tmprss2 유전자의 엑손과 인트론은 서열 번호 1, 3 및 5 내지 6에서 발견되는 것들이다.
일부 구현예에서, 인간화 Tmprss2 유전자는 설치류에서 암호화된 인간화 Tmprss2 단백질의 발현을 초래한다. 일부 구현예에서, 인간화 Tmprss2 단백질은 대조군 설치류(예: 인간화 Tmprss2 유전자가 없는 설치류)에서의 대응 설치류 Tmprss2 단백질과 필적하거나 실질적으로 동일한 패턴으로 발현된다. 일부 구현예에서, 인간화 Tmprss2 단백질은 대조군 설치류(예: 인간화 Tmprss2 유전자가 없는 설치류)에서의 대응 설치류 Tmprss2 단백질과 필적하거나 실질적으로 동일한 레벨로 발현된다. 특정 구현예에서, 인간화 Tmprss2 단백질은 세포 표면에서 발현되고 검출된다. 특정 구현예에서, 인간화 Tmprss2 단백질 또는 가용성 형태(예: 제거된 세포외 도메인 형태)는 설치류의 혈청에서, 예컨대 대조군 설치류에서의 대응 설치류 Tmprss2 단백질 또는 이의 가용성 형태에 필적하거나 실질적으로 동일한 레벨로 발현되고 검출된다.
인간화 Tmprss4 설치류
일부 구현예에서, 본 발명은 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열 및 인간 TMPRSS4 유전자의 뉴클레오티드 서열을 포함하고, 프로모터 및/또는 증강자(들)과 같은 내인성 설치류 Tmprss4 유전자의 5' 조절 요소(들)에 의해 조절되는 인간화 Tmprss4 유전자를 함유하는 게놈을 가진 설치류를 제공한다. 예시적인 설치류는 마우스와 랫트를 포함한다.
일부 구현예에서, 인간화 Tmprss4 유전자는 인간 TMPRSS4 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 함유하는 인간화 Tmprss4 단백질을 암호화한다. 특정 구현예에서, 인간 TMPRSS4 단백질은 서열 번호 11에 명시된 바와 같은 아미노산 서열과 적어도 85%, 90%, 95%, 98%, 99% 또는 100%의 동일성을 갖는 아미노산 서열을 갖는다.
일부 구현예에서, 인간화 Tmprss4 단백질은 인간 TMPRSS4 단백질의 C 말단 384 아미노산, 예를 들어, 인간 TMPRSS4 단백질의 아미노산 54 내지 437을 함유한다. 일부 구현예에서, 인간화 Tmprss4 단백질은 서열 번호 11의 K54 내지 L437로 이루어진 아미노산 서열과 실질적으로 동일한 세포외 도메인을 함유한다. 특정 구현예에서, 인간화 Tmprss4 단백질은, 서열 번호 11의 K54 내지 L437로 이루어진 아미노산 서열과 적어도 85%, 90%, 95%, 98%, 99% 또는 100%의 동일성을 갖는 세포외 도메인; 서열 번호 11의 K54 내지 L437로 이루어진 아미노산 서열과 10, 9, 8, 7, 6, 5, 4, 3, 2 또는 1개 이하의 아미노산(들)만큼 상이한 세포외 도메인; 또는, 예를 들어, N 말단 또는 C 말단에서 1~5개의 아미노산을 결여하거나 추가적인 1~5개의 아미노산을 가짐으로써 서열 번호 11의 K54 내지 L437로 이루어진 아미노산 서열과 N 말단 또는 C 말단에서만 상이한 세포외 도메인을 함유한다.
일부 구현예에서, 인간화 Tmprss4 단백질은 내인성 설치류 Tmprss4 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 함유한다. 일부 구현예에서, 인간화 Tmprss4 단백질은 내인성 설치류 Tmprss4 단백질의 막관통 도메인 및 세포질 도메인을 추가로 포함한다.
특정 구현예에서, 인간화 Tmprss4 단백질은 내인성 설치류 Tmprss4 단백질의 막관통 도메인과 세포질 도메인, 및 인간 TMPRSS4 단백질의 세포외 도메인을 함유한다. 특정 구현예에서, 인간화 Tmprss4 유전자는 서열 번호 14에 명시된 바와 같은 아미노산 서열을 갖는 인간화 Tmprss4 단백질을 암호화한다.
일부 구현예에서, 인간화 Tmprss4 유전자는 내인성 설치류 Tmprss4 유전자좌에서 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열을 인간 TMPRSS4 유전자의 뉴클레오티드 서열과 대체함으로써 생성된다.
일부 구현예에서, 내인성 설치류 Tmprss4 유전자좌에서의 설치류 Tmprss4 유전자의 인접 게놈 서열은 인간화 Tmprss4 유전자를 형성하기 위해 인간 TMPRSS4 유전자의 인접 게놈 서열과 대체되었다.
특정 구현예에서, 내인성 설치류 Tmprss4 유전자에 삽입된 인간 TMPRSS4 유전자의 인접 게놈 서열은 인간 TMPRSS4 유전자에 의해 암호화된 인간 TMPRSS4 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는 인간 TMPRSS4 유전자의 엑손 서열, 즉 엑손을 전체적으로 또는 부분적으로 포함한다. 내인성 Tmprss4 단백질 및 인간 TMPRSS4 단백질이 막관통 도메인 및 세포외 도메인의 접합부 근처에서 공통 아미노산을 공유하는 상황에서, 인간 TMPRSS4 단백질의 세포외 도메인을 정교하게 암호화하는 인간 TMPRSS4 게놈 서열을 삽입하는 것은 필요하지 않을 수 있고, 인간 TMPRSS4 단백질의 세포외 도메인과 동일한 세포외 도메인을 갖는 인간화 Tmprss4 단백질을 만들기 위해 인간 TMPRSS4 단백질의 실질적으로 세포외 도메인을 암호화하는 약간 길거나 짧은 인간 TMPRSS4 게놈 서열을 사용하는 것이 가능하다.
특정 구현예에서, 내인성 설치류 Tmprss4 유전자에 삽입되는 인간 TMPRSS4 유전자의 인접 게놈 서열은 인간 TMPRSS4 유전자의 적어도 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 함유한다.
특정 구현예에서, 내인성 설치류 Tmprss4 유전자에 삽입되는 인간 TMPRSS4 유전자의 인접 게놈 서열은 인간 TMPRSS4 유전자의 인트론 3의 3' 부분, 및 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 함유한다. 특정 구현예에서, 인간화에 포함된 인간 TMPRSS4 유전자의 코딩 엑손 3의 3' 부분은 140~160 염기쌍의 길이, 즉 인트론 3의 3' 말단의 약 140, 145, 150, 155, 160 염기쌍의 길이이다.
일부 구현예에서, 내인성 설치류 Tmprss4 유전자에 삽입되는 인간 TMPRSS4 유전자의 인접 게놈 서열은 인간 TMPRSS4 유전자의 3' UTR을 함유한다. 특정 구현예에서, 내인성 설치류 Tmprss4 유전자에 삽입되는 인간 TMPRSS4 유전자의 인접 게놈 서열은 인간 TMPRSS4 유전자의 3' UTR을 포함하지 않고, 내인성 설치류 Tmprss4 유전자의 3' UTR은 인간화 Tmprss4 유전자 내에서 정지 코돈의 바로 뒤에 위치한다.
일부 구현예에서, 인간화 Tmprss4 유전자좌에 남아 있는 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss4 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화한다. 내인성 Tmprss4 단백질 및 인간 TMPRSS4 단백질이 막관통 도메인 및 세포외 도메인의 접합부 근처에서 공통 아미노산을 공유하는 상황에서, 내인성 설치류 Tmprss4 단백질의 막관통 도메인을 정교하게 암호화하는 내인성 설치류 Tmprss4 게놈 서열을 유지시키는 것은 필요하지 않을 수 있고, 내인성 설치류 Tmprss4 단백질과 동일한 막관통 도메인을 갖는 인간화 Tmprss4 단백질을 암호화하기 위해 인간화 대체에서 내인성 설치류 Tmprss4 단백질의 실질적으로 막관통 도메인을 암호화하는 약간 길거나 짧은 설치류 Tmprss4 게놈 서열을 유지시키는 것이 가능하다.
특정 구현예에서, 인간화 Tmprss4 유전자는 내인성 설치류 Tmprss4 유전자의 코딩 엑손 1 내지 3 및 인간 TMPRSS4 유전자의 코딩 엑손 4 내지 코딩 엑손 13의 정지 코돈을 함유한다. 특정 구현예에서, 인간화 Tmprss4 유전자는 내인성 설치류 Tmprss4 유전자의 코딩 엑손 1 내지 3 및 인트론 3의 5' 부분, 및 인간 TMPRSS4 유전자의 인트론 3의 3' 부분 및 코딩 엑손 4 내지 코딩 엑손 13의 정지 코돈을 함유한다. 특정 구현예에서, 인간화 Tmprss4 유전자는 내인성 설치류 Tmprss4 유전자에 의해 암호화된 설치류 Tmprss4 단백질의 세포질 도메인 및 막관통 도메인, 및 인간 TMPRSS4 유전자에 의해 암호화된 인간 TMPRSS4 단백질의 세포외 도메인을 함유하는 인간화 Tmprss4 단백질을 암호화한다. 특정 구현예에서, 인간화 Tmprss4 유전자는 서열 번호 14에 명시된 바와 같은 아미노산 서열을 갖는 인간화 Tmprss4 단백질을 암호화한다.
일부 구현예에서, 인간화에 사용된 인간 TMPRSS4 유전자 및 설치류 Tmprss4 유전자의 엑손과 인트론은 서열 번호 8, 10 및 12 내지 13에서 발견되는 것들이다.
일부 구현예에서, 인간화 Tmprss4 유전자는 설치류에서 암호화된 인간화 Tmprss4 단백질의 발현을 초래한다. 일부 구현예에서, 인간화 Tmprss4 단백질은 대조군 설치류(예: 인간화 Tmprss4 단백질을 암호화하는 인간화 Tmprss4 유전자가 없는 설치류)에서의 대응 설치류 Tmprss4 단백질과 필적하거나 실질적으로 동일한 패턴으로 발현된다. 일부 구현예에서, 인간화 Tmprss4 단백질은 대조군 설치류(예: 인간화 Tmprss4 단백질을 암호화하는 인간화 Tmprss4 유전자가 없는 설치류)에서의 대응 설치류 Tmprss4 단백질과 필적하거나 실질적으로 동일한 레벨로 발현된다. 특정 구현예에서, 인간화 Tmprss4 단백질은 세포 표면에서 발현되고 검출된다. 특정 구현예에서, 인간화 Tmprss4 단백질 또는 가용성 형태(예: 제거된 세포외 도메인 형태)는 설치류의 혈청에서, 예컨대 대조군 설치류에서의 대응 설치류 Tmprss4 단백질 또는 이의 가용성 형태에 필적하거나 실질적으로 동일한 레벨로 발현되고 검출된다.
인간화 Tmprss11d 설치류
일부 구현예에서, 본 발명은 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열 및 인간 TMPRSS11D 유전자의 뉴클레오티드 서열을 포함하고, 프로모터 및/또는 증강자(들)과 같은 내인성 설치류 Tmprss11d 유전자의 5' 조절 요소(들)에 의해 조절되는 인간화 Tmprss11d 유전자를 함유하는 게놈을 가진 설치류를 제공한다. 예시적인 설치류는 마우스와 랫트를 포함한다.
일부 구현예에서, 인간화 Tmprss11d 유전자는 인간 TMPRSS11D 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 함유하는 인간화 Tmprss11d 단백질을 암호화한다.
특정 구현예에서, 인간 TMPRSS11D 단백질은 서열 번호 18에 명시된 바와 같은 아미노산 서열과 적어도 85%, 90%, 95%, 98%, 99% 또는 100%의 동일성을 갖는 아미노산 서열을 갖는다.
일부 구현예에서, 인간화 Tmprss11d 단백질은 인간 TMPRSS11D 단백질의 C 말단 377 아미노산, 예를 들어, 인간 TMPRSS11D 단백질의 아미노산 42 내지 418을 함유한다. 일부 구현예에서, 인간화 Tmprss11d 단백질은 서열 번호 18의 A42 내지 I418로 이루어진 아미노산 서열과 실질적으로 동일한 세포외 도메인을 함유한다. 특정 구현예에서, 인간화 Tmprss11d 단백질은, 서열 번호 18의 A42 내지 I418로 이루어진 아미노산 서열과 적어도 85%, 90%, 95%, 98%, 99% 또는 100%의 동일성을 갖는 세포외 도메인; 서열 번호 18의 A42 내지 I418로 이루어진 아미노산 서열과 10, 9, 8, 7, 6, 5, 4, 3, 2 또는 1개 이하의 아미노산(들)만큼 상이한 세포외 도메인; 또는, 예를 들어, N 말단 또는 C 말단에서 1~5개의 아미노산을 결여하거나 추가적인 1~5개의 아미노산을 가짐으로써 서열 번호 18의 A42 내지 I418로 이루어진 아미노산 서열과 N 말단 또는 C 말단에서만 상이한 세포외 도메인을 함유한다.
일부 구현예에서, 인간화 Tmprss11d 단백질은 내인성 설치류 Tmprss11d 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 함유한다. 일부 구현예에서, 인간화 Tmprss11d 단백질은 내인성 설치류 Tmprss11d 단백질의 막관통 도메인 및 세포질 도메인을 포함한다.
특정 구현예에서, 인간화 Tmprss11d 단백질은 내인성 설치류 Tmprss11d 단백질의 막관통 도메인과 세포질 도메인, 및 인간 TMPRSS11D 단백질의 세포외 도메인을 함유한다. 특정 구현예에서, 인간화 Tmprss11d 유전자는 서열 번호 21에 명시된 바와 같은 아미노산 서열을 갖는 인간화 Tmprss11d 단백질을 암호화한다.
일부 구현예에서, 인간화 Tmprss11d 유전자는 내인성 설치류 Tmprss11d 유전자좌에서 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열을 인간 TMPRSS11D 유전자의 뉴클레오티드 서열과 대체함으로써 생성된다.
일부 구현예에서, 내인성 설치류 Tmprss11d 유전자좌에서의 설치류 Tmprss11d 유전자의 인접 게놈 서열은 인간화 Tmprss11d 유전자를 형성하기 위해 인간 TMPRSS11D 유전자의 인접 게놈 서열과 대체되었다. 특정 구현예에서, 내인성 설치류 Tmprss11d 유전자에 삽입된 인간 TMPRSS11D 유전자의 인접 게놈 서열은 인간 TMPRSS11D 유전자에 의해 암호화된 인간 TMPRSS11D 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는 인간 TMPRSS11D 유전자의 엑손 서열, 즉 엑손을 전체적으로 또는 부분적으로 포함한다. 내인성 Tmprss11d 단백질 및 인간 TMPRSS11D 단백질이 막관통 도메인 및 세포외 도메인의 접합부 근처에서 공통 아미노산을 공유하는 상황에서, 인간 TMPRSS11D 단백질의 세포외 도메인을 정교하게 암호화하는 인간 TMPRSS11D 게놈 서열을 삽입하는 것은 필요하지 않을 수 있고, 인간 TMPRSS11D 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 갖는 인간화 Tmprss11d 단백질을 만들기 위해 인간 TMPRSS11D 단백질의 실질적으로 세포외 도메인을 암호화하는 약간 길거나 짧은 인간 TMPRSS11D 게놈 서열을 사용하는 것이 가능하다.
특정 구현예에서, 내인성 설치류 Tmprss11d 유전자에 삽입되는 인간 TMPRSS11D 유전자의 인접 게놈 서열은 인간 TMPRSS11D 유전자의 적어도 코딩 엑손 3 내지 코딩 엑손 10 내의 정지 코돈을 함유한다.
특정 구현예에서, 내인성 설치류 Tmprss11d 유전자에 삽입되는 인간 TMPRSS11D 유전자의 인접 게놈 서열은 인간 TMPRSS11D 유전자의 인트론 2의 3' 부분 및 코딩 엑손 3 내지 코딩 엑손 10 내의 정지 코돈을 함유한다. 특정 구현예에서, 인간화에 포함된 인간 TMPRSS2 유전자의 인트론 2의 3' 부분은 약 444 염기쌍의 길이이다.
일부 구현예에서, 내인성 설치류 Tmprss11d 유전자에 삽입되는 인간 TMPRSS11D 유전자의 인접 게놈 서열은 인간 TMPRSS11D 유전자의 3' UTR을 함유한다. 특정 구현예에서, 인간화를 위해, 인간 TMPRSS11D 유전자의 전체 코딩 엑손 10은 인간 TMPRSS11D 유전자의 3' UTR을 포함하는 인접 인간 TMPRSS11D 게놈 서열에 포함된다. 특정 구현예에서, 인간 TMPRSS11D 유전자의 인접 게놈 서열은 인간 TMPRSS11D 유전자의 3' UTR의 하류에서 추가적인 인간 게놈 서열을 포함한다. 추가적인 인간 게놈 서열은 인간 TMPRSS11D 유전자좌에서 인간 TMPRSS11D 유전자의 3' UTR의 바로 하류에서 발견되는 10~200 bp, 50~200 bp, 또는 약 150, 160, 170, 180 bp의 서열일 수 있다.
일부 구현예에서, 인간화 Tmprss11d 유전자좌에 남아 있는 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열은 내인성 설치류 Tmprss11d 유전자에 의해 암호화된 내인성 설치류 Tmprss11d 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화한다. 내인성 Tmprss11d 단백질 및 인간 TMPRSS11D 단백질이 막관통 도메인 및 세포외 도메인의 접합부 근처에서 공통 아미노산을 공유하는 상황에서, 내인성 설치류 Tmprss11d 단백질의 막관통 도메인을 정교하게 암호화하는 내인성 설치류 Tmprss11d 게놈 서열을 유지시키는 것은 필요하지 않을 수 있고, 내인성 설치류 Tmprss11d 단백질과 동일한 막관통 도메인을 갖는 인간화 Tmprss11d 단백질을 암호화하기 위해 인간화 대체에서 내인성 설치류 Tmprss11d 단백질의 실질적으로 막관통 도메인을 암호화하는 약간 길거나 짧은 설치류 Tmprss11d 게놈 서열을 유지시키는 것이 가능하다.
특정 구현예에서, 인간화 Tmprss11d 유전자는 내인성 설치류 Tmprss11d 유전자의 코딩 엑손 1 내지 2 및 인간 TMPRSS11D 유전자의 코딩 엑손 3 내지 코딩 엑손 10을 함유한다. 특정 구현예에서, 인간화 Tmprss11d 유전자는 내인성 설치류 Tmprss11d 유전자에 의해 암호화된 설치류 Tmprss11d 단백질의 세포질 도메인 및 막관통 도메인, 및 인간 TMPRSS11D 유전자에 의해 암호화된 인간 TMPRSS11D 단백질의 세포외 도메인을 함유하는 인간화 Tmprss11d 단백질을 암호화한다. 특정 구현예에서, 인간화 Tmprss11d 유전자는 서열 번호 21에 명시된 바와 같은 아미노산 서열을 갖는 인간화 Tmprss11d 단백질을 암호화한다.
일부 구현예에서, 인간화에 사용된 인간 TMPRSS11D 유전자 및 설치류 Tmprss11d 유전자의 엑손과 인트론은 서열 번호 15, 17 및 19 내지 20에서 발견되는 것들이다.
일부 구현예에서, 인간화 Tmprss11d 유전자는 설치류 내에서 암호화된 인간화 Tmprss11d 단백질의 발현을 초래한다. 일부 구현예에서, 인간화 Tmprss11d 단백질은 대조군 설치류(예: 인간화 Tmprss11d 단백질을 암호화하는 인간화 Tmprss11d 유전자가 없는 설치류)에서의 대응 설치류 Tmprss11d 단백질과 필적하거나 실질적으로 동일한 패턴으로 발현된다. 일부 구현예에서, 인간화 Tmprss11d 단백질은 대조군 설치류(예: 인간화 Tmprss11d 단백질을 암호화하는 인간화 Tmprss11d 유전자가 없는 설치류)에서의 대응 설치류 Tmprss11d 단백질과 필적하거나 실질적으로 동일한 레벨로 발현된다. 특정 구현예에서, 인간화 Tmprss11d 단백질은 세포 표면에서 발현되고 검출된다. 특정 구현예에서, 인간화 Tmprss11d 단백질 또는 가용성 형태(예: 제거된 세포외 도메인 형태)는 설치류의 혈청에서, 예컨대 대조군 설치류에서의 대응 설치류 Tmprss11d 단백질 또는 이의 가용성 형태에 필적하거나 실질적으로 동일한 레벨로 발현되고 검출된다.
인간화 Tmprss 설치류 동물을 만드는 방법
본 개시의 추가적인 양태는 전술한 인간화 Tmprss 설치류를 만드는 방법을 비롯하여 인간화 Tmprss 설치류를 만드는 데 사용하기에 적합한 핵산 벡터 및 비인간 배아 줄기 세포에 관한 것이다.
본원에서 제공된 설치류는 당업계에 공지된 방법을 사용하여 만들 수 있다. 예시적인 구현예에서, 설치류 Tmprss 유전자를 보유하는 박테리아 인공 염색체(BAC) 클론은 박테리아 상동성 재조합 및 VELOCIGENE® 기술을 사용하여 변형될 수 있다(예: 미국 특허 제6,586,251호 및 Valenzuela 외의 (2003), High-throughput engineering of the mouse genome coupled with high-resolution expression analysis, Nature Biotech. 21(6):652~659 참조). 결과적으로, 설치류 Tmprss 뉴클레오티드 서열이 원 BAC 클론으로부터 결실되었고, 인간 Tmprss 뉴클레오티드 서열이 삽입되어, 5' 및 3' 설치류 상동 아암이 측면에 위치한 인간화 Tmprss 유전자를 갖는 변형된 BAC 클론이 생성되었다. 변형된 BAC 클론은, 일단 선형화되면, 예컨대 전기 천공에 의해 설치류 배아 줄기(ES) 내에 도입될 수 있다. 마우스 ES 세포와 랫트 ES 세포 모두는 당업계에 기술되어 있다. 참조: 예를 들어, 미국 특허번호 제7,576,259호, 제7,659,442호, 제7,294,754호, 및 미국 특허 공개번호 제2008-0078000 A1호(이들 모두는 본원에 참조로서 통합됨)는 마우스 ES 세포 및 유전자 변형된 마우스를 만드는 VELOCIMOUSE® 방법을 기술하고 있고; 미국 특허 공개번호 제2014/0235933 A1호, 제2014/0310828 A1호, Tong 외의 (2010) Nature 467:211-215, 및 Tong 외의 (2011) Nat Protoc. 6(6): doi:10.1038/nprot.2011.338(이들 모두는 본원에 참조로서 통합됨)은 랫트 ES 세포 및 유전자 변형된 랫트를 만드는 방법을 기술하고 있다.
게놈에 통합된 인간화 Tmprss 유전자를 갖는 ES 세포가 선택될 수 있다. 일부 구현예에서, 내인성 설치류 Tmprss 유전자좌에 통합된 인간화 Tmprss를 갖는 ES 세포는 설치류 대립유전자의 결실 및/또는 인간 대립유전자의 증가 분석에 기초하여 선택될 수 있다. 그런 다음, 선택된 ES 세포는 VELOCIMOUSE 방법(예: 미국 특허 번호 제7,576,259호, 제7,659,442호, 제7,294,754호, 및 미국 특허 공개번호 제2008-0078000 A1호 참조), 또는 미국 특허 공개번호 제2014/0235933 A1호 및 제2014/0310828 A1호에 기술된 방법을 사용함으로써 상실배 전시기(pre-morula stage)의 배아(예: 8 세포기 배아)에 주입하기 위한 공여자 ES 세포로서 사용된다. 공여자 ES 세포를 포함하는 배아는 배반포기까지 배양된 다음, 대리모에 이식되어 공여자 ES 세포로부터 완전히 유래된 F0 설치류를 생산한다. 인간화 Tmprss 유전자를 가진 설치류 새끼는 설치류 대립유전자의 상실 및/또는 인간 대립유전자의 증가 분석을 사용하여, 꼬리 단편으로부터 단리된 DNA의 유전자형 분석에 의해 확인될 수 있다.
인간화 Tmprss 유전자에 대해 이형접합체인 설치류는 생성된 동형접합체 설치류와 교배시킬 수 있다. 하나의 인간화 Tmprss 유전자를 함유하는 설치류는 또 다른 인간화 Tmprss 유전자를 함유하는 설치류와 교배되어 다수의 인간화 Tmprss 유전자를 함유하는 설치류를 만들 수 있다. 예를 들어, 인간화 Tmprss2 유전자를 함유하는 설치류는 또 다른 인간화 Tmprss4 유전자를 함유하는 설치류와 교배되어 인간화 Tmprss2 유전자와 인간화 Tmprss4 유전자를 함유하는 설치류를 만들 수 있다.
인간화 Tmprss 유전자를 갖는 설치류를 사용하는 방법
본원에 개시된 설치류는 인간 TMPRSS 단백질을 특이적으로 표적화하는 화합물의 식별 및 시험을 위한 인간화 Tmprss 단백질을 발현하는 생물학적 물질(예: 세포)의 유용한 생체 내 시스템 및 공급원을 제공한다.
일 양태에서, 본원에 개시된 설치류는 인플루엔자 바이러스 감염을 치료 및/또는 예방하기 위한 인간 TMPRSS 단백질 억제제와 같은 후보 화합물의 능력을 알아내는 데 사용된다.
일부 구현예에서, 본원에 기술된 인간화 Tmprss 유전자를 함유하고 인간화 Tmprss 단백질을 발현하는 설치류는 인플루엔자 바이러스 감염 실험에 앞서 후보 화합물과 함께 투여된다. 화합물의 예방적 효능은 설치류가 대조 설치류(들)와 비교하여 인플루엔자 바이러스 감염에 대한 더 적은 증상을 나타내고/내거나 덜 위중한 증상을 나타내고/내거나 개선된 생존력을 나타내는지 여부를 알아 냄으로써 평가할 수 있다.
다른 구현예에서, 인간화 Tmprss 유전자를 함유하고 인간 TMPRSS 단백질의 세포외 도메인을 포함하는 인간화 Tmprss 단백질을 발현하는 설치류에게 실험적 인플루엔자 바이러스 감염 후 상기 인간 TMPRSS 단백질의 후보 억제제를 투여한다. 후보 억제제의 치료 효능은 설치류가 대조 설치류(들)와 비교하여 인플루엔자 바이러스 감염에 대한 더 적은 증상을 나타내고/내거나 덜 위중한 증상을 나타내고/내거나 개선된 생존력을 나타내는지 여부를 알아 냄으로써 평가할 수 있다.
적합한 대조 설치류는, 예를 들어, 실험적 감염없이 인간화 Tmprss 유전자를 함유하는 설치류; 실험적 감염으로 인간화 Tmprss 유전자를 함유하고, 임의의 화합물이 없는 설치류; 및 실험적 감염으로 인간화 Tmprss 유전자를 함유하고, 치료 효과가 있는 것으로 알려진 화합물을 함유하는 설치류를 포함한다.
본 발명의 방법에서 평가할 수 있는 화합물은, 후보 TMPRSS 억제제, 예를 들어, 소분자 프로테아제 억제제, 핵산계 억제제(예: siRNA, 리보자임, 안티센스 작제물 등), 항원 결합 단백질(예: 항체 또는 이의 항원 결합 단편), 또는 차단 펩티드/펩티드 억제제를 포함한다. TMPRSS 억제제는 헤마글루티닌(hemagglutinin) 전구체 단백질(HA0)을 단백질 분해에 의해 HA1 및 HA2 서브유닛으로 절단하는 TMPRSS 단백질의 능력을 억제 또는 감소시킴으로써 기능할 수 있다.
일부 구현예에서, 후보 억제제는 항체 또는 이의 항원 결합 단편이다. 단클론 항체와 다클론 항체 모두가 본 발명의 목적에 적합하다. 특정 구현예에서, 항체는 TMPRSS 단백질에 특이적으로 결합하여 상기 TMPRSS 단백질의 프로테아제 활성을 억제하고, 다른 TMPRSS 단백질의 프로테아제 활성은 실질적으로 억제하지 않는다. 예를 들어, 항TMPRSS2 항체 억제제는 TMPRSS2 단백질에 특이적으로 결합하여 TMPRSS2 단백질의 프로테아제 활성을 억제하는데, TMPRSS4 또는 TMPRSS11D의 단백질 분해 활성에 대해서는 영향을 미치지 않거나, 동일하거나 실질적으로 동일한 실험 조건 하에서 시험된 비억제성 대조 분자에 비해 TMPRSS4 또는 TMPRSS11D의 단백질 분해 활성을 25% 이하(예: 20%, 15%, 10%, 5% 이하) 만큼 감소시킨다.
일부 구현예에서, 억제제는 항TMPRSS2 항체 또는 이의 항원 결합 단편이다. 일부 구현예에서, 억제제는 항TMPRSS4 항체 또는 이의 항원 결합 단편이다. 일부 구현예에서, 억제제는 항TMPRSS11D 항체 또는 이의 항원 결합 단편이다.
실험적 인플루엔자 바이러스 감염은 알려진 프로토콜을 따라 유도되고 모니터링될 수 있다. 예를 들어, 미국 특허 공개번호 제2013/0273070 A1호 참조. 예를 들어, 설치류 동물에게 인플루엔자 바이러스가 비강내 투여될 수 있다. 감염된 동물을 평가하여 감염의 증상과 중증도를 알아낼 수 있다. 예를 들어, 동물의 (1) 체중 변화 및 생존, (2) 유동 세포 계측법을 통한 세포 변화, (3) 면역 화학, 폐 전체의 PAS 및 H&E 염색, 및 (4) 혈청 내 사이토카인 레벨에 대해 분석할 수 있다. 바이러스에 걸리기 쉬운 것으로 알려진 대조 동물은 감염되지 않은 동물과 비교하여, 수지상 세포의 빈도, 인플루엔자 양성 폐포 대식세포, 폐에서의 호중구 세포 또는 상피 세포, 및 IFNg 레벨에서 상당한 증가를 보였다.
실시예
다음의 실시예는 당업자에게 본 발명의 방법 및 조성물을 어떻게 제조하고 사용하는지를 설명하기 위해 제공되며, 발명자가 그들의 발명으로 간주한 것의 범위를 제한하고자 하는 것이 아니다. 다르게 명시되지 않는 한, 온도는 섭씨로 표시되고, 압력은 대기압이거나 대기압에 가깝다.
실시예 1. 내인성
Tmprss2
유전자의 인간화
본 실시예는 설치류(예를 들어, 마우스)에서 Tmprss2를 암호화하는 내인성 유전자를 인간화하는 예시적인 방법을 예시한다. 본 실시예에 기술된 방법은 임의의 인간 서열, 또는 원하는 인간 서열(또는 서열 단편)의 조합을 사용하여 설치류의 내인성 Tmprss2 유전자를 인간화하는데 사용될 수 있다.
내인성 Tmprss2 유전자의 인간화를 위한 표적화 벡터를 박테리아 인공 염색체(BAC) 클론 및 VELOCIGENE® 기술을 사용하여 작제하였다(예를 들어, 본원에 참조로서 포함된, 미국 특허 번호 제6,586,251호 및 Valenzuela 외의 (2003) High-throughput engineering of the mouse genome coupled with high-resolution expression analysis, Nature Biotech. 21(6):652-659 참조).
요약하자면, 마우스 Tmprss2 유전자를 함유하는 마우스 박테리아 인공 염색체(BAC) 클론 bMQ-264A15을 사용하여 다음과 같이 변형시켰다. 5' 마우스 상동 뉴클레오티드 서열, (인간 TMPRSS2 유전자의 코딩 엑손 3의 마지막 7 bp, 인트론 3, 및 코딩 엑손 4 내지 코딩 엑손 13(코딩 엑손 13의 일부인 3' UTR을 포함함)을 함유하는) 약 25,091 bp의 인간 TMPRSS2 게놈 DNA, 약 2,691 bp의 자체 결실 네오마이신 카세트, 및 3' 마우스 상동 서열을 포함하도록 DNA 단편을 생성하였다. 이러한 DNA 단편을 사용하여 박테리아 세포에서 상동성 재조합을 통해 BAC 클론 bMQ-264A15를 변형시켰다. 결과적으로, BAC 클론에서 세포외 도메인을 암호화하는 (약 25,291 bp의) 마우스 Tmprss2 게놈 단편을 약 25,091 bp의 인간 TMPRSS2 게놈 단편으로 대체하였고, 약 2,691 bp의 자체 결실 네오마이신 카세트가 그 뒤에 이어졌다. 구체적으로, 대체된 마우스 Tmprss2 게놈 단편은 마우스 Tmprss2 유전자의 코딩 엑손 3의 마지막 7 bp, 인트론 3, 및 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 포함하였다(도 1a 내지 1b). 삽입된 인간 TMPRSS2 게놈 단편은 (인간 TMPRSS2의 3' UTR을 포함하는) 인간 TMPRSS2 유전자의 코딩 엑손 3의 마지막 7 bp, 인트론 3, 및 코딩 엑손 4 내지 코딩 엑손 13, 및 인간 TMPRSS2의 3' UTR 하류의 131 bp의 인간 3' 게놈 서열을 포함하였다(도 1a 내지 1b). 생성된 변형 BAC 클론은, 5'에서 3'까지, (i) 마우스 Tmprss2 5' UTR, 마우스 Tmprss2 엑손 1(비코딩), 코딩 엑손 1 내지 3(코딩 엑손 3의 마지막 7 bp 제외)를 포함하는 약 12 kb의 마우스 게놈 DNA를 함유하는 5' 마우스 상동 아암; (ii) 인간 코딩 엑손 3의 마지막 7 bp, 인트론 3, 인간 코딩 엑손 4 내지 13(인간 TMPRSS2의 3' UTR 포함), 및 인간 3' 게놈 서열을 포함하는 약 25,091 bp의 인간 TMPRSS2 게놈 단편 ; (iii) 약 2,691 bp의 자체 결실 네오마이신 카세트, 그 뒤에 이어지는 (iv) 마우스 Tmprss2 3' UTR 및 원래 BAC 클론에 남아 있는 마우스 게놈 DNA를 함유하는 45 kb의 3' 마우스 상동 아암을 포함하였다. 도 1a 내지 1b 참조. 접합 서열 또한 도 1b의 하단에 명시되어 있다. 인간 TMPRSS2 게놈 단편 및 네오마이신 카세트를 비롯하여 상류 및 하류 삽입 접합부를 함유하는 변형된 BAC 클론의 부분은 서열 번호 5에 명시되어 있다. 인간화 Tmprss2 유전자에 의해 암호화된 단백질의 아미노산 서열은 서열 번호 7에 명시되어 있다. 이러한 인간화 Tmprss2 단백질("7010 돌연변이 단백질"), 마우스 Tmprss2 단백질(서열 번호 2), 및 인간 TMPRSS2 단백질(서열 번호 4)의 배열은 도 1d에 제공된다.
전술한 바와 같이, 인간화 Tmprss2 유전자를 함유하는 변형된 BAC 클론을 사용하여 마우스 배아 줄기(ES) 세포를 전기 천공하여 인간화 Tmprss2 유전자를 포함하는 변형된 ES 세포를 생성시켰다. 인간화 Tmprss2 유전자를 함유하는 양성으로 표적화된 ES 세포를 인간 TMPRSS2 서열(예를 들어, 인간 TMPRSS2의 코딩 엑손 4 내지 13)의 존재를 검출하고 마우스 Tmprss2 서열의 상실 및/또는 보유(예를 들어, 마우스 Tmprss2의 코딩 엑손 4 내지 13의 상실)를 확인한 검정(전술한 Valenzuela 문헌 참조)에 의해 확인하였다. 표 1에는 전술한 바와 같이(도 1a 내지 1b) 내인성 Tmprss2 유전자의 인간화를 확인하기 위해 사용한 프라이머 및 프로브가 명시되어 있다. 정확히 표적화된 ES 세포 클론이 선택되었으면, 예를 들어 전기 천공에 의해 Cre 재조합 효소를 도입함으로써 네오마이신 선택 카세트를 절제할 수 있다. 대안적으로, 네오마이선 선택 카세트는 ES 클론으로부터 생성된 자손을 Cre 재조합 효소를 발현하는 결실자(deletor) 설치류 균주와 교배시킴으로써 제거할 수 있다. 카세트의 결실 후의 인간화 Tmprss2 유전자좌는 도 1c에 도시되어 있으며, 접합 서열은 도 1c의 하단에 도시되어 있다.
선택된 ES 세포 클론(카세트 유무를 불문함)은 인간화 Tmprss2 대립유전자를 게놈에 함유하는 한 배의 새끼를 생성하기 위해 VELOCIMOUSE® 방법을 사용하여 암컷 마우스를 이식하는 데 사용하였다(예: 미국 특허 번호 제7,294,754호 및 Poueymirou 외의 F0 generation mice that are essentially fully derived from the donor gene-targeted ES cells allowing immediate phenotypic analyses, 2007, Nature Biotech. 25(1):91-99 참조). 인간화 Tmprss2 대립유전자를 갖는 마우스는 인간 TMPRSS2 유전자 서열의 존재를 검출하는 대립유전자 검정(전술한 Valenzuela 외의 문헌 참조)의 변형을 사용하여 꼬리 조각으로부터 단리된 DNA의 유전형을 분석함으로써 재확인하고 동정할 수 있다. 새끼의 유전형을 확인하고, 특성화를 위해 인간화 Tmprss2 유전자좌에 대해 이형접합성인 동물 코호트를 선택한다. 인간화 Tmprss2 유전자좌에 대해 동형접합성인 동물은 이형접합성 동물의 교배에 의해 만들어진다.
실시예 2. 내인성
Tmprss4
유전자의 인간화
본 실시예는 설치류(예를 들어, 마우스)에서 Tmprss4를 암호화하는 내인성 유전자를 인간화하는 예시적인 방법을 예시한다. 본 실시예에 기술된 방법은 원하는 대로 임의의 인간 서열, 또는 인간 서열(또는 서열 단편)의 조합을 사용하여 설치류의 내인성 Tmprss4 유전자를 인간화하는데 사용될 수 있다.
박테리아 인공 염색체(BAC) 클론 및 VELOCIGENE® 기술을 사용하여 내인성 Tmprss4 유전자의 인간화를 위한 표적화 벡터를 작제하였다(예: 미국 특허 번호 제6,586,251호 및 전술한 Valenzuela 외의 (2003) 문헌 참조).
요약하자면, 마우스 Tmprss4 유전자를 함유하는 마우스 박테리아 인공 염색체(BAC) 클론 RP23-71M15를 사용하고 다음과 같이 변형시켰다. 5' 마우스 상동 뉴클레오티드 서열, 약 4,996 bp의 자체 결실 네오마이신 카세트, (인간 TMPRSS4 유전자의 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 함유하는) 약 14,963 bp의 게놈 DNA, 및 3' 마우스 상동 서열을 포함하도록 DNA 단편을 생성하였다. 이러한 DNA 단편을 사용하여 박테리아 세포에서 상동성 재조합을 통해 BAC 클론 RP23-71M15를 변형시켰다. 결과적으로, BAC 클론에서 세포외 도메인을 암호화하는 (약 11,074 bp의) 마우스 게놈 단편을 약 4,996 bp의 자체 결실 네오마이신 카세트로 대체하였고, 약 14,963 bp의 인간 게놈 DNA가 그 뒤에 이어졌다. 구체적으로, 결실되고 대체된 마우스 게놈 단편은 마우스 인트론 3의 3' 130 bp, 마우스 Tmprss4 유전자의 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 포함하였다(도 2a 내지 2b). 삽입된 인간 게놈 단편은 약 150 bp의 인간 TMPRSS4 인트론 3의 3' 부분, 및 인간 TMPRSS4 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 포함하였다(도 2a 내지 2b). 생성된 변형된 BAC 클론은, 5'에서 3'까지, (마우스 Tmprss4 5' UTR, 마우스 Tmprss4 코딩 엑손 1 내지 3, (130 bp의 3'이 없는) 마우스 Tmprss4 인트론 3의 일부를 포함하는) 약 44.8 kb의 마우스 게놈 DNA, 약 4,996 bp의 자체 결실 네오마이신 카세트, 약 150 bp의 인간 TMPRSS4 인트론의 3' 부분, 인간 TMPRSS4 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈, 및 바로 뒤에 이어지는 마우스 Tmprss4 3' UTR 및 원래 BAC 클론에 남아 있는 마우스 게놈 DNA(합이 약 118 kb인 3' 마우스 상동 아암)을 포함하였다. 도 2a 내지 2b 참조. 접합 서열 또한 도 2b의 하단에 명시되어 있다. 네오마이신 카세트 및 인간 TMPRSS4 게놈 단편을 비롯하여 상류 및 하류 삽입 접합부를 함유하는 변형된 BAC 클론의 부분은 서열 번호 12에 명시되어 있다. 인간화 Tmprss4 유전자에 의해 암호화된 단백질의 아미노산 서열은 서열 번호 14에 명시되어 있다. 이러한 인간화 Tmprss4 단백질("7224 돌연변이 단백질"), 마우스 Tmprss4 단백질(서열 번호 9), 및 인간 TMPRSS4 단백질(서열 번호 11)의 배열은 도 2d에 제공된다.
전술한 바와 같이, 인간화 Tmprss4 유전자를 함유하는 변형된 BAC 클론을 사용하여 마우스 배아 줄기(ES) 세포를 전기 천공하여 인간화 Tmprss4 유전자를 포함하는 변형된 ES 세포를 생성시켰다. 인간화 Tmprss4 유전자를 함유하는 양성으로 표적화된 ES 세포를, 인간 TMPRSS4 서열(예를 들어, 인간 TMPRSS4의 코딩 엑손 4 내지 13)의 존재를 검출하고 마우스 Tmprss4 서열의 상실 및/또는 보유(예를 들어, 마우스 Tmprss4의 코딩 엑손 4 내지 13의 상실)를 확인한 검정(전술한 Valenzuela 문헌 참조)에 의해 확인하였다. 표 2에는 전술한 바와 같이 (도 2a 내지 2b) 내인성 Tmprss4 유전자의 인간화를 확인하기 위해 사용한 프라이머 및 프로브가 명시되어 있다. 정확히 표적화된 ES 세포 클론이 선택되었으면, 예를 들어 전기 천공에 의해 Cre 재조합 효소를 도입함으로써 네오마이신 선택 카세트를 절제할 수 있다. 대안적으로, 네오마이선 선택 카세트는 ES 클론으로부터 생성된 자손을 Cre 재조합 효소를 발현하는 결실자(deletor) 설치류 균주와 교배시킴으로써 제거할 수 있다. 카세트의 결실 후의 인간화 Tmprss4 유전자좌는 도 2c에 도시되어 있으며, 접합 서열은 도 2c의 하단에 도시되어 있다.
선택된 ES 세포 클론(카세트 유무를 불문함)은 인간화 Tmprss4 대립유전자를 게놈에 함유하는 한 배의 새끼를 생성하기 위해 VELOCIMOUSE® 방법을 사용하여 암컷 마우스를 이식하는 데 사용하였다(예: 미국 특허 번호 제7,294,754호 및 전술한 Poueymirou 외의 (2007) 문헌 참조). 인간화 Tmprss4 대립유전자를 갖는 마우스는 인간 TMPRSS4 유전자 서열의 존재를 검출한 대립유전자 검정(전술한 Valenzuela 외의 문헌 참조)의 변형을 사용하여 꼬리 조각으로부터 단리된 DNA의 유전형을 분석함으로써 재확인하고 동정하였다. 새끼의 유전형을 확인하였고, 특성화를 위해 인간화 Tmprss4 유전자좌에 대해 이형접합성인 동물 코호트를 선택하였다. 인간화 Tmprss4 유전자좌에 대해 동형접합성인 동물을 이형접합성 동물의 교배에 의해 만들었다.
실시예 3. 내인성
Tmprss11d
유전자의 인간화
본 실시예는 설치류(예를 들어, 마우스)에서 Tmprss11d를 암호화하는 내인성 유전자를 인간화하는 예시적인 방법을 예시한다. 본 실시예에 기술된 방법은 원하는 대로 임의의 인간 서열, 또는 인간 서열(또는 서열 단편)의 조합을 사용하여 설치류의 내인성 Tmprss11d 유전자를 인간화하는데 사용될 수 있다.
박테리아 인공 염색체(BAC) 클론 및 VELOCIGENE® 기술을 사용하여 내인성 Tmprss11d 유전자의 인간화를 위한 표적화 벡터를 작제하였다(예: 미국 특허 번호 제6,586,251호 및 전술한 Valenzuela 외의 (2003) 문헌 참조).
요약하자면, 마우스 Tmprss11d 유전자를 함유하는 마우스 박테리아 인공 염색체(BAC) 클론 RP23-95N22를 사용하고 다음과 같이 변형시켰다. 5' 마우스 상동 뉴클레오티드 서열, (인간 TMPRSS11D 유전자의 인트론 2의 3' 말단에서의 444 bp, 및 코딩 엑손 3 내지 코딩 엑손 10(코딩 엑손 10의 일부인 3' UTR을 포함함)을 함유하는) 약 33,927 bp의 인간 TMPRSS11D 게놈 DNA, 약 4,996 bp의 자체 결실 네오마이신 카세트, 및 3' 마우스 상동 서열을 포함하도록 DNA 단편을 생성하였다. 이러한 DNA 단편을 사용하여 박테리아 세포에서 상동성 재조합을 통해 BAC 클론 RP23-95N22를 변형시켰다. 결과적으로, BAC 클론에서 세포외 도메인을 암호화하는 (약 35,667 bp의) 마우스 Tmprss11d 게놈 단편을 약 33,927 bp의 인간 TMPRSS11D 게놈 단편으로 대체하였고, 약 4,996 bp의 자체 결실 네오마이신 카세트가 그 뒤에 이어졌다. 구체적으로, 대체된 마우스 Tmprss11d 게놈 단편은 마우스 Tmprss11d 유전자의 인트론 2의 3' 부분, 및 코딩 엑손 3 내지 코딩 엑손 10 내의 정지 코돈을 포함하였다(도 3a 내지 3b). 삽입된 인간 TMPRSS11D 게놈 단편은 (인간 TMPRSS11D의 3' UTR을 포함하는) 인간 TMPRSS11D 유전자의 인트론 2의 3' 말단에서의 444 bp, 및 코딩 엑손 3 내지 코딩 엑손 10, 및 인간 TMPRSS11D의 3' UTR 하류의 약 172 bp의 인간 3' 게놈 서열을 포함하였다(도 3a 내지 3b). 생성된 변형된 BAC 클론은, 5'에서 3'까지, (i) 마우스 Tmprss11d 5' UTR, 마우스 Tmprss11d 코딩 엑손 1 내지 2 및 인트론 2의 5' 부분을 포함하는 약 143 kb의 마우스 게놈 DNA를 함유하는 5' 마우스 상동 아암; (ii) 인간 TMPRSS11D의 인트론 2의 3' 부분 및 코딩 엑손 3 내지 10(3' UTR 포함함), 및 인간 3' 게놈 서열을 포함하는 인간 TMPRSS11D 게놈 단편; (iii) 약 4,996 bp의 자체 결실 네오마이신 카세트, 그 뒤에 이어지는 (iv) 마우스 Tmprss11d 3' UTR 및 원래 BAC 클론에 남아 있는 마우스 게놈 DNA를 함유하는 10 kb의 3' 마우스 상동 아암을 포함하였다. 도 3a 내지 3b 참조. 접합 서열 또한 도 3b의 하단에 명시되어 있다. 인간 TMPRSS11D 게놈 단편 및 네오마이신 카세트를 비롯하여 상류 및 하류 삽입 접합부를 함유하는 변형된 BAC 클론의 부분은 서열 번호 19에 명시되어 있다. 인간화 Tmprss11d 유전자에 의해 암호화된 단백질의 아미노산 서열은 서열 번호 21에 명시되어 있다. 이러한 인간화 Tmprss11d 단백질("7226 돌연변이 단백질"), 마우스 Tmprss11d 단백질(서열 번호 16), 및 인간 TMPRSS11D 단백질(서열 번호 18)의 배열은 도 3d에 제공된다.
전술한 바와 같이, 인간화 Tmprss11d 유전자를 함유하는 변형된 BAC 클론을 사용하여 마우스 배아 줄기(ES) 세포를 전기 천공하여 인간화 Tmprss11d 유전자를 포함하는 변형된 ES 세포를 생성시켰다. 인간화 Tmprss11d 유전자를 함유하는 양성으로 표적화된 ES 세포는, 인간 TMPRSS11D 서열(예를 들어, 인간 TMPRSS11D의 코딩 엑손 3 내지 10)의 존재를 검출하고 마우스 Tmprss11d 서열의 상실 및/또는 보유(예를 들어, 마우스 Tmprss11d의 코딩 엑손 3 내지 10의 상실)를 확인하는 검정(전술한 Valenzuela 문헌 참조)에 의해 동정하였다. 표 3에는 전술한 바와 같이(도 3a 내지 3b) 내인성 Tmprss11d 유전자의 인간화를 확인하기 위해 사용한 프라이머 및 프로브가 명시되어 있다. 정확히 표적화된 ES 세포 클론이 선택되었으면, 예를 들어 전기 천공에 의해 Cre 재조합 효소를 도입함으로써 네오마이신 선택 카세트를 절제할 수 있다. 대안적으로, 네오마이선 선택 카세트는 ES 클론으로부터 생성된 자손을 Cre 재조합 효소를 발현하는 결실자(deletor) 설치류 균주와 교배시킴으로써 제거할 수 있다. 카세트의 결실 후의 인간화 Tmprss11d 유전자좌는 도 3c에 도시되어 있으며, 접합 서열은 도 3c의 하단에 도시되어 있다.
선택된 ES 세포 클론(카세트 유무를 불문함)은 인간화 Tmprss11d 대립유전자를 게놈에 함유하는 한 배의 새끼를 생성하기 위해 VELOCIMOUSE® 방법을 사용하여 암컷 마우스를 이식하는 데 사용하였다(예: 미국 특허 번호 제7,294,754호 및 전술한 Poueymirou 외의 (2007) 문헌 참조). 인간화 Tmprss11d 대립유전자를 갖는 마우스는 인간 TMPRSS11D 유전자 서열의 존재를 검출하는 대립유전자 검정(전술한 Valenzuela 외의 문헌 참조)의 변형을 사용하여 꼬리 조각으로부터 단리된 DNA의 유전형을 분석함으로써 재확인하고 동정하였다. 새끼의 유전형을 확인하였고, 특성화를 위해 인간화 Tmprss11d 유전자좌에 대해 이형접합성인 동물 코호트를 선택하였다. 인간화 Tmprss11d 유전자좌에 대해 동형접합성인 동물은 이형접합성 동물의 교배에 의해 만들어진다.
실시예 4. MAID7225 HumIn 대 야생형 Tmprss4 마우스에서 1군 및 2군 인플루엔자 A 바이러스의 평가
감염의 동물 모델로서 인간화 Tmprss 설치류를 사용의 유효성을 입증하기 위해, 중증 인플루엔자에 감염된 인플루엔자 A 1군 및 2군 모델에서 MAID7225 HumIn TMPRSS4 마우스의 생존율 대 야생형(WT) 한 배 새끼의 생존율을 평가하는 실험을 수행하였다.
MAID7225 HumIn TMPRSS4 마우스는 그의 게놈 내의 인간화 Tmprss4 유전자에 대해 동형접합체이고, 실시예 2에 기술된 바와 같이 생성되었다. 이들 연구에 사용된 바이러스 균주에는 역사적인 A/Puerto Rico/08/1934 (H1N1) 인플루엔자 A 바이러스 1군 분리 균주 및 실험실 내 마우스 적응형 A/Aichi/02/1968 (HA, NA) X-31 (H3N2) 인플루엔자 A 바이러스 2군 분리 균주가 포함되었다. 모든 실험은 6~8주령 암컷 및 수컷 MAID7225 HumIn TMPRSS4 마우스 또는 WT 한 배 새끼에서 수행하였다. 마우스에 1,150 플라크 형성 단위(PFU)의 A/Puerto Rico/08/1934(H1N1) 또는 10,000 PFU의 A/Aichi/02/1968-X31(H3N2)을 투여하였다. 이들 생존 모델에서, 마우스에 감염 후(p.i.) 0일 차에 비강 내(IN) 투여하였다. 감염 후 14일 차까지 매일 마우스의 몸무게를 재고 관찰하였고, 시작 몸무게의 20% 줄었을 때 희생시켰다. 결과는 생존 백분율로서 보고된다(표 4).
MAID7225 HumIn TMPRSS4 마우스의 생존을 중증 인플루엔자 A 1군 바이러스[A/Puerto Rico/08/1934 (H1N1)] 및 중증 마우스 적응형 인플루엔자 A 2군 바이러스[A/Aichi/02/1968-X31 (H3N2)] 모두를 투여한 후의 WT 한 배 새끼와 비교하였다(도 4). MAID7225 HumIn TMPRSS4 마우스의 생존은 H1N1을 투여하거나 (각각 25%; n=8 및 20%; n=10) H3N2를 투여한 (각각, 25%; n=8 and 11.1%; n=9) 야생형 마우스와 차이가 없었다.
간행물, 웹사이트 및 다른 참조 자료는 본 발명의 배경기술을 설명하고, 그의 시행이 참조로서 본원에 포함되는 것을 고려하여 추가적인 상세한 설명을 제공하기 위해 언급되었다.
SEQUENCE LISTING
<110> REGENERON PHARMACEUTICALS, INC.
<120> RODENTS HAVING A HUMANIZED TMPRSS GENE
<130> 33093PCT (10234WO01)
<150> 62/301,023
<151> 2016-02-29
<160> 72
<170> PatentIn version 3.5
<210> 1
<211> 3175
<212> DNA
<213> Mus musculus
<400> 1
gcctttcctg gccgttccct ccttctggcc gaggtgcctg cgtttagggg tgtcaccctg 60
gctcccggga cgccgcctcc ggagatttaa gcgagaactg gagtaggtcg tgtacttgga 120
gcggacgagg aagccaagag ctcggacaga ggcggagagg ggcgggaagc gcaacaggtc 180
acctggagga agccccatac tgacctcctc atgctgctga cacaggcagg atggcattga 240
actcagggtc acctccagga atcggacctt gctatgagaa ccacgggtat cagtctgagc 300
acatctgtcc tccgagacca ccagtggctc ccaatggcta caacttgtat ccagcccagt 360
actacccatc tccagtgcct cagtatgctc cgaggattac aacgcaagcc tcaacatctg 420
tcatccacac acatcccaag tcctcaggag cactgtgcac ctcaaagtct aagaaatcgc 480
tgtgtttagc cctcgccctg ggcactgtcc tcacgggagc tgctgtggct gctgtcttgc 540
tttggaggtt ctgggacagc aactgttcta cgtctgagat ggagtgtggg tcttcaggca 600
catgcatcag ctcttctctc tggtgtgacg gggtagcaca ttgtcccaac ggagaagatg 660
agaaccgttg tgttcgtctc tacggacaaa gcttcatcct ccaggtttac tcatctcaga 720
ggaaagcctg gtatcccgtg tgccaggatg attggagtga gagctacggg agagcagcat 780
gtaaagacat gggatacaag aacaattttt attctagcca agggatacca gaccagagcg 840
gggcaacgag ctttatgaag ctgaatgtga gctcaggcaa cgttgacctc tataaaaaac 900
tctaccacag tgactcatgt tcatcccgca tggtggtttc tttgcgctgt atagaatgcg 960
gggttcgctc agtgaaacgc cagagcagga ttgtgggtgg attgaatgcc tcaccaggag 1020
actggccctg gcaggtcagc ctgcacgtcc aaggcgtcca cgtctgcgga ggctccatca 1080
tcacccccga gtggattgtg acggccgccc actgtgtgga agaacccctc agcagcccga 1140
ggtactggac ggcatttgcg ggaattctga gacagtctct catgttctat ggaagtagac 1200
accaggtaga aaaagtaatt tcccatccaa attacgactc taagaccaag aataacgaca 1260
ttgctctcat gaagctgcag acacctttgg cttttaatga tctagtgaag ccagtgtgtc 1320
tgccgaaccc aggcatgatg ctagacctag accaggaatg ctggatttcg gggtgggggg 1380
ccacctatga gaaagggaag acctcggacg tgttgaatgc tgccatggta cccttgatcg 1440
agccctccaa atgtaatagt aaatacatat acaacaacct aatcacacca gccatgatct 1500
gtgccggctt cctccagggg tctgtcgact cttgccaggg agacagtgga gggccgctgg 1560
ttactttgaa gaatgggatc tggtggctga ttggggacac gagctggggc tcgggctgtg 1620
ccaaggcact cagacctgga gtatacggga acgtgacggt atttacagat tggatctacc 1680
agcaaatgag ggcgaacagc taatccacgt ggctttgtcc cagacttcct ttgtcttcaa 1740
caaccttctg caagaaaacc aagggcctga attttaactt cctgtgcaca atgtaccttt 1800
tgagatgatt cgaagggcct ttcactttta ttaaacagtg acttgtttga ctgtgctccc 1860
tggtcctgtg agggcttcag tgccccaccc ctgggccact tctgcagctc ccaccagaat 1920
ggatgaccag attctgttgg gtttgggcac atagggccaa aggcagagga gggtggcact 1980
ctcatgttgg aacttctttt gggctcatgc tcaggccttt tttggatcac taaggactat 2040
gacctctgag taacctgatg acctgagaaa gagtaaggag gccaggcagg gccttgggcc 2100
caggaacagg taccttgaga gtgagagcta cccattgcct gtggcctaaa tctgctgtgc 2160
aggttgggct ggtcatactg tcatgatttc attaacagcc tgggtgaaca tggctgggag 2220
taaagggctt gctctcctgc atgttgacat gacggccctt tccaagggtg atggaggctt 2280
tcccaagcta agggcctagg cagatctctc agagcaagaa gctaatgccg gcatgtccct 2340
tgggtgagct ctacatggtg ttattcagtc tggttcttgg ctccccacta ctgtttctct 2400
cagcctctca gagcctgaaa cttacctctt agctttggct acaggcatgg cctagtacct 2460
gatggagcct gtatagctca gctaatcaaa tggaggctca ggtccatcag aatcagggac 2520
ttgtgatttc agtcaccttg cttctgggtt gtgtttcttc tcttactacc tcactgcacc 2580
tggacactag agtggatgaa tgtctggagt tcacctgcat ttggactgtg tgattgtgcc 2640
tcagacacta gacctcttcc agatggttag gttgttctgt agactggcaa tgagattaga 2700
agttcctagc ttcagataaa gatgaaagag aggagatcat tgtcttctgt cttcttctgg 2760
ccctgggttt ataccaggaa agccatgcca gaattaccaa atatgaagta tgaatgtctt 2820
acccacggtg aggctctgcc tccttctctc tgcctggttc ttcagaaggc agtgaatggg 2880
tcataactgg gactccatct ttgctgggga aagtctccca cctagggaat ggttaccact 2940
ccatgtaaag aaaactccct catgcgtcct ctgggacctt cttagatgct gtaaggtacc 3000
tacatacaga ctaaatgtgc aagcaccttg aagtgtgaga acctgtcccc tccttagctc 3060
tccttgtctt tgctgttggt tggttatttc ctgctttgtg tctgttctga gctgtgagat 3120
tccactgtga aatatatgaa taaagtatat aattctttta aaaaaaaaaa aaaaa 3175
<210> 2
<211> 490
<212> PRT
<213> Mus musculus
<400> 2
Met Ala Leu Asn Ser Gly Ser Pro Pro Gly Ile Gly Pro Cys Tyr Glu
1 5 10 15
Asn His Gly Tyr Gln Ser Glu His Ile Cys Pro Pro Arg Pro Pro Val
20 25 30
Ala Pro Asn Gly Tyr Asn Leu Tyr Pro Ala Gln Tyr Tyr Pro Ser Pro
35 40 45
Val Pro Gln Tyr Ala Pro Arg Ile Thr Thr Gln Ala Ser Thr Ser Val
50 55 60
Ile His Thr His Pro Lys Ser Ser Gly Ala Leu Cys Thr Ser Lys Ser
65 70 75 80
Lys Lys Ser Leu Cys Leu Ala Leu Ala Leu Gly Thr Val Leu Thr Gly
85 90 95
Ala Ala Val Ala Ala Val Leu Leu Trp Arg Phe Trp Asp Ser Asn Cys
100 105 110
Ser Thr Ser Glu Met Glu Cys Gly Ser Ser Gly Thr Cys Ile Ser Ser
115 120 125
Ser Leu Trp Cys Asp Gly Val Ala His Cys Pro Asn Gly Glu Asp Glu
130 135 140
Asn Arg Cys Val Arg Leu Tyr Gly Gln Ser Phe Ile Leu Gln Val Tyr
145 150 155 160
Ser Ser Gln Arg Lys Ala Trp Tyr Pro Val Cys Gln Asp Asp Trp Ser
165 170 175
Glu Ser Tyr Gly Arg Ala Ala Cys Lys Asp Met Gly Tyr Lys Asn Asn
180 185 190
Phe Tyr Ser Ser Gln Gly Ile Pro Asp Gln Ser Gly Ala Thr Ser Phe
195 200 205
Met Lys Leu Asn Val Ser Ser Gly Asn Val Asp Leu Tyr Lys Lys Leu
210 215 220
Tyr His Ser Asp Ser Cys Ser Ser Arg Met Val Val Ser Leu Arg Cys
225 230 235 240
Ile Glu Cys Gly Val Arg Ser Val Lys Arg Gln Ser Arg Ile Val Gly
245 250 255
Gly Leu Asn Ala Ser Pro Gly Asp Trp Pro Trp Gln Val Ser Leu His
260 265 270
Val Gln Gly Val His Val Cys Gly Gly Ser Ile Ile Thr Pro Glu Trp
275 280 285
Ile Val Thr Ala Ala His Cys Val Glu Glu Pro Leu Ser Ser Pro Arg
290 295 300
Tyr Trp Thr Ala Phe Ala Gly Ile Leu Arg Gln Ser Leu Met Phe Tyr
305 310 315 320
Gly Ser Arg His Gln Val Glu Lys Val Ile Ser His Pro Asn Tyr Asp
325 330 335
Ser Lys Thr Lys Asn Asn Asp Ile Ala Leu Met Lys Leu Gln Thr Pro
340 345 350
Leu Ala Phe Asn Asp Leu Val Lys Pro Val Cys Leu Pro Asn Pro Gly
355 360 365
Met Met Leu Asp Leu Asp Gln Glu Cys Trp Ile Ser Gly Trp Gly Ala
370 375 380
Thr Tyr Glu Lys Gly Lys Thr Ser Asp Val Leu Asn Ala Ala Met Val
385 390 395 400
Pro Leu Ile Glu Pro Ser Lys Cys Asn Ser Lys Tyr Ile Tyr Asn Asn
405 410 415
Leu Ile Thr Pro Ala Met Ile Cys Ala Gly Phe Leu Gln Gly Ser Val
420 425 430
Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Thr Leu Lys Asn
435 440 445
Gly Ile Trp Trp Leu Ile Gly Asp Thr Ser Trp Gly Ser Gly Cys Ala
450 455 460
Lys Ala Leu Arg Pro Gly Val Tyr Gly Asn Val Thr Val Phe Thr Asp
465 470 475 480
Trp Ile Tyr Gln Gln Met Arg Ala Asn Ser
485 490
<210> 3
<211> 3212
<212> DNA
<213> Homo sapiens
<400> 3
gagtaggcgc gagctaagca ggaggcggag gcggaggcgg agggcgaggg gcggggagcg 60
ccgcctggag cgcggcaggt catattgaac attccagata cctatcatta ctcgatgctg 120
ttgataacag caagatggct ttgaactcag ggtcaccacc agctattgga ccttactatg 180
aaaaccatgg ataccaaccg gaaaacccct atcccgcaca gcccactgtg gtccccactg 240
tctacgaggt gcatccggct cagtactacc cgtcccccgt gccccagtac gccccgaggg 300
tcctgacgca ggcttccaac cccgtcgtct gcacgcagcc caaatcccca tccgggacag 360
tgtgcacctc aaagactaag aaagcactgt gcatcacctt gaccctgggg accttcctcg 420
tgggagctgc gctggccgct ggcctactct ggaagttcat gggcagcaag tgctccaact 480
ctgggataga gtgcgactcc tcaggtacct gcatcaaccc ctctaactgg tgtgatggcg 540
tgtcacactg ccccggcggg gaggacgaga atcggtgtgt tcgcctctac ggaccaaact 600
tcatccttca ggtgtactca tctcagagga agtcctggca ccctgtgtgc caagacgact 660
ggaacgagaa ctacgggcgg gcggcctgca gggacatggg ctataagaat aatttttact 720
ctagccaagg aatagtggat gacagcggat ccaccagctt tatgaaactg aacacaagtg 780
ccggcaatgt cgatatctat aaaaaactgt accacagtga tgcctgttct tcaaaagcag 840
tggtttcttt acgctgtata gcctgcgggg tcaacttgaa ctcaagccgc cagagcagga 900
ttgtgggcgg cgagagcgcg ctcccggggg cctggccctg gcaggtcagc ctgcacgtcc 960
agaacgtcca cgtgtgcgga ggctccatca tcacccccga gtggatcgtg acagccgccc 1020
actgcgtgga aaaacctctt aacaatccat ggcattggac ggcatttgcg gggattttga 1080
gacaatcttt catgttctat ggagccggat accaagtaga aaaagtgatt tctcatccaa 1140
attatgactc caagaccaag aacaatgaca ttgcgctgat gaagctgcag aagcctctga 1200
ctttcaacga cctagtgaaa ccagtgtgtc tgcccaaccc aggcatgatg ctgcagccag 1260
aacagctctg ctggatttcc gggtgggggg ccaccgagga gaaagggaag acctcagaag 1320
tgctgaacgc tgccaaggtg cttctcattg agacacagag atgcaacagc agatatgtct 1380
atgacaacct gatcacacca gccatgatct gtgccggctt cctgcagggg aacgtcgatt 1440
cttgccaggg tgacagtgga gggcctctgg tcacttcgaa gaacaatatc tggtggctga 1500
taggggatac aagctggggt tctggctgtg ccaaagctta cagaccagga gtgtacggga 1560
atgtgatggt attcacggac tggatttatc gacaaatgag ggcagacggc taatccacat 1620
ggtcttcgtc cttgacgtcg ttttacaaga aaacaatggg gctggttttg cttccccgtg 1680
catgatttac tcttagagat gattcagagg tcacttcatt tttattaaac agtgaacttg 1740
tctggctttg gcactctctg ccattctgtg caggctgcag tggctcccct gcccagcctg 1800
ctctccctaa ccccttgtcc gcaaggggtg atggccggct ggttgtgggc actggcggtc 1860
aagtgtggag gagaggggtg gaggctgccc cattgagatc ttcctgctga gtcctttcca 1920
ggggccaatt ttggatgagc atggagctgt cacctctcag ctgctggatg acttgagatg 1980
aaaaaggaga gacatggaaa gggagacagc caggtggcac ctgcagcggc tgccctctgg 2040
ggccacttgg tagtgtcccc agcctacctc tccacaaggg gattttgctg atgggttctt 2100
agagccttag cagccctgga tggtggccag aaataaaggg accagccctt catgggtggt 2160
gacgtggtag tcacttgtaa ggggaacaga aacatttttg ttcttatggg gtgagaatat 2220
agacagtgcc cttggtgcga gggaagcaat tgaaaaggaa cttgccctga gcactcctgg 2280
tgcaggtctc cacctgcaca ttgggtgggg ctcctgggag ggagactcag ccttcctcct 2340
catcctccct gaccctgctc ctagcaccct ggagagtgca catgcccctt ggtcctggca 2400
gggcgccaag tctggcacca tgttggcctc ttcaggcctg ctagtcactg gaaattgagg 2460
tccatggggg aaatcaagga tgctcagttt aaggtacact gtttccatgt tatgtttcta 2520
cacattgcta cctcagtgct cctggaaact tagcttttga tgtctccaag tagtccacct 2580
tcatttaact ctttgaaact gtatcatctt tgccaagtaa gagtggtggc ctatttcagc 2640
tgctttgaca aaatgactgg ctcctgactt aacgttctat aaatgaatgt gctgaagcaa 2700
agtgcccatg gtggcggcga agaagagaaa gatgtgtttt gttttggact ctctgtggtc 2760
ccttccaatg ctgtgggttt ccaaccaggg gaagggtccc ttttgcattg ccaagtgcca 2820
taaccatgag cactactcta ccatggttct gcctcctggc caagcaggct ggtttgcaag 2880
aatgaaatga atgattctac agctaggact taaccttgaa atggaaagtc atgcaatccc 2940
atttgcagga tctgtctgtg cacatgcctc tgtagagagc agcattccca gggaccttgg 3000
aaacagttgg cactgtaagg tgcttgctcc ccaagacaca tcctaaaagg tgttgtaatg 3060
gtgaaaacgt cttccttctt tattgcccct tcttatttat gtgaacaact gtttgtcttt 3120
ttttgtatct tttttaaact gtaaagttca attgtgaaaa tgaatatcat gcaaataaat 3180
tatgcaattt ttttttcaaa gtaaaaaaaa aa 3212
<210> 4
<211> 492
<212> PRT
<213> Homo sapiens
<400> 4
Met Ala Leu Asn Ser Gly Ser Pro Pro Ala Ile Gly Pro Tyr Tyr Glu
1 5 10 15
Asn His Gly Tyr Gln Pro Glu Asn Pro Tyr Pro Ala Gln Pro Thr Val
20 25 30
Val Pro Thr Val Tyr Glu Val His Pro Ala Gln Tyr Tyr Pro Ser Pro
35 40 45
Val Pro Gln Tyr Ala Pro Arg Val Leu Thr Gln Ala Ser Asn Pro Val
50 55 60
Val Cys Thr Gln Pro Lys Ser Pro Ser Gly Thr Val Cys Thr Ser Lys
65 70 75 80
Thr Lys Lys Ala Leu Cys Ile Thr Leu Thr Leu Gly Thr Phe Leu Val
85 90 95
Gly Ala Ala Leu Ala Ala Gly Leu Leu Trp Lys Phe Met Gly Ser Lys
100 105 110
Cys Ser Asn Ser Gly Ile Glu Cys Asp Ser Ser Gly Thr Cys Ile Asn
115 120 125
Pro Ser Asn Trp Cys Asp Gly Val Ser His Cys Pro Gly Gly Glu Asp
130 135 140
Glu Asn Arg Cys Val Arg Leu Tyr Gly Pro Asn Phe Ile Leu Gln Val
145 150 155 160
Tyr Ser Ser Gln Arg Lys Ser Trp His Pro Val Cys Gln Asp Asp Trp
165 170 175
Asn Glu Asn Tyr Gly Arg Ala Ala Cys Arg Asp Met Gly Tyr Lys Asn
180 185 190
Asn Phe Tyr Ser Ser Gln Gly Ile Val Asp Asp Ser Gly Ser Thr Ser
195 200 205
Phe Met Lys Leu Asn Thr Ser Ala Gly Asn Val Asp Ile Tyr Lys Lys
210 215 220
Leu Tyr His Ser Asp Ala Cys Ser Ser Lys Ala Val Val Ser Leu Arg
225 230 235 240
Cys Ile Ala Cys Gly Val Asn Leu Asn Ser Ser Arg Gln Ser Arg Ile
245 250 255
Val Gly Gly Glu Ser Ala Leu Pro Gly Ala Trp Pro Trp Gln Val Ser
260 265 270
Leu His Val Gln Asn Val His Val Cys Gly Gly Ser Ile Ile Thr Pro
275 280 285
Glu Trp Ile Val Thr Ala Ala His Cys Val Glu Lys Pro Leu Asn Asn
290 295 300
Pro Trp His Trp Thr Ala Phe Ala Gly Ile Leu Arg Gln Ser Phe Met
305 310 315 320
Phe Tyr Gly Ala Gly Tyr Gln Val Glu Lys Val Ile Ser His Pro Asn
325 330 335
Tyr Asp Ser Lys Thr Lys Asn Asn Asp Ile Ala Leu Met Lys Leu Gln
340 345 350
Lys Pro Leu Thr Phe Asn Asp Leu Val Lys Pro Val Cys Leu Pro Asn
355 360 365
Pro Gly Met Met Leu Gln Pro Glu Gln Leu Cys Trp Ile Ser Gly Trp
370 375 380
Gly Ala Thr Glu Glu Lys Gly Lys Thr Ser Glu Val Leu Asn Ala Ala
385 390 395 400
Lys Val Leu Leu Ile Glu Thr Gln Arg Cys Asn Ser Arg Tyr Val Tyr
405 410 415
Asp Asn Leu Ile Thr Pro Ala Met Ile Cys Ala Gly Phe Leu Gln Gly
420 425 430
Asn Val Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Thr Ser
435 440 445
Lys Asn Asn Ile Trp Trp Leu Ile Gly Asp Thr Ser Trp Gly Ser Gly
450 455 460
Cys Ala Lys Ala Tyr Arg Pro Gly Val Tyr Gly Asn Val Met Val Phe
465 470 475 480
Thr Asp Trp Ile Tyr Arg Gln Met Arg Ala Asp Gly
485 490
<210> 5
<211> 27947
<212> DNA
<213> Artificial Sequence
<220>
<223> Recombinant polynucleotide
<400> 5
gcagagtcta agaaatcgct gtgtttagcc ctcgccctgg gcactgtcct cacgggagct 60
gctgtggctg ctgtcttgct ttggaagttc agtaagtgca gggagcctcg atcccaccat 120
gtgctcctgc agtccccagt gctctgagcc agaccctgct ctctgggcta ttgagacctc 180
tggaggccct ccgtgaggtt cctctcttac ataacgaggc tgtctctctt cccttctctt 240
gtttagctat gagattgaca catcatgggg aaagcattta gaatgtaccc agtgctttgg 300
ggtgcttggt gccacccagc actgtgagca caggttcttc taccttgggg ccacacccag 360
ttacctgtat ctcactgcac agcagtggct gttggggacc aggcccaccc ctccatgtcc 420
cacctcctgc aactgcagcc tgagccttcc catcagcctg gggtggtgca gacccatgtg 480
ccattgtgga tccttcaagt tacctgtgtg gcagagagga cgtgtgagtg ccgtccaaac 540
ccaaacactg agagggtcct tcccattgcc cccacggaag taaggtgccc cagtgctaat 600
tccacttata cttgctggtg gcaaggacac ttctcctcct tattaaagtg ggggattggc 660
tgggtgaggt ggctcacgcc tgttatccca gcactttaag aggccaaggc aggtggacca 720
cctgaggtca ggagtttgag accacaagcc tggccaacat gttgaaactc catctctact 780
aaaaatacaa aaattagtca ggcgtggtgg cgtgcacctg taatcccagc tacttaggag 840
gctggggcag gaggatcact tgaacccagg agttggaggt tgcagtgagc caagattgtg 900
cccctgcact ccagcctggg tgacagaatg agacttcatc tcaaaaacaa aacaaaacaa 960
aacacagtgg ggccaggagt tggaggctgc agcgagctac agtaatgcca cggtgttcct 1020
cactccatga ggctcattgc gtttctcagc ctgaagggca cctctcttct gttttctctg 1080
caagtgggca gcaagtgctc caactctggg atagagtgcg actcctcagg tacctgcatc 1140
aacccctcta actggtgtga tggcgtgtca cactgccccg gcggggagga cgagaatcgg 1200
tgtggtgagt cagccttgac cttgggaagg gactcctctg ctcaccttgg agacagcagc 1260
cgggtccagg ggcctttggg tgactgggcc tggcgtgcgt ccagtacgct gacacatgat 1320
gtcattgaat ccctgctcca ggctgagccc tggggctcag agaggttgtg tttccggccc 1380
aacctcaccc agcaggtggg agatgacagg gccaccgagg actgtgtcat tggaaccaca 1440
cgtgctctga actgccacag gaagtcagtt aagatgagca aactgtttat aaagttggag 1500
atgcaggcta ggaacggtgg ctcatgcctg taatcccagc actttgggag gccgaggcag 1560
atggatcacc tgaggtcagg agtttgagac cagcctgacc aatatggtga aaccttatct 1620
ccactaaaaa tacaaaaatt agccaagcgc ggtggcgggt gcctgtaatt ccagctattc 1680
aggaggctga ggcaggagaa tcacttgaac ctgggaggcg gaggttgcag tgagctgaga 1740
tcacgccact gcattccagc ctgggagaca gagctggctc aaaaaataaa ttaattaatt 1800
aaaaacaaaa ttggagatgc actatgttat tttcaaaaca agctgccttt aaagatctat 1860
ctgttgtcac agggtgggct catctgtttc attttatttt ctgtggttta tctatttatt 1920
cattttaatg aactaggaag cattgctcct atttatggca taccacatga tgtttggata 1980
cgtgtatgcc tgtggcatgg ctaagtcaag ctagaacatg ggccttacct catatacgtg 2040
tcttattaag aacacataaa acctactctt gtagtgattt tcaaatatgc aacatatagt 2100
ttattaactg cagtcactat gatgtacaat agattgctcg aacttattcc tcctgtctaa 2160
ctaagatttt gtgacctctg accaacatct ccccagtgtt gtcacccccc gcccccagcc 2220
tctgatagct gcctttctac tctctgcttc tgtgagtttg atgtttatac attccacatg 2280
taagtggcct catgcagtgt ttctgtctct gtgtctggct tgttcactta gcgtaatgtc 2340
ctccagcttc atctatgttg ttggaaatga caggatttcc ttctttcttg tggctgaata 2400
gtattgcctt gtgcatatac accacatttt ctttatccct tcattcactg atggactctt 2460
aggttgatgt catgtcttgg ctgttgtgaa aaatgccgca gtgagcgtgg gcgtgcaggt 2520
ccctcttcaa cacacggatt tcctttcctt tggatataaa cccagcagtg agattgctgg 2580
atcacatggc agttctgttt ctcacctttt gaggaaactc catactgttt tccataatgg 2640
ctgtagcaac ttccactccc acccccacgg tgcaaagtct ccatttctct tctacaacct 2700
caccaactcc tgttattttc catctttctg atagtagcca tttgaagagg tatgagatga 2760
tacctcattg tggttttcat ttgcattttt atttgtattt ttcatgaatt tttgagggtg 2820
atttcaaggg tagttagtga ctcgaacagg gaaacgatcc tgagtatgag ggttgtgcta 2880
atcatccccc tcctgccagc tgcgtacgga atggggctct gcagatggca gggagctggc 2940
tcgtttctct ttaagagctg ccttttactt ttcttcctct tcctttaaaa cttatttcct 3000
ggccggacgc agtggctcat gcctgtaatc ccagcacttt gggaggccga ggtgggcgga 3060
tcacgaggtc aggaattcca gaccagcctg gccaacatgg tgaaaccccg tctctactaa 3120
aaatacaaaa attagccaga cgtggtggtg cgggcctata gtcccagcta ctcgggaggc 3180
tgaggcagga gaatcacttg aacctgggag gagggggttg cagtgagccg agattgcgcc 3240
actgcactcc agcctgggcg acagagccag actccatctc aaaaaacaaa aaaaagttat 3300
ttcccaagca cagccatgta ttccaggctt gtggatcagc gttggtggtg gtgtgtgctc 3360
tcatatctta gttccagcta agcacactct gacatgttta cactagaacc atttgttttt 3420
tctagaaata gaaatttcag aattgtagag tcagaggact taccagaaat ctcttaggta 3480
gttctcctcc cctccctcaa gtgcagtcct aacctcctgg agttttctgt agaaaccaca 3540
agcctcagag ctggccgaga attctagcca aagatttttc catgccaaag taatcccccc 3600
tctcctaagg gccatccttg gtggggactg gtttcctgtt aagccctcgc tgtcagtcct 3660
ggctgtggaa tttcctggtg aggagcactg gcccgtggag ctcggccctc gtgccggcct 3720
tgagcaggcc caagtgttcc gtgttcttga tacctttcct ccagcacagt cttgcttccc 3780
agaaaaaggt ttgcacttga aaatgatgca tttgctgatt aaacatagtt cttttgcttt 3840
atttggtttc taaaataaag tgggagtttt tgagattgag taacgtgagg ttaagatagc 3900
acgtggaatg gctttttctt ttctttctat tttttttttt tttttcctgg agacagggtt 3960
tcactctgtt gcccaggctg gagtgcagag gcatgaccat ggctcactgc aacttcgatg 4020
tcctggggtt aagcgatccc ccagcctcag ccccccaagt ggctgggact acaggtgctc 4080
gccaccacac ctggctaatt tttgtatttt ttgtagaaaa tgggtttcat caatgttgtc 4140
cagactggtc tcgaactcct gacctcaagc aattctcctg cctcagcctc ccagactgct 4200
gggattacag gcgtgaacta ccacgcctgg cctggaatgg cttttgatgt tctcctatgt 4260
gcacatgtgg gtgaataaac accaacaaag tccttatgtt acctgaagag ttgctctctt 4320
cttaatattt aagtcgtatt tatttaaata ctttaatagt tgtacactat taaagtatta 4380
ttaggtcaaa atcaaggaag tacaaaaggg tatgctgtga aaaatctctt cttccttgct 4440
ctgcttactt acctaccccg catcccccca tacaccccag acacacacac acacacacac 4500
acacacacac acacacgcat cactcccata catgcccacc tgtttaccag ccaatcacat 4560
ttcttggggc aactcatctg agttgcttct ctttccagag agtttttgca taaagaagca 4620
caggtatttc tgcgttacca tgaccctatt tcccagtggt tcctagccag ttgactctcc 4680
tgcactggat accatcctgg acagcattcc ttagggaaat gagccccctg ttttttccca 4740
ccatggcaca gttggtcctt tgcatggacg caccattatt gcccctgtct cttcttggtg 4800
gaccttaagg ttttctccat ccttttgctg taacacacac tgctccaagt gtgtgagcat 4860
atcagtagga aacgcttcca ggagtagaac tgctaggtca gagggcgtgt ggatctgtaa 4920
cctgacagac ctagaccggc ttcagtttgg ttttatccag tttccatatt gattattcat 4980
ataaaaggaa acagacaaac ataacgctgt gcatgtattc tctcttagac cagaacaggc 5040
atagggtgca cttttaattt gtccatttcg tagagtagaa attgtttttg ctgaaatgaa 5100
caccttagga tgctgaagaa tatgacccgt cccatggaaa acattcaaaa atgtgtgtag 5160
cgctttcttc ccaagggtgt gtgtgcgcat attttaacac taattcactt tctacttccg 5220
ttgctatcct ttctgtgagt ctttctcaga atctcagaaa agaaactaaa ttgttcactc 5280
tagttatcaa tgctgtactc tatacctgga atttgctaaa agggcagatt ttaagtattc 5340
tcaccacaga aaagagaaaa gaaaatggta attatgtgac gtggtggaca tgttaactag 5400
ctttattatg gtgagcattt cacagcggat atccagtcat cacgctgtac acattaaaca 5460
tgtacaattg ggtttttttg agacaaggtc tccttctgtc acccagtctg gagtgcagtg 5520
gctcagtcat ggctcattgc agcctcgacc tcctgggctc aatccatcct tccccctcag 5580
cctcctgaaa agctggggcc acaggcatgt accatcatgc caggctaatg catatatatt 5640
tatatttttt ggtggagatg gggttggtct cgaactctgg gctcaagtga tcctcccgcc 5700
ttgcccttcc aaagtgctga gattacaggc atgaaccaca gcaccaggcc tacatgtaaa 5760
atttttattt gtcaactata ctttgacaaa gctgagaaaa aaaatcctaa tatttaaaaa 5820
aaaaaaaaaa aggactagct tgagaccttt tccagctctc tggcttatca gctgccgtct 5880
cttccgggtg cagatagctg gaagggaaag aaaatcccta aaattaccca caagccaaga 5940
atgaagtgtc tccctttgag ccacagtggc agttttgttt ttaatcatag aagtgtattt 6000
tgagccgggt gtgctggctc acgcctgtaa tccccgcact ttgggaggcc gaggtggggg 6060
gcggaggggg tggggatcgc ctgaggtcag gagttcgaga ccagcctgac caacatggag 6120
aaaccccgtc tctactaaaa atacaaaatt agccggcgtg gtggtgcatg cctgtaatcc 6180
cagctactca tgaggctgag tcaggagaat ctcttgaacc caggaggtgg aggttgcggt 6240
gagctgagat catgccattg cactccagcc tgggaacaag aaaaaaaaag aagaagaaga 6300
agaagtgtat tcatttcagt tacttttaaa aaagtgaaca gactttatat tttagagcgg 6360
ttttaggttt acagaaaatg aaacagacag ggcagcgagc tccttgtact cctccccagc 6420
acacagttgc cctgttatga acatcccaca tcagtgctgt gcgttcatta acaccgatga 6480
acctgatgca tacattatga tgaactgaag tcctggactt caccctttct cttgtacagt 6540
tctgtgggat ttgacaaatg cataatgctg tacagccaca atgatagtat cgtccagagt 6600
agttctcctg ccttaaaacc tcttttgctg cacctgtttc tctctcccca ctcaccccag 6660
ctatctgatc ttcttagtgc ctccgaagtt ttggtctttt caggatgttg tagcgttgga 6720
atcatggagt atgtagcctt caccacatac accttccttc actttgttgg cttcctttac 6780
ttagtaatat gcattcaagt ttcctccatg ccttttcatg gcttgatagc tcatttcttt 6840
ttagcaccaa ataatattcc gttgtccaga tgtagcacaa tgtttatcca ttcatgtaac 6900
ctgtgaccga ctcacagata ggatgtggaa tcactcacca cagaggcatt agacaataat 6960
cagacccaag tcatttcatg ggggaacaag cccacaggta ccagactgtc cagtgagtca 7020
gggccactcg taggaagtaa gaagagaggc tagagcatag ccaggtcctc actttatact 7080
ttaagcccat gtgtatttct cccaaaccac acagcattgt ttccatgctt tcagctttgc 7140
atgaataacg tgatacttga acgcatcatt tatcacttgc tctctttccc acagcgctgt 7200
tttcaagctt cttcctgttc atgatgctct gcttaaccct taagctgcat gggattctgt 7260
tctgtgaata cgcccacccc atgtattatc ctgcccagca aaaagtcccc aaaactctgg 7320
atggtggtta cctctaggga gggagagaag agattgggaa tagggagcga cttcaacggt 7380
gtttgtaatg ttttgtttct ttaaataaaa gagctgagat catttcagca gaatgttgat 7440
ttagagtctc ctggacaatt tgttgctcaa agtgctctct taaagagcac tttaaaaaaa 7500
aaaacctttt atcttattat ttatttattt atttattgag acggagtttt gctctgtcac 7560
ccaggctgga gtggagtggt gtgatctcag ctcactgcaa cctttacctc ctgggttcaa 7620
gcaattcccc tgcctcagcc tcccaagtag gtgggattac agatgcgtgc caccacactt 7680
ggctaatttt tgcattttag tagagatcgg tttctccatg ttggccaggc tgatctcaaa 7740
cgcctgacct caggtgatct gcccgccttg gcctcccaaa gtgctggtat tacaggcgtg 7800
agctaccatg cctggcttat cttatatatt tttaaaaaca gcttattgag atctaattta 7860
tgtaccataa aattcaagta tataattcag tgcttttata tataaaacat atatatgaaa 7920
tagcttattg agatataatt ttttatataa aacagcttat tgatatgtaa tgtatgtacc 7980
ataaaattta aatatataat tcactggctt ttatatattc acgaatatgt gcaactatca 8040
ccacagtcaa ttttagcata ttttcatcag ctcataaaga aaccccaagc ccttgaacta 8100
tcaccccata tccctcctcc cagcccgtcc ctcctactca taagcaacca ctaatctact 8160
tagtgtctat agatttccta ctctaggcat tccatgtgag cgggatcatg caatacgtgg 8220
gctcacacaa tataagtggc attccatgtg agtcggctca tgcagtatgt ccggctcctt 8280
tcactgagca taaggtcttc agcactcatc caggttgcag cctgtgtctg aatttcattc 8340
cctcttctgg ctgaatcgta ttccattgtg tatcttggac atatcctatt ctgctcaccc 8400
agccgttggt gggcgtttgg agtgttttcg cctttcagct gttttaagag ggttgcagtg 8460
aacatttgta caagttttgg acccaatgcc tgttttcaat tctcttgtgt agagagcact 8520
ttttagcaga aaaagaatag atttgtggcc tccctttgtg tgcggtcagt gccttgagaa 8580
gagtgaactg tgctgccacc tccggagccg tggagagcgc ggggcttggg tagcagctag 8640
gacgatacaa gttgggacaa ggccaggtgc aatggctcac gcctgtaatt ccaacacttt 8700
gggagaccga ggcaggggga tcacctgagg tcaggagttc aagaccagcc tggccaacat 8760
ggtgaaaccc catctctaat aaaacagaaa aattaactgg acggggtggt ggacgcctgt 8820
aatcccagct actcgggagg ctgaggcagg agaatcactt gaacctggga ggcggaggct 8880
gcagtgagtg gagatcagac cactgcactt cagcctaggt gacagagcga gactccgtct 8940
caaaaaaaag aaaaaaaaag aaagaaactc atggataatc ctccctctcg tgcagttcgc 9000
ctctacggac caaacttcat ccttcaggtg tactcatctc agaggaagtc ctggcaccct 9060
gtgtgccaag acgactggaa cgagaactac gggcgggcgg cctgcaggga catgggctat 9120
aagtgagtat ggggcagcac ccgccgagtg acagtaacag acagcagaaa cacgagaaga 9180
ccctctctct gcctccctgt gaaagcaccg gcacatgagt gctggggaca attgtcacct 9240
tccaaaagct gagccctata accagcaggt ggaatttgtc ctgctagggc tgtgcccagc 9300
acacagacct tggctcactg ccaccttgcc ctgcctcctc cttggcctct atagactcct 9360
ggttgctcgg gagtgcccag tgctgtggtc atctggtcag aggggtaggc tgagggcgtt 9420
aggtgcctct ttttccaagg tgcctctcag ccagggtcca ttcacctccc tgggtagagg 9480
ttggaccaga acagctggcg aggagggttg ggctggggag agcagcagag acaaatcctg 9540
tgccagtttc acttcattcg ggagccatgg aagccttttg agctggggag agaatcaatc 9600
aatcagactg atacttaaaa aatgtcattc ctgctcgtag ctctgaggga aggtgggaag 9660
gcttaacagg gtgtgtgtcg cctgacagtg attcctaacg ggggtggggc ggtggttacc 9720
atttaccagc actgcctggg gagatgcggc agccctcagg catcggggga gagggtggta 9780
ggatgctact gccactttgt tttccatggg agggtcccca ggtgatttct atgcaacttt 9840
agggtattca atatgccagt tttcagaatg aattaccact cggtgagaaa gttggcatct 9900
tagctagtca ctgtgacatc cctaaacagc aggggtgaat tacacagcaa agccccccca 9960
tcacagtcca ggaacctggt ggaattgata actggggcca tgttaacatc tgtacctttt 10020
attagattaa atgtgtgtat gattatacaa tcctatgtcc ttctcatagt ttcttgatcc 10080
taacctggat aagaaacacg accaatgaag gaattttgtc tgacacttta gggttattga 10140
atcgaaaaat cgttacaata ttctagcact tggttagaac gtgtgatttt ttttcctaaa 10200
tgctaaggtt tttccctctt attctgaatg tcgtatgagc ggtattatga catagtatag 10260
gatttgtgtt tgcttatgcc ttaaccatta tcacaaataa ggttttcttt tttaggaata 10320
atttttactc tagccaagga atagtggatg acagcggatc caccagcttt atgaaactga 10380
acacaagtgc cggcaatgtc gatatctata aaaaactgta ccacaggtat gcagcaattt 10440
cttcttgaaa aattttggaa tgaaatcaac taggagacac catggggaat cgttgtcctg 10500
agtctgattt ctctgagctg caatactcgg tctggatggg ttttgcattg ggaggagatt 10560
agagtctgac caggcctggt tactctaagc agcccttggt ttattcatag gaagtggctg 10620
aggtttctct gctatttcat tttcagcctc taccgtctgc ccttgttggt agcggctcac 10680
acttgcaaca tcgacattca actctattta gttttctttc ctcttcagac atttagaggt 10740
gtacctattt tgtcagggcg tggttctagg aatccaagat aatgtctcag tgtcccagcc 10800
agggtgaccg gctcattcca gtttgccagg gacttcactg gcttgagcaa gggaagtcct 10860
gctccattcc aggcagctgg gctggctggt cccgttagcc ccaaccccgg gacagcagtg 10920
ccagagggtg ctctgtgagg gatgggcagc attctggcgg cctgggaatg agttgtggtg 10980
tttccagggg gtagaagtgg gtacaagcca caggtcacat gatgagtggc tgacctggct 11040
gggagggcag aagaggggat ggacttaggc tcttcctttt gctttgcaca tatttaggat 11100
gtttgcagac ttgctatgat tgttgctgtt atgtgttttc tgatgtgaaa gatacacagt 11160
gtcctttgcc catgagctct ccttgcctcc caggtcccca gggcttatgc ctggtgtcta 11220
ggcatcacct ccctgcctgc caggtgccag gtgctgcatt tcgggggagg atgaactaat 11280
caccccgcgc cacctttcct ctgagtggga gcctggggca ggtttgcatt cctggaggcc 11340
gctggtggag gggtctgggg gcctgacttc cactgcagcc tgctgtcctg gggaatgtgg 11400
cagggcaagc ccagtgggga gggctgtgca cggccaggtg cacccatcaa aacagcaggg 11460
ctgcggtttg tccctgtgga gaagctaaac acagctgcct gggcactttg taaatgctga 11520
gtggttcttt gtctttctgg gttacacacg gaatcaggga gccaagtcca gccgggcagg 11580
gacgggggga ggggaggagg tgctgccgtc ccttggcaag agccttggga actcacaagg 11640
aggctggagg gcttggaaga aagaagagaa ggccattgtc tggtaggctc tattctatct 11700
cggtggtggt ggtgggggga ggcgcacttc ttttcctctt tctgtgcagc agttgccctt 11760
tgatgcctga gttcttggct tgttttctgt cgggcttctg tgaataacca catgtgccct 11820
ggcgctgtga ccacacaggg ctatccctac cgaccttagg attcttagga aatgtcttct 11880
cttaaagggg acatgtcttc acttggccgt gtcagtgccc cagagccaga gtccacctgg 11940
aatgcacctg tagtcactga gaacccgggg ggtgtgcctt agtaagaagg tgtcaggaag 12000
gacctattat tgtagggcct gggctcctgc aaggtggttt gggggtggtt ggaggaagca 12060
gagatttgct ctggattgga tgctgtcagg aagcaggggt aattctgtga ggctgcttta 12120
ttattttttt tctaggagga ggttggaatg aggctaggct aaagctgtga ttggtaaaga 12180
aacgtccgtc gctcaagtta gccaggacag gaggagacat cagatcgtga ttttgtggtt 12240
gtgagcacaa ggttcctgtt ctgtctgttc agacatcatt tcggaggagg ctccttgtgt 12300
cttgccccat ctcaggcatg gaggggccta gtccgatatt gacgctcagt gaaataattc 12360
aggttccgca gagcacacgg cccagctatc agggcgggcc agctctgcat gccaggggcc 12420
gcgtcttccc ttctcagcat agcctgggaa attcactgca ggacaaaatg catcagttac 12480
ttcctcttca tccataacct gggatgtttg actcccaaat gagtaactct tacgtttctt 12540
ctaatcctag ggaaactatt ggttatattg ctttcaacac tacaaattta aagcagttat 12600
aggagcccag aggtttccaa atggcttcct taaaaattag aagatgattt taaattccaa 12660
gaggaaaaac aaaactagca ttattgtata cttaccctca caaccgtcct aggagctggt 12720
acaattttaa gagaggttaa gtaacttgcc caaggtcaca ctgtggggat gtgagccgcg 12780
taccttggct cagtgtctgg tctttgccac tgtccctata tggatttact taccttattg 12840
gagttgtaac tagcagaccc ttctatgtct cagaagacag gagagggaac atcggaagaa 12900
atgactgatt tctaagcatg tgagaggcag gtgactccgc actatcgtga ccagaatttc 12960
ccctgttctt tttgcagtga tgcctgttct tcaaaagcag tggtttcttt acgctgtata 13020
ggtaagttca tctggagtcc cccttttgat acttctaact aggaaaagct ctctactttc 13080
agaacagtac tccctgtgtc tctgggggcg tgggagggaa gaaggtgggg tcacgggttg 13140
gaatgtgccc agcggcgtct cgctctttcc aaggagctcc tggtttagat ttccatggcc 13200
tgtagacacc ttcagccttg ggtccaaggg acaccccctg agatcaggca cgctcaagaa 13260
gctgacaaag ccctacactt tatgccaccc atgagctgga ggcccggcag gtctctttct 13320
ccagaaagca aaggggggtg gcgttagtga gccctggcag ccacctaacg tggacttgga 13380
gcatctgcgg ggctgtggtc cagcaccacc gtgtggccac caggtgctca tcagccagtg 13440
ggacccggga ggagggacaa gaccagagaa caacagtgct cttgcctctt ctctcctgaa 13500
ttttggacgg tggcttagac ttgggtgtcc ccatctctgt gtttagagtg cttacagttt 13560
ccaaactgtt tgcaaatgtg gaagccaccg tccctctcct ctgggatggc ccagtgctgt 13620
cgtggggccg tggtcctgag ctcagctttt catttgaaga ggtggaagga gctgacaccg 13680
tcccatcccg gcagggctgg ctcaggtctt ctttaggtcc tgagtggggg tccagcacag 13740
ccccaagggt gcgtggcacc cgccctgccc tctgcccatg cactcatctc ctggtggaga 13800
agacactcac acacaggaag cagggaaggc agcagacctc actcacccct caccccctca 13860
ctcaccccct actcaccccc tcaacctctc attcaccacc caccccctcg ccccctcact 13920
caccccctca ctccctcaac cctcactcac ctcctcactc cctcaaccct cactcacctc 13980
ctcacctcct cactctcccc ctcatccctc cctcacccca ccccgtcacc tcctcactca 14040
cctcctcacc ccctcactca cccttcaccc cctcactcac cacctcacct cctcactcac 14100
cccctactca acccctcatt cacccctcac cccctcactc acccctgcac cccctcactc 14160
accccttcat ccactcaccc acctgctcac ctcctcactc aacccctcac cccctcacta 14220
atccctcact ccctcacccc ctcacgccct cactcacacc ttcacctcct cactcacccc 14280
ctcaccccct caacccctta cttaccccct cactcatccc ttcacccctc actcaccccc 14340
tctctcaccc attcaccccc tcactcatgc cttcaccccc tcactcacct cctcactcac 14400
accttcaccc ctcagtcacc ccctcactca ccccttcacc ccctcaatca tgccttcact 14460
ccctcactca ccccttcacc ctctgaatta ctccctcatc ccctcactca ccccctcact 14520
caccccttca ccccctcacc caccacctca cccacccctc acccaccccc tcacctcctt 14580
acccctcacc cccctcactc acccctcacc ccctcactca ccacctcacc cacccctcac 14640
ccaccccctc actcactccc tcatcccctc actcaccccc tcaccccctc actcaccccc 14700
tcacccaccc ctcacccacc ccctcacccc ctcactcacc ccttcacccc ctcactcacc 14760
ccctcactca ccccttcacc ccctcactca ccacctcacc cacccctcac ccaccccctc 14820
actcactccc tcaccccctc actcaccccc tcaccccctc actcaccccc tcatctcctc 14880
actcaccccc tcacctcctc actcacccgc tcacctcctc actcaccccc tcgccccctc 14940
actcacccct caccccctca ccccctcact cacccctcac cccctcgccc cctcactcac 15000
cccctcgccc cctcactcac ccctcacccc ctcaccccct cactcatccc ctcacctcct 15060
cactcacccc ctcacctcct cactcacccc ctcacctcct cactcacccc ctcacctcct 15120
cacccacccc ctcactcact ccctcacccc ctcaccccct cactcacccc ctcacctcct 15180
cactcacccc ctcacctcct cacccacccc ctcactcact ccctcacccc ctcaccccct 15240
cactcacccc ctcacctcct cactcacccc ctcacctcct cactcacccc ctcacctcct 15300
cactcatgcc ctcaccccct cactcaccct ttcacctcct tgctcatccc ctcacttacc 15360
ccctcacttc gtcaatcacc cccccacctc gtcaatcacc ccctcacctt ttcactcacc 15420
ccctcactca cccccttact tcctcactta cctcctcacc ccccactcac cccctcaccc 15480
cccactcacc ccctcacccc acactcaccc cctcaccccc cactcacccc ctcacccctc 15540
tcacctcctc actcaccccc tcacctcctc acttatcccc tcaccccctc aattaccccc 15600
tcaccccctc aattactccc tcatcctttc aattacccac tcaccccctc acctcctcac 15660
tcctcactca ctccctcact caccccttca ccttctcact cacctcctcg tctcctcacc 15720
ccctcactca cttccagccc tgcccctccc atcttccttt tctttgtgtg agaatctggg 15780
gtccctgagt ggtgtcagtc cctccaagac tcaaggagtc cccagggcct tgttatccag 15840
aacaccccca cctgggtccc gggagacccc atgggatcac aggagtgttc agggaagtgg 15900
tgcttcctgg gtctgggtgg gctggagggg catcctccct tccccaagag gagaccccca 15960
ggagccccct aagtccatcc ccagcagtgg tgcccctgcc ctgtccttgc agcctgggag 16020
acccttggga ggggcgggcg ctgggtggct gggcggcttc tgctggtctc accccactgg 16080
cctcctgttt gtcatcctca gcctgcgggg tcaacttgaa ctcaagccgc cagagcagga 16140
ttgtgggcgg cgagagcgcg ctcccggggg cctggccctg gcaggtcagc ctgcacgtcc 16200
agaacgtcca cgtgtgcgga ggctccatca tcacccccga gtggatcgtg acagccgccc 16260
actgcgtgga aaagtatgcc aggggcggcg cgggccgggt gggggctcag ggctggccta 16320
cagccaccct gtgaccttga gcaggtctca acccttgcag ccccggcatc cttgtgttta 16380
aatggggaga gtattgcacc tgcttcctag ggctgtgaga catcaagtgc gctcatgcca 16440
ggcagtgcat ggctgtatgc actgagtgtc ccctgcacgc agggcacagg gtgcaggtgg 16500
aacattctcc acgatgtcgc cgtgaccagc gttccttcca gccactgtcc tctgagctct 16560
gtcctgccct tgagcaaagc ccctgccccc tgaggtatcc tgtctccggg acgctagtcc 16620
caggagaggg cacactcaga caggcttcag gctgccctgc tggaaggtcc ctggggttaa 16680
gcgttcttgg ccacagcatt gctcatgcag agggttaggt aggggtgagg ctagccgtga 16740
cagtattagc atttatggac gctaccaccc cctccccttt tccttaaaca catagtgctt 16800
ttggtcacat gctgctttgg aggaggcctc acttggcgga tgtatttttc tgccttagag 16860
agaggctgaa ctgggtttga ctgttggccc agccctctct tgctgcgtgc ccttagacga 16920
ttcactcaac gtctctgatc catggcatgt acaactataa gatgggcatg cccttctcct 16980
ctcgggctgt tatgaaggtc aaggaagcaa gggctgttac ccaagggtgc tcccttctct 17040
ccccctcttc acacccccag gtgctctggg ccctctagga actgggtttc tctcaagggc 17100
tgttacccaa gggtgctccc ttctctcccc ctcttcacac cactgggtgc tctgggccca 17160
ctaggagctg ggattctctt aagagggaaa ctcttggata aaggaaatgg tttgattgat 17220
atcggacaag tctgttcatt agtatccatt tattaagcac ctaccatgtg ccaggaaatg 17280
ctttggcgta caaaggaaaa taagggccag tcctgctaga aatggccttg aaaccccagg 17340
gagggatgtc ggcccattgt gggtgctgca gattccttga aggtgatgca agagccagaa 17400
agaaggatga tgtggggggc tgaggcaggg agtcggggtt gggggagtgt gggggagaag 17460
gggagaccga gcacctcttc cactatctcc ctgtgtggtt tttggtgaac catcctgcct 17520
ctgggtgtct tgcctccagc ttctgacgtt ggaagttcat ccactgagag ctctgtgttt 17580
atggctctga gatactgagt ccttcttctc tcccagacct cttaacaatc catggcattg 17640
gacggcattt gcggggattt tgagacaatc tttcatgttc tatggagccg gataccaagt 17700
agaaaaagtg atttctcatc caaattatga ctccaagacc aagaacaatg acattgcgct 17760
gatgaagctg cagaagcctc tgactttcaa cggtacgtgt ggctcaggct tggcaagcag 17820
gttggcagaa tcttaaagag atgttgattg gaaatgacac ttgtgctatg ccaaatggaa 17880
gggaggcatt tgcgttgagc gagggtagcg tgcagcgggt ggccaatggg agaggctcac 17940
agaggctaag agcacctgcc gcattttggg ggaggcagca gccaccacat ctgttctgta 18000
ctgtactgag tggtggtgat tcaagccagg catggaaaag gctagaacag ggctttccca 18060
ctgcagcacc cttgacatct gggtggttct ctgttgtagg gctctcttgt gccttgtagg 18120
atgtttaaca gcgtccccag cctctaccca ctggaggcca gtagctacca agctgtgaca 18180
accagtgttg cctgctgaca ttgccaaaca tccgctttga ggcaaagtca cttccagttg 18240
agaactactg gcctaaaatg tgtaaagatc cttgattttt aaagatacat tctaaaacca 18300
agttgcttaa ttcaggacaa acatgctttc tcttagcctc ttattcggtc ccactctggt 18360
ccatccaagg gtctggaatg ttctagcccc atgtggatac agaagaagca aaacctcagc 18420
cctccctaca gcatgtctgt attcacattg ggaaatggtt cacatataga agagcgaatg 18480
cctgagcaat ggcgtggtgc ctctggggcg aaagctgact ccattgactc catcggcttt 18540
ttggctgttg cctcctgtgt gtctttcccg tcttgatcac ctggagatat gtaattttgg 18600
aagcagagct agcaaataat tcctcttata agcagagcta gcaaataatt ctacttataa 18660
gtagcataac gtcttgcctg ccagaaggag aggtctggca gggggagaaa gtgagaatgt 18720
gggacttgtt gggatgcagg gtcctctggg cagggtggcc agggtgccag gcccagcagc 18780
ctgcatgtgg gaaggccagg tggagacata ggtgataccc gcctggctca ctgtgttttc 18840
tcttcttgaa acagacctag tgaaaccagt gtgtctgccc aacccaggca tgatgctgca 18900
gccagaacag ctctgctgga tttccgggtg gggggccacc gaggagaaag gtgaggctgc 18960
tcctgggcac acaggactgc agggcccaca gatggagcat tgggttcgga agtgggaggt 19020
ccaggtttta atcccagttc tactactcaa tgactggatg actttggttg attcccccag 19080
tccttgtgcc tcagtttctc catctgctaa gtgggagaaa tcctgcccag cctacctaat 19140
acactgtgtt cttatcgtga tcacacagag cagcatgtgg aatggctttt gaagtatctg 19200
ggccatacga gtttagaggt gcaggatctc ctgtgttgca ctcattgtga gtttagagct 19260
gccctggaga tcccaccaag gcctgcgtgg ctgagtgaca gggggcttgg tgaggacggg 19320
catcctggac ccatggtggc cacatctaag cctgtcctct gccctgataa ccacagagag 19380
aggctctctc cacccacttc ctttgcaatc tgcatttctc tctgacagtc tttcaaatga 19440
agggagcctg gctgcttcat ttttatggag ggttggaagt gcttagtggc aggcacaaag 19500
gttcatttta catattgttt atatccttct caaaagcgtc taggccatac agacaacaaa 19560
tcctttcaaa caaggggaaa agtacaaagg ttgggtgatt tctggggagc gtcagggaag 19620
gtagtggggg gcatcctggc tcctcatcag cagaaactta ctacagtaga gccacaggct 19680
gggcaaaaga cctcatggaa tccaagatga agggaatatc gacaaatatt tgtgcgcacc 19740
tgcacctagt acaggctggg tgctactcag gtgctgggaa tgcagaagtg aacagagtaa 19800
gacaaatgtc tctgctgtca ggagctttac ctctcttctg gatgtcggtg gtggggacgg 19860
ggcaggtgtg gtcagacaga tgggagacaa acaactgagc gaggtacttc caaacatctg 19920
agggtgggga tcacaaggtc ccggctattt tgaaggggtg gtcaggaaag gcttctcgga 19980
agaggtggca tttgagctga gactcaaatg gcaaaaatgt gtacacatca aaaaggctag 20040
tgcatgtatc ttcaggtgtg gtcaaggggc caaggaggtg ggctggggcc agattgcata 20100
ggtccttgtg gattatggtg aagacaccag cttctcatct gcttgaggtg gggagatcgt 20160
gagccgggga gtgccatgat ctggcagctg cgtggggagt ggggatgaat ggatggagac 20220
gaggatgatg gtgacaagtc cattgctgtg gttccttgag acaggaagcc agctcatagc 20280
agagtgcggg cgtggatgtg aagagatgag ggtacactag ggctagagcc accagactta 20340
ctgatgggtt gcatgtctgt gggagagaga gtgagaagtc agggacgatg gctttccact 20400
ctgtggctga agccccaggg tggcgggtgg tgccattttt caagccagga aatattggtt 20460
ggtgagaatt tggggtggga gaaggtgtga cggagggttc tggttttgca cactaagccc 20520
acggtgccca gaagatgccc gaggggaggc agcaaagcga gagtgggaaa tgcagaggtg 20580
gcaagtgcag gccgtgtctt gagaagctct aatgtgcagg ggagccgaga agcaggcggc 20640
ctagggaggg tcacgtgtgc tccagaagag tgtgtgcatg ccagagggga aacaggcgcc 20700
tgtgtgtcct gggtggggtt cagtgaggag tgggaaattg gttcagcaga accaagccgt 20760
tgggtgaata agagggggat tccatggcac tgatagagcc ctatagtttc agagctggga 20820
atttctttcc ctgaagctga actccagagc tgcattcagc acaggcaccg ccagttgtaa 20880
ggagaatcca ggtttcccag gagaggggtt ggtgctggga tgagctgacc ggggcagggc 20940
tggaaaatag ggctgtgacc atctgtgtag tgcgtgtgga ggtctcaggg agggaagtgt 21000
gctctccctg cgagagctgc aggcaacact gggagctcaa caagtctccc tgtccttagg 21060
gaagacctca gaagtgctga acgctgccaa ggtgcttctc attgagacac agagatgcaa 21120
cagcagatat gtctatgaca acctgatcac accagccatg atctgtgccg gcttcctgca 21180
ggggaacgtc gattcttgcc aggtaattca acatttttat tctacctttg gtccttacca 21240
gatcctactg aaccccccat gagagagagg gcattcttgg ggtcagcaga gcctcctcag 21300
tgacacggag ccagctcggg gcagtcatgg gaagtgacgg ccacaaacag tgcgaacgct 21360
tctggtggca gaaggaagta cagtcaacaa atcacacaca ccctctgaaa aaccggtatt 21420
tggtaaaagt gccagtggaa cagaaacaag tatttagact attttaaatt atgaacggca 21480
atttatttag taacttttag cttgaacaga ttaaaattca ggatgggggc tatctctttg 21540
ggggttacat ctctgttacc atcacccctt gatggtggag attcgaagcc cacacagtca 21600
ctcgtaactc acactgcgac ccccgccccc caactcctct aggcctggtc agtggtgtgc 21660
ggcagattgt gacttgattt tctgctctct gtaccttgct gtgtcccaca gggtgacagt 21720
ggagggcctc tggtcacttc gaagaacaat atctggtggc tgatagggga tacaagctgg 21780
ggttctggct gtgccaaagc ttacagacca ggagtgtacg ggaatgtgat ggtattcacg 21840
gactggattt atcgacaaat gagggtaact atcctgtcct ccttctgact gtgttctccg 21900
attcctcgag ccaaagccag acatctgtta ggcgtggttc tgctgctgga agctgactgg 21960
tgaccactgg tcagcatgaa gcaaactctg cttcctccag ccacagcccc atccccccag 22020
tgtccaccca ttgcccattg cctctcactg gcttcacttg catatttccc ctggtgtttg 22080
gatgaaaagc gctggggctc agcttgtgtg aaattccttg gtgctctgcc aaccacactt 22140
cgttctggct cagctgactc agctgttcca cccaggccac ctcacatcaa actttttttt 22200
tttttttttg agatggagtc tcactgtgtc gcccaggctg gagtgcagtg gcacaatctc 22260
gactcactgc aacctttgcc tcctgggttc aagtgattct cctgcctcag cctcccaagt 22320
agctgggact acaggcatgc gccaccacgc ccagctactt tttgtatttt tagtagagat 22380
ggggtttctc catgttggcc aggctggtct cgaagccctg acctcaggtg attcacccac 22440
ctcagcctcc cacagtgctg ggattacaag tgtgaaccac ggtgcccggc ctcacatgaa 22500
acttttgatt tatagagagc agagggaaga gccggctgtg cccatccttt tctggggcca 22560
tcgagtggct cctgggcagc ccccaaggtt aggaagggca ggagcagcca gggttctctg 22620
atgccccaga ctcaagcacg agggaaggtc tcaggggttc catgtgagcc tcatggatgt 22680
ctctgcttag cagagccctg gctttgggca ttgtccagat agggggtgag aaccagatct 22740
tctcatctcc aggacctcag acgtatagtt ttctcagatt tctgtgcttt ctggggctgg 22800
gctactagtg gaagaaagca gtctattctg tcttctccca aatctcccag atgcccagtc 22860
tgttgaagga ggagcagaac cagggggcct ttcccgctga ggcccgacct gtgtctcctt 22920
caaatgacac gcgggactca gggccttccc atgaccatgg ggcccagggg gcgtcacctg 22980
gcccagggcc cagtgctaga aacagatgac cccaggagga ggaggcaggg caggagggaa 23040
gctggcaggg ctgggatggt cagccaggct gaggggcgga ctcgcaccag gatggagcta 23100
ggaaatgatc caggtgtgtt tggcggctgc aggtgggtcc gcatggctgt gcagggaggg 23160
aagggctgcg tggcaggaga gcagccgggg gaggcccaga ctctgctgaa gagatgcctg 23220
ttgtgccggc ctccacatcc gctgcccgct ccttccggag ctcctgcccc gccatgctca 23280
gcctgactct gaccaacacg ttggagagaa gaatgatccc tttgtgctat taagcttgct 23340
tatttggttt ctaagtgctt catgcgaacc tagaggaaaa aattattttc cacctttgtt 23400
tgtcttaaga aaataacaca cttttttttt tcctatttga acaggcagac ggctaatcca 23460
catggtcttc gtccttgacg tcgttttaca agaaaacaat ggggctggtt ttgcttcccc 23520
gtgcatgatt tactcttaga gatgattcag aggtcacttc atttttatta aacagtgaac 23580
ttgtctggct ttggcactct ctgccattct gtgcaggctg cagtggctcc cctgcccagc 23640
ctgctctccc taaccccttg tccgcaaggg gtgatggccg gctggttgtg ggcactggcg 23700
gtcaagtgtg gaggagaggg gtggaggctg ccccattgag atcttcctgc tgagtccttt 23760
ccaggggcca attttggatg agcatggagc tgtcacctct cagctgctgg atgacttgag 23820
atgaaaaagg agagacatgg aaagggagac agccaggtgg cacctgcagc ggctgccctc 23880
tggggccact tggtagtgtc cccagcctac ctctccacaa ggggattttg ctgatgggtt 23940
cttagagcct tagcagccct ggatggtggc cagaaataaa gggaccagcc cttcatgggt 24000
ggtgacgtgg tagtcacttg taaggggaac agaaacattt ttgttcttat ggggtgagaa 24060
tatagacagt gcccttggtg cgagggaagc aattgaaaag gaacttgccc tgagcactcc 24120
tggtgcaggt ctccacctgc acattgggtg gggctcctgg gagggagact cagccttcct 24180
cctcatcctc cctgaccctg ctcctagcac cctggagagt gcacatgccc cttggtcctg 24240
gcagggcgcc aagtctggca ccatgttggc ctcttcaggc ctgctagtca ctggaaattg 24300
aggtccatgg gggaaatcaa ggatgctcag tttaaggtac actgtttcca tgttatgttt 24360
ctacacattg ctacctcagt gctcctggaa acttagcttt tgatgtctcc aagtagtcca 24420
ccttcattta actctttgaa actgtatcat ctttgccaag taagagtggt ggcctatttc 24480
agctgctttg acaaaatgac tggctcctga cttaacgttc tataaatgaa tgtgctgaag 24540
caaagtgccc atggtggcgg cgaagaagag aaagatgtgt tttgttttgg actctctgtg 24600
gtcccttcca atgctgtggg tttccaacca ggggaagggt cccttttgca ttgccaagtg 24660
ccataaccat gagcactact ctaccatggt tctgcctcct ggccaagcag gctggtttgc 24720
aagaatgaaa tgaatgattc tacagctagg acttaacctt gaaatggaaa gtcatgcaat 24780
cccatttgca ggatctgtct gtgcacatgc ctctgtagag agcagcattc ccagggacct 24840
tggaaacagt tggcactgta aggtgcttgc tccccaagac acatcctaaa aggtgttgta 24900
atggtgaaaa cgtcttcctt ctttattgcc ccttcttatt tatgtgaaca actgtttgtc 24960
tttttttgta tcttttttaa actgtaaagt tcaattgtga aaatgaatat catgcaaata 25020
aattatgcaa tttttttttc aaagtaacta ctgcatcttt gaagttctgc ctggtgagta 25080
ggaccagcct ccatttcctt ataagggggt gatgttgagg ctgctggtca gaggaccaaa 25140
ggtgaggcaa ggccagactt ggtgctcctg tggttctcga gataacttcg tataatgtat 25200
gctatacgaa gttatatgca tggcctccgc gccgggtttt ggcgcctccc gcgggcgccc 25260
ccctcctcac ggcgagcgct gccacgtcag acgaagggcg cagcgagcgt cctgatcctt 25320
ccgcccggac gctcaggaca gcggcccgct gctcataaga ctcggcctta gaaccccagt 25380
atcagcagaa ggacatttta ggacgggact tgggtgactc tagggcactg gttttctttc 25440
cagagagcgg aacaggcgag gaaaagtagt cccttctcgg cgattctgcg gagggatctc 25500
cgtggggcgg tgaacgccga tgattatata aggacgcgcc gggtgtggca cagctagttc 25560
cgtcgcagcc gggatttggg tcgcggttct tgtttgtgga tcgctgtgat cgtcacttgg 25620
tgagtagcgg gctgctgggc tggccggggc tttcgtggcc gccgggccgc tcggtgggac 25680
ggaagcgtgt ggagagaccg ccaagggctg tagtctgggt ccgcgagcaa ggttgccctg 25740
aactgggggt tggggggagc gcagcaaaat ggcggctgtt cccgagtctt gaatggaaga 25800
cgcttgtgag gcgggctgtg aggtcgttga aacaaggtgg ggggcatggt gggcggcaag 25860
aacccaaggt cttgaggcct tcgctaatgc gggaaagctc ttattcgggt gagatgggct 25920
ggggcaccat ctggggaccc tgacgtgaag tttgtcactg actggagaac tcggtttgtc 25980
gtctgttgcg ggggcggcag ttatggcggt gccgttgggc agtgcacccg tacctttggg 26040
agcgcgcgcc ctcgtcgtgt cgtgacgtca cccgttctgt tggcttataa tgcagggtgg 26100
ggccacctgc cggtaggtgt gcggtaggct tttctccgtc gcaggacgca gggttcgggc 26160
ctagggtagg ctctcctgaa tcgacaggcg ccggacctct ggtgagggga gggataagtg 26220
aggcgtcagt ttctttggtc ggttttatgt acctatcttc ttaagtagct gaagctccgg 26280
ttttgaacta tgcgctcggg gttggcgagt gtgttttgtg aagtttttta ggcacctttt 26340
gaaatgtaat catttgggtc aatatgtaat tttcagtgtt agactagtaa attgtccgct 26400
aaattctggc cgtttttggc ttttttgtta gacgtgttga caattaatca tcggcatagt 26460
atatcggcat agtataatac gacaaggtga ggaactaaac catgggatcg gccattgaac 26520
aagatggatt gcacgcaggt tctccggccg cttgggtgga gaggctattc ggctatgact 26580
gggcacaaca gacaatcggc tgctctgatg ccgccgtgtt ccggctgtca gcgcaggggc 26640
gcccggttct ttttgtcaag accgacctgt ccggtgccct gaatgaactg caggacgagg 26700
cagcgcggct atcgtggctg gccacgacgg gcgttccttg cgcagctgtg ctcgacgttg 26760
tcactgaagc gggaagggac tggctgctat tgggcgaagt gccggggcag gatctcctgt 26820
catctcacct tgctcctgcc gagaaagtat ccatcatggc tgatgcaatg cggcggctgc 26880
atacgcttga tccggctacc tgcccattcg accaccaagc gaaacatcgc atcgagcgag 26940
cacgtactcg gatggaagcc ggtcttgtcg atcaggatga tctggacgaa gagcatcagg 27000
ggctcgcgcc agccgaactg ttcgccaggc tcaaggcgcg catgcccgac ggcgatgatc 27060
tcgtcgtgac ccatggcgat gcctgcttgc cgaatatcat ggtggaaaat ggccgctttt 27120
ctggattcat cgactgtggc cggctgggtg tggcggaccg ctatcaggac atagcgttgg 27180
ctacccgtga tattgctgaa gagcttggcg gcgaatgggc tgaccgcttc ctcgtgcttt 27240
acggtatcgc cgctcccgat tcgcagcgca tcgccttcta tcgccttctt gacgagttct 27300
tctgagggga tccgctgtaa gtctgcagaa attgatgatc tattaaacaa taaagatgtc 27360
cactaaaatg gaagtttttc ctgtcatact ttgttaagaa gggtgagaac agagtaccta 27420
cattttgaat ggaaggattg gagctacggg ggtgggggtg gggtgggatt agataaatgc 27480
ctgctcttta ctgaaggctc tttactattg ctttatgata atgtttcata gttggatatc 27540
ataatttaaa caagcaaaac caaattaagg gccagctcat tcctcccact catgatctat 27600
agatctatag atctctcgtg ggatcattgt ttttctcttg attcccactt tgtggttcta 27660
agtactgtgg tttccaaatg tgtcagtttc atagcctgaa gaacgagatc agcagcctct 27720
gttccacata cacttcattc tcagtattgt tttgccaagt tctaattcca tcagacctcg 27780
acctgcagcc cctagataac ttcgtataat gtatgctata cgaagttatg ctagtaacta 27840
taacggtcct aaggtagcga gctagctcca cgtggctttg tcccagactt cctttgtctt 27900
caacaacctt ctgcaagaaa accaagggcc tgaattttaa cttcctg 27947
<210> 6
<211> 25333
<212> DNA
<213> Artificial Sequence
<220>
<223> Recombinant polynucleotide
<400> 6
gcagagtcta agaaatcgct gtgtttagcc ctcgccctgg gcactgtcct cacgggagct 60
gctgtggctg ctgtcttgct ttggaagttc agtaagtgca gggagcctcg atcccaccat 120
gtgctcctgc agtccccagt gctctgagcc agaccctgct ctctgggcta ttgagacctc 180
tggaggccct ccgtgaggtt cctctcttac ataacgaggc tgtctctctt cccttctctt 240
gtttagctat gagattgaca catcatgggg aaagcattta gaatgtaccc agtgctttgg 300
ggtgcttggt gccacccagc actgtgagca caggttcttc taccttgggg ccacacccag 360
ttacctgtat ctcactgcac agcagtggct gttggggacc aggcccaccc ctccatgtcc 420
cacctcctgc aactgcagcc tgagccttcc catcagcctg gggtggtgca gacccatgtg 480
ccattgtgga tccttcaagt tacctgtgtg gcagagagga cgtgtgagtg ccgtccaaac 540
ccaaacactg agagggtcct tcccattgcc cccacggaag taaggtgccc cagtgctaat 600
tccacttata cttgctggtg gcaaggacac ttctcctcct tattaaagtg ggggattggc 660
tgggtgaggt ggctcacgcc tgttatccca gcactttaag aggccaaggc aggtggacca 720
cctgaggtca ggagtttgag accacaagcc tggccaacat gttgaaactc catctctact 780
aaaaatacaa aaattagtca ggcgtggtgg cgtgcacctg taatcccagc tacttaggag 840
gctggggcag gaggatcact tgaacccagg agttggaggt tgcagtgagc caagattgtg 900
cccctgcact ccagcctggg tgacagaatg agacttcatc tcaaaaacaa aacaaaacaa 960
aacacagtgg ggccaggagt tggaggctgc agcgagctac agtaatgcca cggtgttcct 1020
cactccatga ggctcattgc gtttctcagc ctgaagggca cctctcttct gttttctctg 1080
caagtgggca gcaagtgctc caactctggg atagagtgcg actcctcagg tacctgcatc 1140
aacccctcta actggtgtga tggcgtgtca cactgccccg gcggggagga cgagaatcgg 1200
tgtggtgagt cagccttgac cttgggaagg gactcctctg ctcaccttgg agacagcagc 1260
cgggtccagg ggcctttggg tgactgggcc tggcgtgcgt ccagtacgct gacacatgat 1320
gtcattgaat ccctgctcca ggctgagccc tggggctcag agaggttgtg tttccggccc 1380
aacctcaccc agcaggtggg agatgacagg gccaccgagg actgtgtcat tggaaccaca 1440
cgtgctctga actgccacag gaagtcagtt aagatgagca aactgtttat aaagttggag 1500
atgcaggcta ggaacggtgg ctcatgcctg taatcccagc actttgggag gccgaggcag 1560
atggatcacc tgaggtcagg agtttgagac cagcctgacc aatatggtga aaccttatct 1620
ccactaaaaa tacaaaaatt agccaagcgc ggtggcgggt gcctgtaatt ccagctattc 1680
aggaggctga ggcaggagaa tcacttgaac ctgggaggcg gaggttgcag tgagctgaga 1740
tcacgccact gcattccagc ctgggagaca gagctggctc aaaaaataaa ttaattaatt 1800
aaaaacaaaa ttggagatgc actatgttat tttcaaaaca agctgccttt aaagatctat 1860
ctgttgtcac agggtgggct catctgtttc attttatttt ctgtggttta tctatttatt 1920
cattttaatg aactaggaag cattgctcct atttatggca taccacatga tgtttggata 1980
cgtgtatgcc tgtggcatgg ctaagtcaag ctagaacatg ggccttacct catatacgtg 2040
tcttattaag aacacataaa acctactctt gtagtgattt tcaaatatgc aacatatagt 2100
ttattaactg cagtcactat gatgtacaat agattgctcg aacttattcc tcctgtctaa 2160
ctaagatttt gtgacctctg accaacatct ccccagtgtt gtcacccccc gcccccagcc 2220
tctgatagct gcctttctac tctctgcttc tgtgagtttg atgtttatac attccacatg 2280
taagtggcct catgcagtgt ttctgtctct gtgtctggct tgttcactta gcgtaatgtc 2340
ctccagcttc atctatgttg ttggaaatga caggatttcc ttctttcttg tggctgaata 2400
gtattgcctt gtgcatatac accacatttt ctttatccct tcattcactg atggactctt 2460
aggttgatgt catgtcttgg ctgttgtgaa aaatgccgca gtgagcgtgg gcgtgcaggt 2520
ccctcttcaa cacacggatt tcctttcctt tggatataaa cccagcagtg agattgctgg 2580
atcacatggc agttctgttt ctcacctttt gaggaaactc catactgttt tccataatgg 2640
ctgtagcaac ttccactccc acccccacgg tgcaaagtct ccatttctct tctacaacct 2700
caccaactcc tgttattttc catctttctg atagtagcca tttgaagagg tatgagatga 2760
tacctcattg tggttttcat ttgcattttt atttgtattt ttcatgaatt tttgagggtg 2820
atttcaaggg tagttagtga ctcgaacagg gaaacgatcc tgagtatgag ggttgtgcta 2880
atcatccccc tcctgccagc tgcgtacgga atggggctct gcagatggca gggagctggc 2940
tcgtttctct ttaagagctg ccttttactt ttcttcctct tcctttaaaa cttatttcct 3000
ggccggacgc agtggctcat gcctgtaatc ccagcacttt gggaggccga ggtgggcgga 3060
tcacgaggtc aggaattcca gaccagcctg gccaacatgg tgaaaccccg tctctactaa 3120
aaatacaaaa attagccaga cgtggtggtg cgggcctata gtcccagcta ctcgggaggc 3180
tgaggcagga gaatcacttg aacctgggag gagggggttg cagtgagccg agattgcgcc 3240
actgcactcc agcctgggcg acagagccag actccatctc aaaaaacaaa aaaaagttat 3300
ttcccaagca cagccatgta ttccaggctt gtggatcagc gttggtggtg gtgtgtgctc 3360
tcatatctta gttccagcta agcacactct gacatgttta cactagaacc atttgttttt 3420
tctagaaata gaaatttcag aattgtagag tcagaggact taccagaaat ctcttaggta 3480
gttctcctcc cctccctcaa gtgcagtcct aacctcctgg agttttctgt agaaaccaca 3540
agcctcagag ctggccgaga attctagcca aagatttttc catgccaaag taatcccccc 3600
tctcctaagg gccatccttg gtggggactg gtttcctgtt aagccctcgc tgtcagtcct 3660
ggctgtggaa tttcctggtg aggagcactg gcccgtggag ctcggccctc gtgccggcct 3720
tgagcaggcc caagtgttcc gtgttcttga tacctttcct ccagcacagt cttgcttccc 3780
agaaaaaggt ttgcacttga aaatgatgca tttgctgatt aaacatagtt cttttgcttt 3840
atttggtttc taaaataaag tgggagtttt tgagattgag taacgtgagg ttaagatagc 3900
acgtggaatg gctttttctt ttctttctat tttttttttt tttttcctgg agacagggtt 3960
tcactctgtt gcccaggctg gagtgcagag gcatgaccat ggctcactgc aacttcgatg 4020
tcctggggtt aagcgatccc ccagcctcag ccccccaagt ggctgggact acaggtgctc 4080
gccaccacac ctggctaatt tttgtatttt ttgtagaaaa tgggtttcat caatgttgtc 4140
cagactggtc tcgaactcct gacctcaagc aattctcctg cctcagcctc ccagactgct 4200
gggattacag gcgtgaacta ccacgcctgg cctggaatgg cttttgatgt tctcctatgt 4260
gcacatgtgg gtgaataaac accaacaaag tccttatgtt acctgaagag ttgctctctt 4320
cttaatattt aagtcgtatt tatttaaata ctttaatagt tgtacactat taaagtatta 4380
ttaggtcaaa atcaaggaag tacaaaaggg tatgctgtga aaaatctctt cttccttgct 4440
ctgcttactt acctaccccg catcccccca tacaccccag acacacacac acacacacac 4500
acacacacac acacacgcat cactcccata catgcccacc tgtttaccag ccaatcacat 4560
ttcttggggc aactcatctg agttgcttct ctttccagag agtttttgca taaagaagca 4620
caggtatttc tgcgttacca tgaccctatt tcccagtggt tcctagccag ttgactctcc 4680
tgcactggat accatcctgg acagcattcc ttagggaaat gagccccctg ttttttccca 4740
ccatggcaca gttggtcctt tgcatggacg caccattatt gcccctgtct cttcttggtg 4800
gaccttaagg ttttctccat ccttttgctg taacacacac tgctccaagt gtgtgagcat 4860
atcagtagga aacgcttcca ggagtagaac tgctaggtca gagggcgtgt ggatctgtaa 4920
cctgacagac ctagaccggc ttcagtttgg ttttatccag tttccatatt gattattcat 4980
ataaaaggaa acagacaaac ataacgctgt gcatgtattc tctcttagac cagaacaggc 5040
atagggtgca cttttaattt gtccatttcg tagagtagaa attgtttttg ctgaaatgaa 5100
caccttagga tgctgaagaa tatgacccgt cccatggaaa acattcaaaa atgtgtgtag 5160
cgctttcttc ccaagggtgt gtgtgcgcat attttaacac taattcactt tctacttccg 5220
ttgctatcct ttctgtgagt ctttctcaga atctcagaaa agaaactaaa ttgttcactc 5280
tagttatcaa tgctgtactc tatacctgga atttgctaaa agggcagatt ttaagtattc 5340
tcaccacaga aaagagaaaa gaaaatggta attatgtgac gtggtggaca tgttaactag 5400
ctttattatg gtgagcattt cacagcggat atccagtcat cacgctgtac acattaaaca 5460
tgtacaattg ggtttttttg agacaaggtc tccttctgtc acccagtctg gagtgcagtg 5520
gctcagtcat ggctcattgc agcctcgacc tcctgggctc aatccatcct tccccctcag 5580
cctcctgaaa agctggggcc acaggcatgt accatcatgc caggctaatg catatatatt 5640
tatatttttt ggtggagatg gggttggtct cgaactctgg gctcaagtga tcctcccgcc 5700
ttgcccttcc aaagtgctga gattacaggc atgaaccaca gcaccaggcc tacatgtaaa 5760
atttttattt gtcaactata ctttgacaaa gctgagaaaa aaaatcctaa tatttaaaaa 5820
aaaaaaaaaa aggactagct tgagaccttt tccagctctc tggcttatca gctgccgtct 5880
cttccgggtg cagatagctg gaagggaaag aaaatcccta aaattaccca caagccaaga 5940
atgaagtgtc tccctttgag ccacagtggc agttttgttt ttaatcatag aagtgtattt 6000
tgagccgggt gtgctggctc acgcctgtaa tccccgcact ttgggaggcc gaggtggggg 6060
gcggaggggg tggggatcgc ctgaggtcag gagttcgaga ccagcctgac caacatggag 6120
aaaccccgtc tctactaaaa atacaaaatt agccggcgtg gtggtgcatg cctgtaatcc 6180
cagctactca tgaggctgag tcaggagaat ctcttgaacc caggaggtgg aggttgcggt 6240
gagctgagat catgccattg cactccagcc tgggaacaag aaaaaaaaag aagaagaaga 6300
agaagtgtat tcatttcagt tacttttaaa aaagtgaaca gactttatat tttagagcgg 6360
ttttaggttt acagaaaatg aaacagacag ggcagcgagc tccttgtact cctccccagc 6420
acacagttgc cctgttatga acatcccaca tcagtgctgt gcgttcatta acaccgatga 6480
acctgatgca tacattatga tgaactgaag tcctggactt caccctttct cttgtacagt 6540
tctgtgggat ttgacaaatg cataatgctg tacagccaca atgatagtat cgtccagagt 6600
agttctcctg ccttaaaacc tcttttgctg cacctgtttc tctctcccca ctcaccccag 6660
ctatctgatc ttcttagtgc ctccgaagtt ttggtctttt caggatgttg tagcgttgga 6720
atcatggagt atgtagcctt caccacatac accttccttc actttgttgg cttcctttac 6780
ttagtaatat gcattcaagt ttcctccatg ccttttcatg gcttgatagc tcatttcttt 6840
ttagcaccaa ataatattcc gttgtccaga tgtagcacaa tgtttatcca ttcatgtaac 6900
ctgtgaccga ctcacagata ggatgtggaa tcactcacca cagaggcatt agacaataat 6960
cagacccaag tcatttcatg ggggaacaag cccacaggta ccagactgtc cagtgagtca 7020
gggccactcg taggaagtaa gaagagaggc tagagcatag ccaggtcctc actttatact 7080
ttaagcccat gtgtatttct cccaaaccac acagcattgt ttccatgctt tcagctttgc 7140
atgaataacg tgatacttga acgcatcatt tatcacttgc tctctttccc acagcgctgt 7200
tttcaagctt cttcctgttc atgatgctct gcttaaccct taagctgcat gggattctgt 7260
tctgtgaata cgcccacccc atgtattatc ctgcccagca aaaagtcccc aaaactctgg 7320
atggtggtta cctctaggga gggagagaag agattgggaa tagggagcga cttcaacggt 7380
gtttgtaatg ttttgtttct ttaaataaaa gagctgagat catttcagca gaatgttgat 7440
ttagagtctc ctggacaatt tgttgctcaa agtgctctct taaagagcac tttaaaaaaa 7500
aaaacctttt atcttattat ttatttattt atttattgag acggagtttt gctctgtcac 7560
ccaggctgga gtggagtggt gtgatctcag ctcactgcaa cctttacctc ctgggttcaa 7620
gcaattcccc tgcctcagcc tcccaagtag gtgggattac agatgcgtgc caccacactt 7680
ggctaatttt tgcattttag tagagatcgg tttctccatg ttggccaggc tgatctcaaa 7740
cgcctgacct caggtgatct gcccgccttg gcctcccaaa gtgctggtat tacaggcgtg 7800
agctaccatg cctggcttat cttatatatt tttaaaaaca gcttattgag atctaattta 7860
tgtaccataa aattcaagta tataattcag tgcttttata tataaaacat atatatgaaa 7920
tagcttattg agatataatt ttttatataa aacagcttat tgatatgtaa tgtatgtacc 7980
ataaaattta aatatataat tcactggctt ttatatattc acgaatatgt gcaactatca 8040
ccacagtcaa ttttagcata ttttcatcag ctcataaaga aaccccaagc ccttgaacta 8100
tcaccccata tccctcctcc cagcccgtcc ctcctactca taagcaacca ctaatctact 8160
tagtgtctat agatttccta ctctaggcat tccatgtgag cgggatcatg caatacgtgg 8220
gctcacacaa tataagtggc attccatgtg agtcggctca tgcagtatgt ccggctcctt 8280
tcactgagca taaggtcttc agcactcatc caggttgcag cctgtgtctg aatttcattc 8340
cctcttctgg ctgaatcgta ttccattgtg tatcttggac atatcctatt ctgctcaccc 8400
agccgttggt gggcgtttgg agtgttttcg cctttcagct gttttaagag ggttgcagtg 8460
aacatttgta caagttttgg acccaatgcc tgttttcaat tctcttgtgt agagagcact 8520
ttttagcaga aaaagaatag atttgtggcc tccctttgtg tgcggtcagt gccttgagaa 8580
gagtgaactg tgctgccacc tccggagccg tggagagcgc ggggcttggg tagcagctag 8640
gacgatacaa gttgggacaa ggccaggtgc aatggctcac gcctgtaatt ccaacacttt 8700
gggagaccga ggcaggggga tcacctgagg tcaggagttc aagaccagcc tggccaacat 8760
ggtgaaaccc catctctaat aaaacagaaa aattaactgg acggggtggt ggacgcctgt 8820
aatcccagct actcgggagg ctgaggcagg agaatcactt gaacctggga ggcggaggct 8880
gcagtgagtg gagatcagac cactgcactt cagcctaggt gacagagcga gactccgtct 8940
caaaaaaaag aaaaaaaaag aaagaaactc atggataatc ctccctctcg tgcagttcgc 9000
ctctacggac caaacttcat ccttcaggtg tactcatctc agaggaagtc ctggcaccct 9060
gtgtgccaag acgactggaa cgagaactac gggcgggcgg cctgcaggga catgggctat 9120
aagtgagtat ggggcagcac ccgccgagtg acagtaacag acagcagaaa cacgagaaga 9180
ccctctctct gcctccctgt gaaagcaccg gcacatgagt gctggggaca attgtcacct 9240
tccaaaagct gagccctata accagcaggt ggaatttgtc ctgctagggc tgtgcccagc 9300
acacagacct tggctcactg ccaccttgcc ctgcctcctc cttggcctct atagactcct 9360
ggttgctcgg gagtgcccag tgctgtggtc atctggtcag aggggtaggc tgagggcgtt 9420
aggtgcctct ttttccaagg tgcctctcag ccagggtcca ttcacctccc tgggtagagg 9480
ttggaccaga acagctggcg aggagggttg ggctggggag agcagcagag acaaatcctg 9540
tgccagtttc acttcattcg ggagccatgg aagccttttg agctggggag agaatcaatc 9600
aatcagactg atacttaaaa aatgtcattc ctgctcgtag ctctgaggga aggtgggaag 9660
gcttaacagg gtgtgtgtcg cctgacagtg attcctaacg ggggtggggc ggtggttacc 9720
atttaccagc actgcctggg gagatgcggc agccctcagg catcggggga gagggtggta 9780
ggatgctact gccactttgt tttccatggg agggtcccca ggtgatttct atgcaacttt 9840
agggtattca atatgccagt tttcagaatg aattaccact cggtgagaaa gttggcatct 9900
tagctagtca ctgtgacatc cctaaacagc aggggtgaat tacacagcaa agccccccca 9960
tcacagtcca ggaacctggt ggaattgata actggggcca tgttaacatc tgtacctttt 10020
attagattaa atgtgtgtat gattatacaa tcctatgtcc ttctcatagt ttcttgatcc 10080
taacctggat aagaaacacg accaatgaag gaattttgtc tgacacttta gggttattga 10140
atcgaaaaat cgttacaata ttctagcact tggttagaac gtgtgatttt ttttcctaaa 10200
tgctaaggtt tttccctctt attctgaatg tcgtatgagc ggtattatga catagtatag 10260
gatttgtgtt tgcttatgcc ttaaccatta tcacaaataa ggttttcttt tttaggaata 10320
atttttactc tagccaagga atagtggatg acagcggatc caccagcttt atgaaactga 10380
acacaagtgc cggcaatgtc gatatctata aaaaactgta ccacaggtat gcagcaattt 10440
cttcttgaaa aattttggaa tgaaatcaac taggagacac catggggaat cgttgtcctg 10500
agtctgattt ctctgagctg caatactcgg tctggatggg ttttgcattg ggaggagatt 10560
agagtctgac caggcctggt tactctaagc agcccttggt ttattcatag gaagtggctg 10620
aggtttctct gctatttcat tttcagcctc taccgtctgc ccttgttggt agcggctcac 10680
acttgcaaca tcgacattca actctattta gttttctttc ctcttcagac atttagaggt 10740
gtacctattt tgtcagggcg tggttctagg aatccaagat aatgtctcag tgtcccagcc 10800
agggtgaccg gctcattcca gtttgccagg gacttcactg gcttgagcaa gggaagtcct 10860
gctccattcc aggcagctgg gctggctggt cccgttagcc ccaaccccgg gacagcagtg 10920
ccagagggtg ctctgtgagg gatgggcagc attctggcgg cctgggaatg agttgtggtg 10980
tttccagggg gtagaagtgg gtacaagcca caggtcacat gatgagtggc tgacctggct 11040
gggagggcag aagaggggat ggacttaggc tcttcctttt gctttgcaca tatttaggat 11100
gtttgcagac ttgctatgat tgttgctgtt atgtgttttc tgatgtgaaa gatacacagt 11160
gtcctttgcc catgagctct ccttgcctcc caggtcccca gggcttatgc ctggtgtcta 11220
ggcatcacct ccctgcctgc caggtgccag gtgctgcatt tcgggggagg atgaactaat 11280
caccccgcgc cacctttcct ctgagtggga gcctggggca ggtttgcatt cctggaggcc 11340
gctggtggag gggtctgggg gcctgacttc cactgcagcc tgctgtcctg gggaatgtgg 11400
cagggcaagc ccagtgggga gggctgtgca cggccaggtg cacccatcaa aacagcaggg 11460
ctgcggtttg tccctgtgga gaagctaaac acagctgcct gggcactttg taaatgctga 11520
gtggttcttt gtctttctgg gttacacacg gaatcaggga gccaagtcca gccgggcagg 11580
gacgggggga ggggaggagg tgctgccgtc ccttggcaag agccttggga actcacaagg 11640
aggctggagg gcttggaaga aagaagagaa ggccattgtc tggtaggctc tattctatct 11700
cggtggtggt ggtgggggga ggcgcacttc ttttcctctt tctgtgcagc agttgccctt 11760
tgatgcctga gttcttggct tgttttctgt cgggcttctg tgaataacca catgtgccct 11820
ggcgctgtga ccacacaggg ctatccctac cgaccttagg attcttagga aatgtcttct 11880
cttaaagggg acatgtcttc acttggccgt gtcagtgccc cagagccaga gtccacctgg 11940
aatgcacctg tagtcactga gaacccgggg ggtgtgcctt agtaagaagg tgtcaggaag 12000
gacctattat tgtagggcct gggctcctgc aaggtggttt gggggtggtt ggaggaagca 12060
gagatttgct ctggattgga tgctgtcagg aagcaggggt aattctgtga ggctgcttta 12120
ttattttttt tctaggagga ggttggaatg aggctaggct aaagctgtga ttggtaaaga 12180
aacgtccgtc gctcaagtta gccaggacag gaggagacat cagatcgtga ttttgtggtt 12240
gtgagcacaa ggttcctgtt ctgtctgttc agacatcatt tcggaggagg ctccttgtgt 12300
cttgccccat ctcaggcatg gaggggccta gtccgatatt gacgctcagt gaaataattc 12360
aggttccgca gagcacacgg cccagctatc agggcgggcc agctctgcat gccaggggcc 12420
gcgtcttccc ttctcagcat agcctgggaa attcactgca ggacaaaatg catcagttac 12480
ttcctcttca tccataacct gggatgtttg actcccaaat gagtaactct tacgtttctt 12540
ctaatcctag ggaaactatt ggttatattg ctttcaacac tacaaattta aagcagttat 12600
aggagcccag aggtttccaa atggcttcct taaaaattag aagatgattt taaattccaa 12660
gaggaaaaac aaaactagca ttattgtata cttaccctca caaccgtcct aggagctggt 12720
acaattttaa gagaggttaa gtaacttgcc caaggtcaca ctgtggggat gtgagccgcg 12780
taccttggct cagtgtctgg tctttgccac tgtccctata tggatttact taccttattg 12840
gagttgtaac tagcagaccc ttctatgtct cagaagacag gagagggaac atcggaagaa 12900
atgactgatt tctaagcatg tgagaggcag gtgactccgc actatcgtga ccagaatttc 12960
ccctgttctt tttgcagtga tgcctgttct tcaaaagcag tggtttcttt acgctgtata 13020
ggtaagttca tctggagtcc cccttttgat acttctaact aggaaaagct ctctactttc 13080
agaacagtac tccctgtgtc tctgggggcg tgggagggaa gaaggtgggg tcacgggttg 13140
gaatgtgccc agcggcgtct cgctctttcc aaggagctcc tggtttagat ttccatggcc 13200
tgtagacacc ttcagccttg ggtccaaggg acaccccctg agatcaggca cgctcaagaa 13260
gctgacaaag ccctacactt tatgccaccc atgagctgga ggcccggcag gtctctttct 13320
ccagaaagca aaggggggtg gcgttagtga gccctggcag ccacctaacg tggacttgga 13380
gcatctgcgg ggctgtggtc cagcaccacc gtgtggccac caggtgctca tcagccagtg 13440
ggacccggga ggagggacaa gaccagagaa caacagtgct cttgcctctt ctctcctgaa 13500
ttttggacgg tggcttagac ttgggtgtcc ccatctctgt gtttagagtg cttacagttt 13560
ccaaactgtt tgcaaatgtg gaagccaccg tccctctcct ctgggatggc ccagtgctgt 13620
cgtggggccg tggtcctgag ctcagctttt catttgaaga ggtggaagga gctgacaccg 13680
tcccatcccg gcagggctgg ctcaggtctt ctttaggtcc tgagtggggg tccagcacag 13740
ccccaagggt gcgtggcacc cgccctgccc tctgcccatg cactcatctc ctggtggaga 13800
agacactcac acacaggaag cagggaaggc agcagacctc actcacccct caccccctca 13860
ctcaccccct actcaccccc tcaacctctc attcaccacc caccccctcg ccccctcact 13920
caccccctca ctccctcaac cctcactcac ctcctcactc cctcaaccct cactcacctc 13980
ctcacctcct cactctcccc ctcatccctc cctcacccca ccccgtcacc tcctcactca 14040
cctcctcacc ccctcactca cccttcaccc cctcactcac cacctcacct cctcactcac 14100
cccctactca acccctcatt cacccctcac cccctcactc acccctgcac cccctcactc 14160
accccttcat ccactcaccc acctgctcac ctcctcactc aacccctcac cccctcacta 14220
atccctcact ccctcacccc ctcacgccct cactcacacc ttcacctcct cactcacccc 14280
ctcaccccct caacccctta cttaccccct cactcatccc ttcacccctc actcaccccc 14340
tctctcaccc attcaccccc tcactcatgc cttcaccccc tcactcacct cctcactcac 14400
accttcaccc ctcagtcacc ccctcactca ccccttcacc ccctcaatca tgccttcact 14460
ccctcactca ccccttcacc ctctgaatta ctccctcatc ccctcactca ccccctcact 14520
caccccttca ccccctcacc caccacctca cccacccctc acccaccccc tcacctcctt 14580
acccctcacc cccctcactc acccctcacc ccctcactca ccacctcacc cacccctcac 14640
ccaccccctc actcactccc tcatcccctc actcaccccc tcaccccctc actcaccccc 14700
tcacccaccc ctcacccacc ccctcacccc ctcactcacc ccttcacccc ctcactcacc 14760
ccctcactca ccccttcacc ccctcactca ccacctcacc cacccctcac ccaccccctc 14820
actcactccc tcaccccctc actcaccccc tcaccccctc actcaccccc tcatctcctc 14880
actcaccccc tcacctcctc actcacccgc tcacctcctc actcaccccc tcgccccctc 14940
actcacccct caccccctca ccccctcact cacccctcac cccctcgccc cctcactcac 15000
cccctcgccc cctcactcac ccctcacccc ctcaccccct cactcatccc ctcacctcct 15060
cactcacccc ctcacctcct cactcacccc ctcacctcct cactcacccc ctcacctcct 15120
cacccacccc ctcactcact ccctcacccc ctcaccccct cactcacccc ctcacctcct 15180
cactcacccc ctcacctcct cacccacccc ctcactcact ccctcacccc ctcaccccct 15240
cactcacccc ctcacctcct cactcacccc ctcacctcct cactcacccc ctcacctcct 15300
cactcatgcc ctcaccccct cactcaccct ttcacctcct tgctcatccc ctcacttacc 15360
ccctcacttc gtcaatcacc cccccacctc gtcaatcacc ccctcacctt ttcactcacc 15420
ccctcactca cccccttact tcctcactta cctcctcacc ccccactcac cccctcaccc 15480
cccactcacc ccctcacccc acactcaccc cctcaccccc cactcacccc ctcacccctc 15540
tcacctcctc actcaccccc tcacctcctc acttatcccc tcaccccctc aattaccccc 15600
tcaccccctc aattactccc tcatcctttc aattacccac tcaccccctc acctcctcac 15660
tcctcactca ctccctcact caccccttca ccttctcact cacctcctcg tctcctcacc 15720
ccctcactca cttccagccc tgcccctccc atcttccttt tctttgtgtg agaatctggg 15780
gtccctgagt ggtgtcagtc cctccaagac tcaaggagtc cccagggcct tgttatccag 15840
aacaccccca cctgggtccc gggagacccc atgggatcac aggagtgttc agggaagtgg 15900
tgcttcctgg gtctgggtgg gctggagggg catcctccct tccccaagag gagaccccca 15960
ggagccccct aagtccatcc ccagcagtgg tgcccctgcc ctgtccttgc agcctgggag 16020
acccttggga ggggcgggcg ctgggtggct gggcggcttc tgctggtctc accccactgg 16080
cctcctgttt gtcatcctca gcctgcgggg tcaacttgaa ctcaagccgc cagagcagga 16140
ttgtgggcgg cgagagcgcg ctcccggggg cctggccctg gcaggtcagc ctgcacgtcc 16200
agaacgtcca cgtgtgcgga ggctccatca tcacccccga gtggatcgtg acagccgccc 16260
actgcgtgga aaagtatgcc aggggcggcg cgggccgggt gggggctcag ggctggccta 16320
cagccaccct gtgaccttga gcaggtctca acccttgcag ccccggcatc cttgtgttta 16380
aatggggaga gtattgcacc tgcttcctag ggctgtgaga catcaagtgc gctcatgcca 16440
ggcagtgcat ggctgtatgc actgagtgtc ccctgcacgc agggcacagg gtgcaggtgg 16500
aacattctcc acgatgtcgc cgtgaccagc gttccttcca gccactgtcc tctgagctct 16560
gtcctgccct tgagcaaagc ccctgccccc tgaggtatcc tgtctccggg acgctagtcc 16620
caggagaggg cacactcaga caggcttcag gctgccctgc tggaaggtcc ctggggttaa 16680
gcgttcttgg ccacagcatt gctcatgcag agggttaggt aggggtgagg ctagccgtga 16740
cagtattagc atttatggac gctaccaccc cctccccttt tccttaaaca catagtgctt 16800
ttggtcacat gctgctttgg aggaggcctc acttggcgga tgtatttttc tgccttagag 16860
agaggctgaa ctgggtttga ctgttggccc agccctctct tgctgcgtgc ccttagacga 16920
ttcactcaac gtctctgatc catggcatgt acaactataa gatgggcatg cccttctcct 16980
ctcgggctgt tatgaaggtc aaggaagcaa gggctgttac ccaagggtgc tcccttctct 17040
ccccctcttc acacccccag gtgctctggg ccctctagga actgggtttc tctcaagggc 17100
tgttacccaa gggtgctccc ttctctcccc ctcttcacac cactgggtgc tctgggccca 17160
ctaggagctg ggattctctt aagagggaaa ctcttggata aaggaaatgg tttgattgat 17220
atcggacaag tctgttcatt agtatccatt tattaagcac ctaccatgtg ccaggaaatg 17280
ctttggcgta caaaggaaaa taagggccag tcctgctaga aatggccttg aaaccccagg 17340
gagggatgtc ggcccattgt gggtgctgca gattccttga aggtgatgca agagccagaa 17400
agaaggatga tgtggggggc tgaggcaggg agtcggggtt gggggagtgt gggggagaag 17460
gggagaccga gcacctcttc cactatctcc ctgtgtggtt tttggtgaac catcctgcct 17520
ctgggtgtct tgcctccagc ttctgacgtt ggaagttcat ccactgagag ctctgtgttt 17580
atggctctga gatactgagt ccttcttctc tcccagacct cttaacaatc catggcattg 17640
gacggcattt gcggggattt tgagacaatc tttcatgttc tatggagccg gataccaagt 17700
agaaaaagtg atttctcatc caaattatga ctccaagacc aagaacaatg acattgcgct 17760
gatgaagctg cagaagcctc tgactttcaa cggtacgtgt ggctcaggct tggcaagcag 17820
gttggcagaa tcttaaagag atgttgattg gaaatgacac ttgtgctatg ccaaatggaa 17880
gggaggcatt tgcgttgagc gagggtagcg tgcagcgggt ggccaatggg agaggctcac 17940
agaggctaag agcacctgcc gcattttggg ggaggcagca gccaccacat ctgttctgta 18000
ctgtactgag tggtggtgat tcaagccagg catggaaaag gctagaacag ggctttccca 18060
ctgcagcacc cttgacatct gggtggttct ctgttgtagg gctctcttgt gccttgtagg 18120
atgtttaaca gcgtccccag cctctaccca ctggaggcca gtagctacca agctgtgaca 18180
accagtgttg cctgctgaca ttgccaaaca tccgctttga ggcaaagtca cttccagttg 18240
agaactactg gcctaaaatg tgtaaagatc cttgattttt aaagatacat tctaaaacca 18300
agttgcttaa ttcaggacaa acatgctttc tcttagcctc ttattcggtc ccactctggt 18360
ccatccaagg gtctggaatg ttctagcccc atgtggatac agaagaagca aaacctcagc 18420
cctccctaca gcatgtctgt attcacattg ggaaatggtt cacatataga agagcgaatg 18480
cctgagcaat ggcgtggtgc ctctggggcg aaagctgact ccattgactc catcggcttt 18540
ttggctgttg cctcctgtgt gtctttcccg tcttgatcac ctggagatat gtaattttgg 18600
aagcagagct agcaaataat tcctcttata agcagagcta gcaaataatt ctacttataa 18660
gtagcataac gtcttgcctg ccagaaggag aggtctggca gggggagaaa gtgagaatgt 18720
gggacttgtt gggatgcagg gtcctctggg cagggtggcc agggtgccag gcccagcagc 18780
ctgcatgtgg gaaggccagg tggagacata ggtgataccc gcctggctca ctgtgttttc 18840
tcttcttgaa acagacctag tgaaaccagt gtgtctgccc aacccaggca tgatgctgca 18900
gccagaacag ctctgctgga tttccgggtg gggggccacc gaggagaaag gtgaggctgc 18960
tcctgggcac acaggactgc agggcccaca gatggagcat tgggttcgga agtgggaggt 19020
ccaggtttta atcccagttc tactactcaa tgactggatg actttggttg attcccccag 19080
tccttgtgcc tcagtttctc catctgctaa gtgggagaaa tcctgcccag cctacctaat 19140
acactgtgtt cttatcgtga tcacacagag cagcatgtgg aatggctttt gaagtatctg 19200
ggccatacga gtttagaggt gcaggatctc ctgtgttgca ctcattgtga gtttagagct 19260
gccctggaga tcccaccaag gcctgcgtgg ctgagtgaca gggggcttgg tgaggacggg 19320
catcctggac ccatggtggc cacatctaag cctgtcctct gccctgataa ccacagagag 19380
aggctctctc cacccacttc ctttgcaatc tgcatttctc tctgacagtc tttcaaatga 19440
agggagcctg gctgcttcat ttttatggag ggttggaagt gcttagtggc aggcacaaag 19500
gttcatttta catattgttt atatccttct caaaagcgtc taggccatac agacaacaaa 19560
tcctttcaaa caaggggaaa agtacaaagg ttgggtgatt tctggggagc gtcagggaag 19620
gtagtggggg gcatcctggc tcctcatcag cagaaactta ctacagtaga gccacaggct 19680
gggcaaaaga cctcatggaa tccaagatga agggaatatc gacaaatatt tgtgcgcacc 19740
tgcacctagt acaggctggg tgctactcag gtgctgggaa tgcagaagtg aacagagtaa 19800
gacaaatgtc tctgctgtca ggagctttac ctctcttctg gatgtcggtg gtggggacgg 19860
ggcaggtgtg gtcagacaga tgggagacaa acaactgagc gaggtacttc caaacatctg 19920
agggtgggga tcacaaggtc ccggctattt tgaaggggtg gtcaggaaag gcttctcgga 19980
agaggtggca tttgagctga gactcaaatg gcaaaaatgt gtacacatca aaaaggctag 20040
tgcatgtatc ttcaggtgtg gtcaaggggc caaggaggtg ggctggggcc agattgcata 20100
ggtccttgtg gattatggtg aagacaccag cttctcatct gcttgaggtg gggagatcgt 20160
gagccgggga gtgccatgat ctggcagctg cgtggggagt ggggatgaat ggatggagac 20220
gaggatgatg gtgacaagtc cattgctgtg gttccttgag acaggaagcc agctcatagc 20280
agagtgcggg cgtggatgtg aagagatgag ggtacactag ggctagagcc accagactta 20340
ctgatgggtt gcatgtctgt gggagagaga gtgagaagtc agggacgatg gctttccact 20400
ctgtggctga agccccaggg tggcgggtgg tgccattttt caagccagga aatattggtt 20460
ggtgagaatt tggggtggga gaaggtgtga cggagggttc tggttttgca cactaagccc 20520
acggtgccca gaagatgccc gaggggaggc agcaaagcga gagtgggaaa tgcagaggtg 20580
gcaagtgcag gccgtgtctt gagaagctct aatgtgcagg ggagccgaga agcaggcggc 20640
ctagggaggg tcacgtgtgc tccagaagag tgtgtgcatg ccagagggga aacaggcgcc 20700
tgtgtgtcct gggtggggtt cagtgaggag tgggaaattg gttcagcaga accaagccgt 20760
tgggtgaata agagggggat tccatggcac tgatagagcc ctatagtttc agagctggga 20820
atttctttcc ctgaagctga actccagagc tgcattcagc acaggcaccg ccagttgtaa 20880
ggagaatcca ggtttcccag gagaggggtt ggtgctggga tgagctgacc ggggcagggc 20940
tggaaaatag ggctgtgacc atctgtgtag tgcgtgtgga ggtctcaggg agggaagtgt 21000
gctctccctg cgagagctgc aggcaacact gggagctcaa caagtctccc tgtccttagg 21060
gaagacctca gaagtgctga acgctgccaa ggtgcttctc attgagacac agagatgcaa 21120
cagcagatat gtctatgaca acctgatcac accagccatg atctgtgccg gcttcctgca 21180
ggggaacgtc gattcttgcc aggtaattca acatttttat tctacctttg gtccttacca 21240
gatcctactg aaccccccat gagagagagg gcattcttgg ggtcagcaga gcctcctcag 21300
tgacacggag ccagctcggg gcagtcatgg gaagtgacgg ccacaaacag tgcgaacgct 21360
tctggtggca gaaggaagta cagtcaacaa atcacacaca ccctctgaaa aaccggtatt 21420
tggtaaaagt gccagtggaa cagaaacaag tatttagact attttaaatt atgaacggca 21480
atttatttag taacttttag cttgaacaga ttaaaattca ggatgggggc tatctctttg 21540
ggggttacat ctctgttacc atcacccctt gatggtggag attcgaagcc cacacagtca 21600
ctcgtaactc acactgcgac ccccgccccc caactcctct aggcctggtc agtggtgtgc 21660
ggcagattgt gacttgattt tctgctctct gtaccttgct gtgtcccaca gggtgacagt 21720
ggagggcctc tggtcacttc gaagaacaat atctggtggc tgatagggga tacaagctgg 21780
ggttctggct gtgccaaagc ttacagacca ggagtgtacg ggaatgtgat ggtattcacg 21840
gactggattt atcgacaaat gagggtaact atcctgtcct ccttctgact gtgttctccg 21900
attcctcgag ccaaagccag acatctgtta ggcgtggttc tgctgctgga agctgactgg 21960
tgaccactgg tcagcatgaa gcaaactctg cttcctccag ccacagcccc atccccccag 22020
tgtccaccca ttgcccattg cctctcactg gcttcacttg catatttccc ctggtgtttg 22080
gatgaaaagc gctggggctc agcttgtgtg aaattccttg gtgctctgcc aaccacactt 22140
cgttctggct cagctgactc agctgttcca cccaggccac ctcacatcaa actttttttt 22200
tttttttttg agatggagtc tcactgtgtc gcccaggctg gagtgcagtg gcacaatctc 22260
gactcactgc aacctttgcc tcctgggttc aagtgattct cctgcctcag cctcccaagt 22320
agctgggact acaggcatgc gccaccacgc ccagctactt tttgtatttt tagtagagat 22380
ggggtttctc catgttggcc aggctggtct cgaagccctg acctcaggtg attcacccac 22440
ctcagcctcc cacagtgctg ggattacaag tgtgaaccac ggtgcccggc ctcacatgaa 22500
acttttgatt tatagagagc agagggaaga gccggctgtg cccatccttt tctggggcca 22560
tcgagtggct cctgggcagc ccccaaggtt aggaagggca ggagcagcca gggttctctg 22620
atgccccaga ctcaagcacg agggaaggtc tcaggggttc catgtgagcc tcatggatgt 22680
ctctgcttag cagagccctg gctttgggca ttgtccagat agggggtgag aaccagatct 22740
tctcatctcc aggacctcag acgtatagtt ttctcagatt tctgtgcttt ctggggctgg 22800
gctactagtg gaagaaagca gtctattctg tcttctccca aatctcccag atgcccagtc 22860
tgttgaagga ggagcagaac cagggggcct ttcccgctga ggcccgacct gtgtctcctt 22920
caaatgacac gcgggactca gggccttccc atgaccatgg ggcccagggg gcgtcacctg 22980
gcccagggcc cagtgctaga aacagatgac cccaggagga ggaggcaggg caggagggaa 23040
gctggcaggg ctgggatggt cagccaggct gaggggcgga ctcgcaccag gatggagcta 23100
ggaaatgatc caggtgtgtt tggcggctgc aggtgggtcc gcatggctgt gcagggaggg 23160
aagggctgcg tggcaggaga gcagccgggg gaggcccaga ctctgctgaa gagatgcctg 23220
ttgtgccggc ctccacatcc gctgcccgct ccttccggag ctcctgcccc gccatgctca 23280
gcctgactct gaccaacacg ttggagagaa gaatgatccc tttgtgctat taagcttgct 23340
tatttggttt ctaagtgctt catgcgaacc tagaggaaaa aattattttc cacctttgtt 23400
tgtcttaaga aaataacaca cttttttttt tcctatttga acaggcagac ggctaatcca 23460
catggtcttc gtccttgacg tcgttttaca agaaaacaat ggggctggtt ttgcttcccc 23520
gtgcatgatt tactcttaga gatgattcag aggtcacttc atttttatta aacagtgaac 23580
ttgtctggct ttggcactct ctgccattct gtgcaggctg cagtggctcc cctgcccagc 23640
ctgctctccc taaccccttg tccgcaaggg gtgatggccg gctggttgtg ggcactggcg 23700
gtcaagtgtg gaggagaggg gtggaggctg ccccattgag atcttcctgc tgagtccttt 23760
ccaggggcca attttggatg agcatggagc tgtcacctct cagctgctgg atgacttgag 23820
atgaaaaagg agagacatgg aaagggagac agccaggtgg cacctgcagc ggctgccctc 23880
tggggccact tggtagtgtc cccagcctac ctctccacaa ggggattttg ctgatgggtt 23940
cttagagcct tagcagccct ggatggtggc cagaaataaa gggaccagcc cttcatgggt 24000
ggtgacgtgg tagtcacttg taaggggaac agaaacattt ttgttcttat ggggtgagaa 24060
tatagacagt gcccttggtg cgagggaagc aattgaaaag gaacttgccc tgagcactcc 24120
tggtgcaggt ctccacctgc acattgggtg gggctcctgg gagggagact cagccttcct 24180
cctcatcctc cctgaccctg ctcctagcac cctggagagt gcacatgccc cttggtcctg 24240
gcagggcgcc aagtctggca ccatgttggc ctcttcaggc ctgctagtca ctggaaattg 24300
aggtccatgg gggaaatcaa ggatgctcag tttaaggtac actgtttcca tgttatgttt 24360
ctacacattg ctacctcagt gctcctggaa acttagcttt tgatgtctcc aagtagtcca 24420
ccttcattta actctttgaa actgtatcat ctttgccaag taagagtggt ggcctatttc 24480
agctgctttg acaaaatgac tggctcctga cttaacgttc tataaatgaa tgtgctgaag 24540
caaagtgccc atggtggcgg cgaagaagag aaagatgtgt tttgttttgg actctctgtg 24600
gtcccttcca atgctgtggg tttccaacca ggggaagggt cccttttgca ttgccaagtg 24660
ccataaccat gagcactact ctaccatggt tctgcctcct ggccaagcag gctggtttgc 24720
aagaatgaaa tgaatgattc tacagctagg acttaacctt gaaatggaaa gtcatgcaat 24780
cccatttgca ggatctgtct gtgcacatgc ctctgtagag agcagcattc ccagggacct 24840
tggaaacagt tggcactgta aggtgcttgc tccccaagac acatcctaaa aggtgttgta 24900
atggtgaaaa cgtcttcctt ctttattgcc ccttcttatt tatgtgaaca actgtttgtc 24960
tttttttgta tcttttttaa actgtaaagt tcaattgtga aaatgaatat catgcaaata 25020
aattatgcaa tttttttttc aaagtaacta ctgcatcttt gaagttctgc ctggtgagta 25080
ggaccagcct ccatttcctt ataagggggt gatgttgagg ctgctggtca gaggaccaaa 25140
ggtgaggcaa ggccagactt ggtgctcctg tggttctcga gataacttcg tataatgtat 25200
gctatacgaa gttatgctag taactataac ggtcctaagg tagcgagcta gctccacgtg 25260
gctttgtccc agacttcctt tgtcttcaac aaccttctgc aagaaaacca agggcctgaa 25320
ttttaacttc ctg 25333
<210> 7
<211> 491
<212> PRT
<213> Artificial Sequence
<220>
<223> Recombinant protein
<400> 7
Met Ala Leu Asn Ser Gly Ser Pro Pro Gly Ile Gly Pro Cys Tyr Glu
1 5 10 15
Asn His Gly Tyr Gln Ser Glu His Ile Cys Pro Pro Arg Pro Pro Val
20 25 30
Ala Pro Asn Gly Tyr Asn Leu Tyr Pro Ala Gln Tyr Tyr Pro Ser Pro
35 40 45
Val Pro Gln Tyr Ala Pro Arg Ile Thr Thr Gln Ala Ser Thr Ser Val
50 55 60
Ile His Thr His Pro Lys Ser Ser Gly Ala Leu Cys Thr Ser Lys Ser
65 70 75 80
Lys Lys Ser Leu Cys Leu Ala Leu Ala Leu Gly Thr Val Leu Thr Gly
85 90 95
Ala Ala Val Ala Ala Val Leu Leu Trp Lys Phe Met Gly Ser Lys Cys
100 105 110
Ser Asn Ser Gly Ile Glu Cys Asp Ser Ser Gly Thr Cys Ile Asn Pro
115 120 125
Ser Asn Trp Cys Asp Gly Val Ser His Cys Pro Gly Gly Glu Asp Glu
130 135 140
Asn Arg Cys Val Arg Leu Tyr Gly Pro Asn Phe Ile Leu Gln Val Tyr
145 150 155 160
Ser Ser Gln Arg Lys Ser Trp His Pro Val Cys Gln Asp Asp Trp Asn
165 170 175
Glu Asn Tyr Gly Arg Ala Ala Cys Arg Asp Met Gly Tyr Lys Asn Asn
180 185 190
Phe Tyr Ser Ser Gln Gly Ile Val Asp Asp Ser Gly Ser Thr Ser Phe
195 200 205
Met Lys Leu Asn Thr Ser Ala Gly Asn Val Asp Ile Tyr Lys Lys Leu
210 215 220
Tyr His Ser Asp Ala Cys Ser Ser Lys Ala Val Val Ser Leu Arg Cys
225 230 235 240
Ile Ala Cys Gly Val Asn Leu Asn Ser Ser Arg Gln Ser Arg Ile Val
245 250 255
Gly Gly Glu Ser Ala Leu Pro Gly Ala Trp Pro Trp Gln Val Ser Leu
260 265 270
His Val Gln Asn Val His Val Cys Gly Gly Ser Ile Ile Thr Pro Glu
275 280 285
Trp Ile Val Thr Ala Ala His Cys Val Glu Lys Pro Leu Asn Asn Pro
290 295 300
Trp His Trp Thr Ala Phe Ala Gly Ile Leu Arg Gln Ser Phe Met Phe
305 310 315 320
Tyr Gly Ala Gly Tyr Gln Val Glu Lys Val Ile Ser His Pro Asn Tyr
325 330 335
Asp Ser Lys Thr Lys Asn Asn Asp Ile Ala Leu Met Lys Leu Gln Lys
340 345 350
Pro Leu Thr Phe Asn Asp Leu Val Lys Pro Val Cys Leu Pro Asn Pro
355 360 365
Gly Met Met Leu Gln Pro Glu Gln Leu Cys Trp Ile Ser Gly Trp Gly
370 375 380
Ala Thr Glu Glu Lys Gly Lys Thr Ser Glu Val Leu Asn Ala Ala Lys
385 390 395 400
Val Leu Leu Ile Glu Thr Gln Arg Cys Asn Ser Arg Tyr Val Tyr Asp
405 410 415
Asn Leu Ile Thr Pro Ala Met Ile Cys Ala Gly Phe Leu Gln Gly Asn
420 425 430
Val Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Val Thr Ser Lys
435 440 445
Asn Asn Ile Trp Trp Leu Ile Gly Asp Thr Ser Trp Gly Ser Gly Cys
450 455 460
Ala Lys Ala Tyr Arg Pro Gly Val Tyr Gly Asn Val Met Val Phe Thr
465 470 475 480
Asp Trp Ile Tyr Arg Gln Met Arg Ala Asp Gly
485 490
<210> 8
<211> 2267
<212> DNA
<213> Mus musculus
<400> 8
ccggttgtgt tataggactt gaccagcccc aatagtcctc aagtcactcc tagatacagt 60
ggcaggtggt agctggcttg cggaaggaag aggaagaaga gaatgtgggc catcaaggag 120
caaggccagc cttgcacttg ggccccctct gctcagtgct gaccagggct ttctgagccg 180
cttcctaatg aggctcattt gaagaccccc ccccaccccc ctcctgctgt cttgggtggc 240
agagctagct ccaggctgta agaaaattag gaggattacc aaagcagtat ggagtcagac 300
agtggccaac ccctcaacaa ccgtgatatt gttccctttc gcaaaccccg aaggccccag 360
gagaccttca aaaaggtggg gatccccatc attgcagtgc tgctgagcct gatagccctc 420
gtgattgtgg cccttctcat caaggtgatt ctggataaat actacttcat ctgcggcagt 480
cccctgacct tcattcagag gggccagttg tgtgacggcc accttgactg cgcctcaggg 540
gaggatgagg aacactgtgt caaggacttc cctgaaaagc ccggagtggc agtccggctc 600
tccaaggaca gatccaccct gcaggtgctg gatgcagcca cagggacctg ggcctcagtc 660
tgtttcgaca acttcacaga agcactggcc aagacagcct gcagacagat gggctatgac 720
agccagcccg ctttcagagc agtggagatc cgtccagatc agaacctccc tgttgctcaa 780
gtcacaggaa acagccagga acttcaggtg cagaatggaa gcagatcctg cctctcaggc 840
tccctggttt ccttgcgctg ccttgactgt ggaaagagcc tgaagactcc tcgtgtggtg 900
ggtggggtgg aggcccctgt ggattcttgg ccgtggcagg tcagcatcca gtacaacaag 960
cagcatgtct gtggtgggag catcctggat ccccactgga tcctcacagc agcccactgc 1020
ttcaggaagt atcttgatgt gtcaagctgg aaggtcaggg caggctcaaa catactgggt 1080
aactctccat ccttgcctgt ggccaagatc ttcatcgctg aacccaatcc tctgtacccc 1140
aaagagaagg acattgccct tgttaagctg cagatgccac tcacattctc aggctcagtc 1200
aggcccatct gcctgccctt ctctgatgag gtgcttgtcc cagccacacc agtctgggtc 1260
attggatggg gctttacaga agaaaacgga ggaaagatgt ctgacatgct actgcaggca 1320
tcagtccagg tcattgacag cacacggtgc aatgcagagg atgcctacga aggggaagtg 1380
accgctgaga tgctgtgtgc aggtacccca cagggtggca aggacacctg ccagggtgac 1440
agtggtgggc ctttgatgta ccattctgac aagtggcagg tagtaggcat cgtgagctgg 1500
ggccatggat gcggcggccc aagtactcct ggagtgtata ccaaggtcac tgcctatctc 1560
aactggatct acaatgttcg gaagtctgag atgtaacgct gccgtccccc acatccagaa 1620
gctgcttccc ttcagaccta cctacggcat gacccctcaa agtcagatat gggacaagag 1680
cctccttgaa caaactctgg tatccctgca gcaagcaagg atacattgca gaggtgcccg 1740
gagtggagtc agatgggcta gctcagccac ccctgcatct cccaaaccct gggagacatg 1800
tggcccatgg gagtaaatcc aggacattga ctcaactctc agaagtgtta ttcagtcaag 1860
gaggctctcc cttccactga aggaaggaaa gtcagctctc tcctgaaagg ccagatcact 1920
ggctgagtag atgagacaag ggtatgaaag gcctttgcca tcttctttgc ccagtcctga 1980
aagcactgac gtaagagacc agtcagttct aatgtaaggt gtatatttta gtgtcagggt 2040
attgcaattg tcacctctgt ggtcaatatc attaaacagg tatgagaatt cgctggcata 2100
gacttcctgg tctgcttaat aagaatccaa ctaaggatgt cacatgacag tttcccagaa 2160
aatgtgaaca agtgtccatc tgacacacgg caccaatgac aaaccaaaga agttattctg 2220
cctgagtctc agttgctgaa ctaataaatt agctgcggtt tcttgca 2267
<210> 9
<211> 435
<212> PRT
<213> Mus musculus
<400> 9
Met Glu Ser Asp Ser Gly Gln Pro Leu Asn Asn Arg Asp Ile Val Pro
1 5 10 15
Phe Arg Lys Pro Arg Arg Pro Gln Glu Thr Phe Lys Lys Val Gly Ile
20 25 30
Pro Ile Ile Ala Val Leu Leu Ser Leu Ile Ala Leu Val Ile Val Ala
35 40 45
Leu Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Ile Cys Gly Ser
50 55 60
Pro Leu Thr Phe Ile Gln Arg Gly Gln Leu Cys Asp Gly His Leu Asp
65 70 75 80
Cys Ala Ser Gly Glu Asp Glu Glu His Cys Val Lys Asp Phe Pro Glu
85 90 95
Lys Pro Gly Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr Leu Gln
100 105 110
Val Leu Asp Ala Ala Thr Gly Thr Trp Ala Ser Val Cys Phe Asp Asn
115 120 125
Phe Thr Glu Ala Leu Ala Lys Thr Ala Cys Arg Gln Met Gly Tyr Asp
130 135 140
Ser Gln Pro Ala Phe Arg Ala Val Glu Ile Arg Pro Asp Gln Asn Leu
145 150 155 160
Pro Val Ala Gln Val Thr Gly Asn Ser Gln Glu Leu Gln Val Gln Asn
165 170 175
Gly Ser Arg Ser Cys Leu Ser Gly Ser Leu Val Ser Leu Arg Cys Leu
180 185 190
Asp Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val Gly Gly Val Glu
195 200 205
Ala Pro Val Asp Ser Trp Pro Trp Gln Val Ser Ile Gln Tyr Asn Lys
210 215 220
Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His Trp Ile Leu Thr
225 230 235 240
Ala Ala His Cys Phe Arg Lys Tyr Leu Asp Val Ser Ser Trp Lys Val
245 250 255
Arg Ala Gly Ser Asn Ile Leu Gly Asn Ser Pro Ser Leu Pro Val Ala
260 265 270
Lys Ile Phe Ile Ala Glu Pro Asn Pro Leu Tyr Pro Lys Glu Lys Asp
275 280 285
Ile Ala Leu Val Lys Leu Gln Met Pro Leu Thr Phe Ser Gly Ser Val
290 295 300
Arg Pro Ile Cys Leu Pro Phe Ser Asp Glu Val Leu Val Pro Ala Thr
305 310 315 320
Pro Val Trp Val Ile Gly Trp Gly Phe Thr Glu Glu Asn Gly Gly Lys
325 330 335
Met Ser Asp Met Leu Leu Gln Ala Ser Val Gln Val Ile Asp Ser Thr
340 345 350
Arg Cys Asn Ala Glu Asp Ala Tyr Glu Gly Glu Val Thr Ala Glu Met
355 360 365
Leu Cys Ala Gly Thr Pro Gln Gly Gly Lys Asp Thr Cys Gln Gly Asp
370 375 380
Ser Gly Gly Pro Leu Met Tyr His Ser Asp Lys Trp Gln Val Val Gly
385 390 395 400
Ile Val Ser Trp Gly His Gly Cys Gly Gly Pro Ser Thr Pro Gly Val
405 410 415
Tyr Thr Lys Val Thr Ala Tyr Leu Asn Trp Ile Tyr Asn Val Arg Lys
420 425 430
Ser Glu Met
435
<210> 10
<211> 3543
<212> DNA
<213> Homo sapiens
<400> 10
atcattccag tttggcaact tcacttgtag ggctgtttta atcaagctgc ccaaagtccc 60
ccaatcactc ctggaataca cagagagagg cagcagcttg ctcagcggac aaggatgctg 120
ggcgtgaggg accaaggcct gccctgcact cgggcctcct ccagccagtg ctgaccaggg 180
acttctgacc tgctggccag ccaggacctg tgtggggagg ccctcctgct gccttggggt 240
gacaatctca gctccaggct acagggagac cgggaggatc acagagccag catggatcct 300
gacagtgatc aacctctgaa cagcctcgat gtcaaacccc tgcgcaaacc ccgtatcccc 360
atggagacct tcagaaaggt ggggatcccc atcatcatag cactactgag cctggcgagt 420
atcatcattg tggttgtcct catcaaggtg attctggata aatactactt cctctgcggg 480
cagcctctcc acttcatccc gaggaagcag ctgtgtgacg gagagctgga ctgtcccttg 540
ggggaggacg aggagcactg tgtcaagagc ttccccgaag ggcctgcagt ggcagtccgc 600
ctctccaagg accgatccac actgcaggtg ctggactcgg ccacagggaa ctggttctct 660
gcctgtttcg acaacttcac agaagctctc gctgagacag cctgtaggca gatgggctac 720
agcagcaaac ccactttcag agctgtggag attggcccag accaggatct ggatgttgtt 780
gaaatcacag aaaacagcca ggagcttcgc atgcggaact caagtgggcc ctgtctctca 840
ggctccctgg tctccctgca ctgtcttgcc tgtgggaaga gcctgaagac cccccgtgtg 900
gtgggtgggg aggaggcctc tgtggattct tggccttggc aggtcagcat ccagtacgac 960
aaacagcacg tctgtggagg gagcatcctg gacccccact gggtcctcac ggcagcccac 1020
tgcttcagga aacataccga tgtgttcaac tggaaggtgc gggcaggctc agacaaactg 1080
ggcagcttcc catccctggc tgtggccaag atcatcatca ttgaattcaa ccccatgtac 1140
cccaaagaca atgacatcgc cctcatgaag ctgcagttcc cactcacttt ctcaggcaca 1200
gtcaggccca tctgtctgcc cttctttgat gaggagctca ctccagccac cccactctgg 1260
atcattggat ggggctttac gaagcagaat ggagggaaga tgtctgacat actgctgcag 1320
gcgtcagtcc aggtcattga cagcacacgg tgcaatgcag acgatgcgta ccagggggaa 1380
gtcaccgaga agatgatgtg tgcaggcatc ccggaagggg gtgtggacac ctgccagggt 1440
gacagtggtg ggcccctgat gtaccaatct gaccagtggc atgtggtggg catcgttagt 1500
tggggctatg gctgcggggg cccgagcacc ccaggagtat acaccaaggt ctcagcctat 1560
ctcaactgga tctacaatgt ctggaaggct gagctgtaat gctgctgccc ctttgcagtg 1620
ctgggagccg cttccttcct gccctgccca cctggggatc ccccaaagtc agacacagag 1680
caagagtccc cttgggtaca cccctctgcc cacagcctca gcatttcttg gagcagcaaa 1740
gggcctcaat tcctataaga gaccctcgca gcccagaggc gcccagagga agtcagcagc 1800
cctagctcgg ccacacttgg tgctcccagc atcccaggga gagacacagc ccactgaaca 1860
aggtctcagg ggtattgcta agccaagaag gaactttccc acactactga atggaagcag 1920
gctgtcttgt aaaagcccag atcactgtgg gctggagagg agaaggaaag ggtctgcgcc 1980
agccctgtcc gtcttcaccc atccccaagc ctactagagc aagaaaccag ttgtaatata 2040
aaatgcactg ccctactgtt ggtatgacta ccgttaccta ctgttgtcat tgttattaca 2100
gctatggcca ctattattaa agagctgtgt aacatctctg gcataggcta gctggaatgc 2160
ttgataagaa ctgagctggg atgattgaac tttcattctt tggcttgggg agaaaagaag 2220
tcctggggaa gcaattgagt ctcaaagtag aggcagggga aaaaagagtt agggagacca 2280
gatctgctga gtggcagcaa gagtgagctg cagattacag aaaccagggt gagcaagttt 2340
gagtcccaca cagggccttc tccctttgcc tctttccctc cctccctgcc tgtgataatc 2400
agccaggagc cagggataac ctatgacttg ggaaagagat gagttaggca gtcaagggtg 2460
acattcaatc agggatccac aagtggctgg aaagaaatgc tggtcctgtg tcctaacttt 2520
ttccgcctgg agagccctca gtgtggcttc ttacatttaa aaaacaaaaa ggatcagctg 2580
ccaggtgtga ggcagtcccc aagctgagtt gtgaggatgt aagcatgaat aagtccctgc 2640
actcaaaatg gtcaaagaat taaaccccat ggactttttt ggcatctgta tgaaagcttg 2700
ggttttctga ggactgtctt gctatagtta agtcagatcc tagatgaaat atacttgttc 2760
atactgtact aggttcttag gaaacaacag aattcctcaa atgccaaaaa caaagaaaat 2820
agaaacccag aaaacaaaac aaaataaaac aaaaccatca gaactgtgag tggaaactaa 2880
ggtgatgatc tgggagcaat acactaaaat cttgggtcga gacctatatg aaggctggca 2940
gtggagctaa acctggacac actgaagaca agggagctga accagggctc ctacatgaag 3000
cagggataac tgatggcagt aaatgtggtc tcaaattgca gatggtctgg aggaaaattt 3060
cccaaattta gagcctcagg attcccaaag atcctccaaa tatgagctca caatcaaaga 3120
tcagagacgt tgaaaaataa aaaacacctt aagtgggcag cataaaaaac agctaattta 3180
gaaccccaaa ggcttcagat gtcagaatat tagagactta tgataataag caatatttgc 3240
agagtatttg tatgtgccag acactattgt aagtgcttca tcatgtactg attcatttaa 3300
tactcacaga aatctgtgag atgggtatta ttcttatcct cactctatgg attaaaaaaa 3360
ctaaggcaca aagtggttaa gctccttgcc tgagattata gactgtaagt tgaacgtgag 3420
cacttggaat acagagttca tgctgtaaac taccacacta tagggcctcc aatatgataa 3480
tttataaaat atttgaataa aaaatgaata ctagttccac attttaaaaa aaaaaaaaaa 3540
aaa 3543
<210> 11
<211> 437
<212> PRT
<213> Homo sapiens
<400> 11
Met Leu Gln Asp Pro Asp Ser Asp Gln Pro Leu Asn Ser Leu Asp Val
1 5 10 15
Lys Pro Leu Arg Lys Pro Arg Ile Pro Met Glu Thr Phe Arg Lys Val
20 25 30
Gly Ile Pro Ile Ile Ile Ala Leu Leu Ser Leu Ala Ser Ile Ile Ile
35 40 45
Val Val Val Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Leu Cys
50 55 60
Gly Gln Pro Leu His Phe Ile Pro Arg Lys Gln Leu Cys Asp Gly Glu
65 70 75 80
Leu Asp Cys Pro Leu Gly Glu Asp Glu Glu His Cys Val Lys Ser Phe
85 90 95
Pro Glu Gly Pro Ala Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr
100 105 110
Leu Gln Val Leu Asp Ser Ala Thr Gly Asn Trp Phe Ser Ala Cys Phe
115 120 125
Asp Asn Phe Thr Glu Ala Leu Ala Glu Thr Ala Cys Arg Gln Met Gly
130 135 140
Tyr Ser Ser Lys Pro Thr Phe Arg Ala Val Glu Ile Gly Pro Asp Gln
145 150 155 160
Asp Leu Asp Val Val Glu Ile Thr Glu Asn Ser Gln Glu Leu Arg Met
165 170 175
Arg Asn Ser Ser Gly Pro Cys Leu Ser Gly Ser Leu Val Ser Leu His
180 185 190
Cys Leu Ala Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val Gly Gly
195 200 205
Glu Glu Ala Ser Val Asp Ser Trp Pro Trp Gln Val Ser Ile Gln Tyr
210 215 220
Asp Lys Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His Trp Val
225 230 235 240
Leu Thr Ala Ala His Cys Phe Arg Lys His Thr Asp Val Phe Asn Trp
245 250 255
Lys Val Arg Ala Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala
260 265 270
Val Ala Lys Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp
275 280 285
Asn Asp Ile Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly
290 295 300
Thr Val Arg Pro Ile Cys Leu Pro Phe Phe Asp Glu Glu Leu Thr Pro
305 310 315 320
Ala Thr Pro Leu Trp Ile Ile Gly Trp Gly Phe Thr Lys Gln Asn Gly
325 330 335
Gly Lys Met Ser Asp Ile Leu Leu Gln Ala Ser Val Gln Val Ile Asp
340 345 350
Ser Thr Arg Cys Asn Ala Asp Asp Ala Tyr Gln Gly Glu Val Thr Glu
355 360 365
Lys Met Met Cys Ala Gly Ile Pro Glu Gly Gly Val Asp Thr Cys Gln
370 375 380
Gly Asp Ser Gly Gly Pro Leu Met Tyr Gln Ser Asp Gln Trp His Val
385 390 395 400
Val Gly Ile Val Ser Trp Gly Tyr Gly Cys Gly Gly Pro Ser Thr Pro
405 410 415
Gly Val Tyr Thr Lys Val Ser Ala Tyr Leu Asn Trp Ile Tyr Asn Val
420 425 430
Trp Lys Ala Glu Leu
435
<210> 12
<211> 20078
<212> DNA
<213> Artificial Sequence
<220>
<223> Recombinant polynucleotide
<400> 12
ccacccgcac acactacagt cgagataact tcgtataatg tatgctatac gaagttatat 60
gcatggcctc cgcgccgggt tttggcgcct cccgcgggcg cccccctcct cacggcgagc 120
gctgccacgt cagacgaagg gcgcagcgag cgtcctgatc cttccgcccg gacgctcagg 180
acagcggccc gctgctcata agactcggcc ttagaacccc agtatcagca gaaggacatt 240
ttaggacggg acttgggtga ctctagggca ctggttttct ttccagagag cggaacaggc 300
gaggaaaagt agtcccttct cggcgattct gcggagggat ctccgtgggg cggtgaacgc 360
cgatgattat ataaggacgc gccgggtgtg gcacagctag ttccgtcgca gccgggattt 420
gggtcgcggt tcttgtttgt ggatcgctgt gatcgtcact tggtgagtag cgggctgctg 480
ggctggccgg ggctttcgtg gccgccgggc cgctcggtgg gacggaagcg tgtggagaga 540
ccgccaaggg ctgtagtctg ggtccgcgag caaggttgcc ctgaactggg ggttgggggg 600
agcgcagcaa aatggcggct gttcccgagt cttgaatgga agacgcttgt gaggcgggct 660
gtgaggtcgt tgaaacaagg tggggggcat ggtgggcggc aagaacccaa ggtcttgagg 720
ccttcgctaa tgcgggaaag ctcttattcg ggtgagatgg gctggggcac catctgggga 780
ccctgacgtg aagtttgtca ctgactggag aactcggttt gtcgtctgtt gcgggggcgg 840
cagttatggc ggtgccgttg ggcagtgcac ccgtaccttt gggagcgcgc gccctcgtcg 900
tgtcgtgacg tcacccgttc tgttggctta taatgcaggg tggggccacc tgccggtagg 960
tgtgcggtag gcttttctcc gtcgcaggac gcagggttcg ggcctagggt aggctctcct 1020
gaatcgacag gcgccggacc tctggtgagg ggagggataa gtgaggcgtc agtttctttg 1080
gtcggtttta tgtacctatc ttcttaagta gctgaagctc cggttttgaa ctatgcgctc 1140
ggggttggcg agtgtgtttt gtgaagtttt ttaggcacct tttgaaatgt aatcatttgg 1200
gtcaatatgt aattttcagt gttagactag taaattgtcc gctaaattct ggccgttttt 1260
ggcttttttg ttagacgtgt tgacaattaa tcatcggcat agtatatcgg catagtataa 1320
tacgacaagg tgaggaacta aaccatggga tcggccattg aacaagatgg attgcacgca 1380
ggttctccgg ccgcttgggt ggagaggcta ttcggctatg actgggcaca acagacaatc 1440
ggctgctctg atgccgccgt gttccggctg tcagcgcagg ggcgcccggt tctttttgtc 1500
aagaccgacc tgtccggtgc cctgaatgaa ctgcaggacg aggcagcgcg gctatcgtgg 1560
ctggccacga cgggcgttcc ttgcgcagct gtgctcgacg ttgtcactga agcgggaagg 1620
gactggctgc tattgggcga agtgccgggg caggatctcc tgtcatctca ccttgctcct 1680
gccgagaaag tatccatcat ggctgatgca atgcggcggc tgcatacgct tgatccggct 1740
acctgcccat tcgaccacca agcgaaacat cgcatcgagc gagcacgtac tcggatggaa 1800
gccggtcttg tcgatcagga tgatctggac gaagagcatc aggggctcgc gccagccgaa 1860
ctgttcgcca ggctcaaggc gcgcatgccc gacggcgatg atctcgtcgt gacccatggc 1920
gatgcctgct tgccgaatat catggtggaa aatggccgct tttctggatt catcgactgt 1980
ggccggctgg gtgtggcgga ccgctatcag gacatagcgt tggctacccg tgatattgct 2040
gaagagcttg gcggcgaatg ggctgaccgc ttcctcgtgc tttacggtat cgccgctccc 2100
gattcgcagc gcatcgcctt ctatcgcctt cttgacgagt tcttctgagg ggatccgctg 2160
taagtctgca gaaattgatg atctattaaa caataaagat gtccactaaa atggaagttt 2220
ttcctgtcat actttgttaa gaagggtgag aacagagtac ctacattttg aatggaagga 2280
ttggagctac gggggtgggg gtggggtggg attagataaa tgcctgctct ttactgaagg 2340
ctctttacta ttgctttatg ataatgtttc atagttggat atcataattt aaacaagcaa 2400
aaccaaatta agggccagct cattcctccc actcatgatc tatagatcta tagatctctc 2460
gtgggatcat tgtttttctc ttgattccca ctttgtggtt ctaagtactg tggtttccaa 2520
atgtgtcagt ttcatagcct gaagaacgag atcagcagcc tctgttccac atacacttca 2580
ttctcagtat tgttttgcca agttctaatt ccatcagacc tcgacctgca gcccctagcc 2640
cgggcgccag tagcagcacc cacgtccacc ttctgtctag taatgtccaa cacctccctc 2700
agtccaaaca ctgctctgca tccatgtggc tcccatttat acctgaagca cttgatgggg 2760
cctcaatgtt ttactagagc ccacccccct gcaactctga gaccctctgg atttgtctgt 2820
cagtgcctca ctggggcgtt ggataatttc ttaaaaggtc aagttccctc agcagcattc 2880
tctgagcagt ctgaagatgt gtgcttttca cagttcaaat ccatgtggct gtttcaccca 2940
cctgcctggc cttgggttat ctatcaggac ctagcctaga agcaggtgtg tggcacttaa 3000
cacctaagct gagtgactaa ctgaacactc aagtggatgc catctttgtc acttcttgac 3060
tgtgacacaa gcaactcctg atgccaaagc cctgcccacc cctctcatgc ccatatttgg 3120
acatggtaca ggtcctcact ggccatggtc tgtgaggtcc tggtcctctt tgacttcata 3180
attcctaggg gccactagta tctataagag gaagagggtg ctggctccca ggccacagcc 3240
cacaaaattc cacctgctca caggttggct ggctcgaccc aggtggtgtc ccctgctctg 3300
agccagctcc cggccaagcc agcaccatgg gtacccccaa gaagaagagg aaggtgcgta 3360
ccgatttaaa ttccaattta ctgaccgtac accaaaattt gcctgcatta ccggtcgatg 3420
caacgagtga tgaggttcgc aagaacctga tggacatgtt cagggatcgc caggcgtttt 3480
ctgagcatac ctggaaaatg cttctgtccg tttgccggtc gtgggcggca tggtgcaagt 3540
tgaataaccg gaaatggttt cccgcagaac ctgaagatgt tcgcgattat cttctatatc 3600
ttcaggcgcg cggtctggca gtaaaaacta tccagcaaca tttgggccag ctaaacatgc 3660
ttcatcgtcg gtccgggctg ccacgaccaa gtgacagcaa tgctgtttca ctggttatgc 3720
ggcggatccg aaaagaaaac gttgatgccg gtgaacgtgc aaaacaggct ctagcgttcg 3780
aacgcactga tttcgaccag gttcgttcac tcatggaaaa tagtgatcgc tgccaggata 3840
tacgtaatct ggcatttctg gggattgctt ataacaccct gttacgtata gccgaaattg 3900
ccaggatcag ggttaaagat atctcacgta ctgacggtgg gagaatgtta atccatattg 3960
gcagaacgaa aacgctggtt agcaccgcag gtgtagagaa ggcacttagc ctgggggtaa 4020
ctaaactggt cgagcgatgg atttccgtct ctggtgtagc tgatgatccg aataactacc 4080
tgttttgccg ggtcagaaaa aatggtgttg ccgcgccatc tgccaccagc cagctatcaa 4140
ctcgcgccct ggaagggatt tttgaagcaa ctcatcgatt gatttacggc gctaaggtaa 4200
atataaaatt tttaagtgta taatgtgtta aactactgat tctaattgtt tgtgtatttt 4260
aggatgactc tggtcagaga tacctggcct ggtctggaca cagtgcccgt gtcggagccg 4320
cgcgagatat ggcccgcgct ggagtttcaa taccggagat catgcaagct ggtggctgga 4380
ccaatgtaaa tattgtcatg aactatatcc gtaacctgga tagtgaaaca ggggcaatgg 4440
tgcgcctgct ggaagatggc gattgatcta gataagtaat gatcataatc agccatatca 4500
catctgtaga ggttttactt gctttaaaaa acctcccaca cctccccctg aacctgaaac 4560
ataaaatgaa tgcaattgtt gttgttaaac ctgccctagt tgcggccaat tccagctgag 4620
cgtgcctccg caccattacc agttggtctg gtgtcaaaaa taataataac cgggcagggg 4680
ggatctaagc tctagataag taatgatcat aatcagccat atcacatctg tagaggtttt 4740
acttgcttta aaaaacctcc cacacctccc cctgaacctg aaacataaaa tgaatgcaat 4800
tgttgttgtt aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac 4860
aaatttcaca aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat 4920
caatgtatct tatcatgtct ggaataactt cgtataatgt atgctatacg aagttatgct 4980
agtaactata acggtcctaa ggtagcgagc tagccaagtc tgtgtgctac caagtagcaa 5040
aactgagcct ggaactcaca catgcgtgtc tgagagccca gcactatcgc caggaaaacc 5100
cagcgtctcc ctgctcaagc ctgaccctca gccctctctg cctctccctg cacttgcctt 5160
ccagtcaagg tgattctgga taaatactac ttcctctgcg ggcagcctct ccacttcatc 5220
ccgaggaagc agctgtgtga cggagagctg gactgtccct tgggggagga cgaggagcac 5280
tgtgtcaaga gcttccccga agggcctgca gtggcaggtg agtgcagggt ctgaggcaca 5340
agagaagtgg gcccagcagg aggtctgctc aggcccccac ggcccactgc atagtatctg 5400
ccccctactt gtcacttttc atccttgttg tataaggttc tttgtttgtt tgtttgttgt 5460
tgttttgagg cagagtgctc tgtggcccaa gatggagtgc agtgtcttgg tctcggctca 5520
ctgcaacctc tgcctcccag tttcaagtga ttcttctgcc tcagcctcat gagtagctgg 5580
gattacaggt gccagccacc acgcctggct aatttttata tttttagtag agacggggtt 5640
ttgccacatt ggtcaggctg atcttgaact cctgacctca ggtgatctgc ccgcctcagc 5700
ctcccaaagt gctgggatta caggcgtgag ccaccgtgcc cagctgtgta agtttcttga 5760
gagcaggacc ctgtcttgtc tacctttaaa tcctagtact taacacacag caaacagtaa 5820
ctatttgatg accaaatgtg agccagaaag gacaggaaat tgtaactgag gctgccccat 5880
gcgtgctgcg cctggtggat ttcaggcaga gggctagact gggtgacctt ggggcattcc 5940
tcctttctat gaaatttgtt atttcaagga gactagaaaa gagacttctc agccacttcg 6000
ccagctattg gtccttctat tcattagtgt ttgctgagac atgctatgtg acaggactga 6060
gccaggtcct ttcaatggat aggagatgtt ttgagcataa aatccacgtt ctctcttggg 6120
ctgggctctt ctaccttctt ccccctggtg cttgggctct gaagaaaaaa agataggtag 6180
gagatgagtg atggggcttc tgagggcagg gctgagtgac tttctgtgta tttgctcttt 6240
ctttatcaga agtcaaatgc ccacaggcac ctgtcatcct actgccagta ggacttctca 6300
ctcaaccttc ccctctgacc ttacttggag aaggacttag gtccctctct cagacatttc 6360
cccaggctgg gcaagttgtg tggaccatgg atgggtatgt ggtccataca atttaaacaa 6420
gctgtatatg gtcgctgggt agagtgacca cataattgat catcaaaact gatacctgta 6480
agagcaaaag ggggcactat taaccattgg gtcagggcaa caggtcaaaa tggagaccta 6540
ccctgggact tctggtcaca ctagctactg tcaaaatggg gcccaaatag acaaagccaa 6600
atggaagaaa ttcccttgac attgaaagtg ttggggctct gtggcacccc cagttctagg 6660
ttgggggagc ttgggctggt ctcatgatga gttctgaggg ggatgggcca gttgggcccc 6720
ccgttccatc taactcaggt tcctttcctc ccagtccgcc tctccaagga ccgatccaca 6780
ctgcaggtgc tggactcggc cacagggaac tggttctctg cctgtttcga caacttcaca 6840
gaagctctcg ctgagacagc ctgtaggcag atgggctaca gcaggtaacc aacctgggcc 6900
tctctccttt ttccctcctt cctccttcct cctcttcctc ctttccttcc tcccttcttc 6960
tctctttcct aaaaattacg ggcattggag ccaggcagaa tggcttttga atcccagcat 7020
ttcacttata agcaacatga agttaaattt cctaagcctc aggttcctca ggagttaatt 7080
gggggaacta atgccaacct cataggatag ttttgcaatg ccagtgagag aatgtgtgct 7140
gccctccaac acacacacac acacttctag cgtctatgca gtcctctcct ttcctttact 7200
cctcaacctt cactcctttg tgctggcttt gcaagaaact gttcctgccc agtaatacaa 7260
aagctaagtt aacttattca aagtttcgtt agttaagatt tagcttaagt gagcctagtt 7320
tcagtggggc cccatcttca gcaatcccag ctctctctgc aaatttcaaa agcagttcca 7380
aatctggagt ggatgaaaag gtgtaagatg atagtaagag taatttgcat tctatatatt 7440
tatattcact tgattttggc agaaaaccaa aaagatagtt attatatctt atatatagat 7500
atatattata tctatttcat aaataggctc aaacaaagta agtaacttgc tagggtacta 7560
gctgggaggt agagggctag aatttgagcc caagacccct aattcttgcg cattaggagt 7620
tcccacattg tttctgtttc tagactgagt aattctttat tctcatgtag gacatcatct 7680
ctaagggaag gggctaatga gatggttgat cactcagaga gtttagctgg agaggatgga 7740
aaagaaccca tacattcagt tgcagattga gatagcctat ctctggcagg cctcagattt 7800
cttcaggatt ctaacagact ggacccagag actaggccaa acaaacaaac aaacaaaaac 7860
tctactaggc agacatcacc aaccaatcac agaactctct cccatggatc cctaatacag 7920
cctcaaagtc cttttcagta aatgctccag gcagccatta caaatcaatc agaattattt 7980
gcctttctct tctctgctca acgggcttct gctgctctct actttccata gggggcaact 8040
tccattaccc tctagaaagc acaccccacc accttcattt caaggagagt gaggaactca 8100
tgcccagcac ctgctattct cccctcttcc tgcagccacg gagcccagcc tcgctgcagc 8160
cagccctgcc tccccactgt agtccagtca actgctgcat cagccgttcc tggcacagca 8220
ggctgagcct tgattatgaa acctgggtgt ctccaggggt tcttaagatg ataggctcct 8280
ggaatttctg tccttttgga gctcagtaag gcaccaaacc acctgagtct tgtgcttcac 8340
aaaatcaaag ttcatcagaa tcattcattg ggatggaatt ggtgaacaga agttaacttt 8400
cctgggaatg tccatttcca ccatattccg tccttctagg tctcagactt ctctactttc 8460
tttcctctct ctagatcgga ggcccttctt gtcctagaac cataggcatt tcaagatgtg 8520
ggagacccta gggatcatct agtccacgca tctttttttt ttttttttga cagagtctca 8580
ctctgtcacc caggctggag tgcaatggca ccatctctgc ttactgcaac ctccacctcc 8640
caggttcaag tgattctttc gcctcagcct cccaagtagc tgggattaca ggcacgcacc 8700
atcatgccca gctaattttt atatttttgt agagaccgag tttcaccatg ttggccaggc 8760
tggtcttgaa ctcctgacct caggtgatcc acccacctcg gcctcccaaa gtgctgggat 8820
tacaggcgtg agccactgca cccagccccg tgcatctttt tatagagggg gaaactgagg 8880
cttggagaga cccagaaaaa gaatatgacc tgcccaaggc cacacatcaa actagtgcca 8940
gagccaggga cagaacctag atcatgagga ctcttaaaat gcactctagt cctcccaggt 9000
ctgagacttg ggtccttcca ggaagtgcca gcattcctgc ctgagaatgt gccaatccac 9060
cagtattgcc aatgactcag ccctccatgg agagcttcta ctaacattac tagcatagtt 9120
agggatggaa ggaaaagatt tagaagaggc agattcagta aaggaacaat cagagagatg 9180
gaattaatca aggaaggctt cctggaggag gaaaaacttc aacccaaggt ttgaaagtag 9240
caagcatgga ttagcaggga gaaagaggga gagtggtcca gttgagagaa acgtttgtct 9300
ggattcatat gaagacagat ctagtcctgt tctattaaat atctctaagg gggccaaaaa 9360
catacccccg ctatcaaagt cagaccagat gctttgtttg gagaacgaaa tatccacatt 9420
ccaactccct cccaggtgag aagggagcta acctgagccc ctatgcctct ttgtttccct 9480
gctgtgaacc agaagacatt gctgggatat ttgaaatagg gacagagctg ggaatatgga 9540
aaggagaccc ctaacatttc tccagggctc tgggttctgg atttggattc cccacccaag 9600
aaagcaagtt acatcagcaa tgcactgagg gttgagtcct gggatgccaa gggtcggttc 9660
tttattgtat agcaaagcag gccccatctt cactgactaa gaccatctcc actccctggc 9720
cactccccac caagcattct ctgccactct ttctcctgaa agtgggggcc aactctacca 9780
tcttgttcta accccctgcc ccagctcaca actctctctc cctcttgatg tgagcagcaa 9840
acccactttc agagctgtgg agattggccc agaccaggat ctggatgttg ttgaaatcac 9900
agaaaacagc caggagcttc gcatgcggaa ctcaagtggg taagtgaggg gacaccttct 9960
ggcctacaga aggcccccac atggacgctg ctcttcaggt tgcaaccagc tcacctggaa 10020
ccccaagcag ccaggggaat gtaagcagac atcaggaaga actcctagcc agatggatca 10080
ttcaatgcca agagctatag actcacattt tggagaggtt ttctgtgttg acttgttttt 10140
aatacaatgg acagctggac aaagtgtgtt gtcctactca gagccagagg gatggataat 10200
gtgacctttc catcaatctg gatagtaaat agtttttgct actgctgtag gttttctaat 10260
aaattgccca ataggcaaga ttccaaagtc actttgtcct tccctaccac ttacccagcc 10320
agagctcccc accttcttga tgctccaggg aagaggctcc atggcccttg tgggtggcct 10380
gttcctgagc ctcgccaccc tgtgttagag cagagcatcc agatgaaatc tgtcacactg 10440
tggcaaagtg gctcagagag gaggctggct tcctagcatt cagggacgtt gctgagggcc 10500
gcttattcac cgaaaataaa tcttgaaaag gacagggctg gtagcagaat gatcctttac 10560
ctaaaattct atcaaaatcc cattcttcca tttggaaagc ccacagtgtc acagactctg 10620
ttccgggctc tgtcctcttc cctcttgggt cccaggagcc caggctgggc tttgaagcag 10680
gcagggccca gcacacagta ggtactcagc agtgggggtg ttgaatccaa tcaaacggaa 10740
gtgtcaatgc aggaaatgca atggatgtca atgcagtctc caaatgttcc ccactgtgca 10800
gcttccacat tcccgaggta ttgggagggg acttgaatta acagcttcgg gaggcctgag 10860
tccctgcctc ccagctgagg aagaagctta aatcacaggg cgctgtgtct gtcttccagg 10920
ccctgtctct caggctccct ggtctccctg cactgtcttg gtgagtaccc ccaatctctg 10980
agggtttggg gcctgggcca gcaatgagca gggaggaaga ccttcatctt cactcctaaa 11040
tttctgggac tccaagtttc attctgcctt ggtctacagc ccttgggctt gtcggtcaat 11100
gccccctcga gttgttggtg gccttgggca ggtcacattc tttttctggg tctttccaag 11160
ccccagtttc ccccttctac catctgtgca tggctccatg acctaagtgg agacctggga 11220
gagagtgtta ggaagaccga aaagggcagg acggggcctc cactgcctcc catccctggt 11280
ccgggcccac atagccttct ttgtcacaat cagctcaggt atccaagatc agattaccca 11340
cattcattat ttgagcaact attcattgaa cagttagaat atgtctcact ctgtcagttg 11400
ctggctagaa gtagaaagta ccagatgagt gaaataattg gccactatcc ttggtagctg 11460
atgactaagt aagagagaga tgcaagacaa catgtggaaa atgccaaact gagtagcagt 11520
cacagttgac atgctgcaga gagagctggc cgggggtcag aagacctggg caccagtcct 11580
gttcatttcc agtgtggcct cgagtcattc acctgacctc cctgaagttc attttcccaa 11640
gaagttgttt agtccaactg cccatcaagg atctttaggg acccttctag ctctaacaga 11700
ggagatcaga aaagaaaaca agcaatgtgg ctcagctcat cctacaagct tcatagagaa 11760
ctgagactgg cctggaagca tagccagaaa ttagaacgcc taagggaaga aggtcacaac 11820
gctgcctctg caatttagga gtgtatatgc tttcctgcag gatgttgaga gtttcattca 11880
ttatcgtatg ccccctaccc cggccccaca atacctagtg cgtgggatct gacacgtggt 11940
ggctggtcaa tgaatgaatg aatgaatggt cacaccatct gaggttctgc actgagtagc 12000
cctgaaggct tgaagcagca taagtgacag gtcctccctt gaggggcctc tgttttacca 12060
ataagccaag acctaagctc aacaacactg aaagggtggc caatacccag gacagcctgt 12120
gggaattcca gagaaaggga gattcccagg gactgggggc ccaggctaaa cactgaaaaa 12180
tgcatctgta ggctcaagga ggaaaagccc atgtctgtct gtcttgccca ccactctctc 12240
ccagcaccca gcactgcccc aggacagaga gcacttgaca caagttggtt agattaatga 12300
atgatttaga gttcagtggt ccccaacctt tttggcacaa gagactggtt gcatggaaga 12360
caatttttcc gcaaaccaag agggggatag agagcattag attctctctt tttttttttt 12420
ttgagaccaa gtctggctct tgtcactcag cctggagtaa agtgttgcga tctcggctca 12480
ctgcaacctc cgcctcctgg attcaagcga ttctcctgcc tcagccccct aaatagctgg 12540
gattacaggc acccgtcacc agcccagctg ggactatagg catgtgccac catgcccggc 12600
taatttttgt atttttagta gagacggcgt ttcaccatgt tggccaggct agtctcgaac 12660
tcctgacctc aggtgatctg cccgcctgag cctcccaaag tgctgggatt acaggcatga 12720
gctgcctcac ccagcctaaa gtctcataag gaacgtacag catagatccc tcacatgtgc 12780
agttcacaat aaggttgtgc tcctacaaga atctaacgcc acctctgatc tgacaggagg 12840
tgaagctcag gtggtcatgc tcgcttgtcc ctgccactca cttcctaatg tacagccagg 12900
ttcctaacag gccacgaacc agtgggaagg gcatcttttt ggatcaaaaa cagaattact 12960
ttttagagaa ctacaagcag atcaatttgg ctagacagag actttatatg aaacagcagg 13020
aggctgctag gaggagtgga aactctactt tgccctcaag ggagatcccg aagggctttg 13080
caggagcggg caaggtggca tgaagaaagc agtgtttgaa atcaggtggt atttgaaaag 13140
cccagccctt ccccttagaa tggcccttct accatctgtg catggctcca caaccgtggt 13200
ggtggctgcc agaagaattg gaaaggcaga gcatgggtgg agagggggga cctgagggct 13260
ttacaggagt tccgggggtg gtgagggtgt gaaagccagg tcagtcagta ggaagacagg 13320
atgtcagatt gagagactcc cctggccggg gaaacagact tggagaaggg ggagttttgg 13380
atgagacagt ccacttccga gtcacaaaat agcttgtggg tgtctgttta ctgttactca 13440
gtgggagtgg ctggggacac gccacctggg cagggctttc gtaattctgc atcacttgtg 13500
aaggtcacag attcccagca caacggacac acccatgttc atagtctgaa ctcctaaaca 13560
catcttaaac caaaataaaa aaaaaagaaa gaaagaaaga aaaaggagag ggaggtttga 13620
ggaaagccta tggtctggga cactcaatac ctcccatgaa tatctcatat tgggctggtc 13680
ctctctccac tctggcccca gccataaggg ccctgcttag agcagatttt gggtgctgag 13740
tggaggcagc ctcatcccca acagcctgac ttcctgcctc ctccctgcct ctgcctgtgt 13800
ccagcctgtg ggaagagcct gaagaccccc cgtgtggtgg gtgtggagga ggcctctgtg 13860
gattcttggc cttggcaggt cagcatccag tacgacaaac agcacgtctg tggagggagc 13920
atcctggacc cccactgggt cctcacggca gcccactgct tcaggtaaga ccccagctgt 13980
aaggaggtct ctggggacca aggccagtca gggaccagag agcttggggt cctgtctcct 14040
ggcaccgtcc ttctcttcac tctcccacta gagacgtttt ccaggttgtg gtggccccaa 14100
tgagacaatg gccatgatgc cctttgttag gcttttgggt gtctgagcag agggtgctgg 14160
tcaccaagca tggcctcttc ctggtgggac accagcagat acccagagtc ctcaccccac 14220
ccccatatcg ttcaagctac aaaagctctt cccacctgcc tcaacttcca agaactcact 14280
ctctttttgc ttgtttccag gaagttgttc cagggtctag agtcatagcc acgtcctcat 14340
tatgtctgga aactttaaaa aaattaaaga gcataggttc ctttcagtcc acagagaagc 14400
ctggccttac ctcagggaag ggctactccc agaccccctt cacttttttt tttttttttt 14460
tttttttttt ttttgagaca gagtcttgct ctgttgctta ggctggagcg cagcagcatg 14520
atcttggctc actgcaacct ccgcctcctg agttcaagca attctcctgc ctcagcttcc 14580
caagtagctg ggactatagg catgggccac catgcccggc taatttttgt atttttggta 14640
gagacagggt ttcaccatgt tggccaggct gatctctaac tcctgacctc aagtgatctg 14700
cccacctcag cctcccaaac tgctgggatt acaggcatga gccagggcat ccggctttta 14760
tttattcatt cattcaatat ctaatgagca cctaccaggt accaaacacc agatgatgcg 14820
cccaagttca ttagacccca ccgctgtctt caaggcactc atgatctagg ccagcgtttt 14880
ttaaccactt tttttttttt tttttttgag attctggtga gagctataaa ttctttcctg 14940
gaaaaacatc tctgcacact aagctgtgcc tggcattggg aaaaagaaag cacgtaatgt 15000
aactgacagc atgagtaaca cagtgagaaa ggttggagga gagagcgcca ggacctcaga 15060
actcaggcat tagaggagcc ccttccccag ccctccttga ggtttcgttg ggcaggtttc 15120
actgaggaaa aagggtcaaa tccctttttc gaatttgact tcttgtaagt gccagaagac 15180
tgccccttct ccaccatccc tgcctcacca tcatctttcc tcccaaggca gtgacatcca 15240
gcaccccgat ccctagggcc ctggggaccc agcctttggc aaagtctcct caggcttgga 15300
tcaggcctga acccagctgt ctctaccccc aggaaacata ccgatgtgtt caactggaag 15360
gtgcgggcag gctcagacaa actgggcagc ttcccatccc tggctgtggc caagatcatc 15420
atcattgaat tcaaccccat gtaccccaaa gacaatgaca tcgccctcat gaagctgcag 15480
ttcccactca ctttctcagg tgagaagcag ggcccaaggc cactcaagcc tcttacatca 15540
gttttcacgc ccactctgct attagctcac tgaccgccct tggcacataa tgtctcctct 15600
caagtcctca gcttgcccat ttgtctctaa tacgtcagcc taacatcact gatgccatga 15660
ggcctcctca agctgtcagc taacacctcc actccattcc ctgccagaga ttcttccaag 15720
gcctgtcttc cctatgtgga gcccctcgag tgagaactgg agtttcatcc aatcttggag 15780
ttttaggaga ccttttaaaa agattatcga gctaattccc caccactgac caacacgcaa 15840
gagcctgctc agtatccctg ccaaggagtc attgtgcccc tgtttgctct cctccagggg 15900
cagggaaccc attacctgtg aggcagccca cagagtcttt gaacagctct gttggatgcc 15960
ttgtgcttat actgaaatgt atttagatca ggattcccaa ctgtggggtc cacaagacac 16020
tggccccttg gagaagagag gattccattg tcaaataagt ttggggaaca ttttcatact 16080
acagctccct tcttggaaca cattagttta ttaaaggtag gagaagtttt taaaataatc 16140
tgttttattg cgtttaacct acatttttta aatttatttg accacagaat ccttttttca 16200
tgctacttct attagcatcc catagaacaa gtgttctaga gaccctggtg tgaccccttt 16260
cagagagctt aactgccagg ctctcctgag ccctggtgtg tgtttcaaga tttgtgcctg 16320
ggaattgttt taatcaggta tggcaaggtg acagatacag acacagctat ctttgaaaga 16380
agagtttatt atttataatt cctgagagaa agggacatac cccacccccc aacacaggga 16440
cacccgggga agcagctggg tccaccagga ggcaggagtg aggggaaggc atggcccaga 16500
gccacctgtg gcttccatgg gcaggtctgg ccaaggtagg gtaggcaaga ttgagcatgc 16560
tcaggattgg atagtgtgga caattctcta ggctatagat gtcagcctct ggttgtctag 16620
tatctgtccc tggggtgatt tagggcaggg aaaatattgg cttggtgtct gagagtcaga 16680
taaaggaagt ggttggggat atgggctttg ggttggctgg tttgcctatt aaaggcgtgc 16740
ccaaagccaa gttgtttact atctgcagga attagctaac ccagtctctc ccagaccagc 16800
aagatcccca taatcataaa gcatcataat ttacagaaaa ttaacactta tgatgaataa 16860
aagatctcct tcttcctctg tgctcctggc aggcacagtc aggcccatct gtctgccctt 16920
ctttgatgag gagctcactc cagccacccc actctggatc attggatggg gctttacgaa 16980
gcagaatgga ggtaagtcct gggtgcagga ccacagggca ggagatgccc ttgtatgagg 17040
gagcagcttc cagaagtaat gggaaggagg accacccttc agagaaaccc atcctggagg 17100
accaagcacc aaggcgccag gcagaaagca aagtggtttg gcaatccagg gctgggggat 17160
agaaggcaag gatgggaatg tgagtgtttt taccctccca gggaagatgt ctgacatact 17220
gctgcaggcg tcagtccagg tcattgacag cacacggtgc aatgcagacg atgcgtacca 17280
gggggaagtc accgagaaga tgatgtgtgc aggcatcccg gaagggggtg tggacacctg 17340
ccaggtgggg cctccaagaa tcatggggag ttctaagaat agggtttagg tcctagagag 17400
atgagaaaac ccagaggctg catgccctac aggaagcctt gcatatcatg ggcactcaat 17460
gtgtgatgat gggaggaaga gagggaggga aggaaaggat agtcagataa aagtgtacca 17520
atagatgagt gggtggatgg atggatgcag acaagcagag agatttcaaa tgtctctttc 17580
acattcgaag atgatgttac tggcctggca tggtggctca cgcttgtaat cccagcactt 17640
tgggaggctg aggcgggcag gtgatttgag gtcaggaatt caagaccagc ctggccaaca 17700
tggtgaaatc ccatctctac taaaaagaat acaaaaatta gctgggcgtg gtggcacgtg 17760
cctgtaatcc cagctacttg ggaggctgag gcaggagaat tgcttgaacc caggaggcag 17820
aggttgcagt aagctgagat tgcgccactg cactccagcc tgggtgaccc agcaagactc 17880
catctgaaaa caacaacaac aacaaagatg acattactca tccaccccac ccacccttct 17940
cactagctac agaatgatta gccccttgag gtcaggaatc ccaggtctat tttctctgtg 18000
actctcccca agctgctgaa ctacactagg aaagaattac cgcctgcaga atgctggaag 18060
cacatctgtg tgtgccctca ccccggcctc attggccatc aggactgctt agcaatccct 18120
gtagaccttc ttcctccccc atacttccag aggatcttct gaactatttt ctttttttat 18180
tttttctttt atgtttttta acagagacag ggtcactatg ttgcccagtc tggtctcaaa 18240
ctcctgggtt caagggattc tcccacctca gctttccaaa atgctgggat tacaggcatg 18300
agccatcgtg cttggcctga accattttca ttaaaacccc taccctactc tcacctccat 18360
ttccagtcat taaattcctt catttaagag gcatctctta gtcatcgcat gtgtgccatg 18420
aacatggtag tctttggaga cccctcaggg agctcacagt ggttggggga aaggggggca 18480
ttaaacagac atttaagcta tagttttggg ttcagaggga ggaagcccca ggggctaaaa 18540
cagctgataa ggactcccag ataagtgcac ttttcactat ctggcatttt cttgttttgt 18600
tatttgcttg ttcactgtct ctcaccccat ttgatcctaa gctttctgag ggcagggatc 18660
tttgtttttt ttcatcagtt ggatcccaat tgcttagaac actacctggc acaaaatagg 18720
cactctataa gtgattacac aaattttgga acgactaggt taaacaatga taaccaggct 18780
tttttttttt tttttgagac tgagtctcac tctgttgccc aggctagagt gaagtggttt 18840
gatctcggct cactgcagcc tccgcctctg ggttcgaatg attctccacc tcagcctcct 18900
gagtagctgg gattacaggt gcctgccact atgcccagct aatttttgta tttgtagtag 18960
agacgggttt caccatgttg gccaggctgg tcttgaactc ctgacctcaa gtgattcacc 19020
cgcctcagcc tcccaaggtg ctgggattac aggtgtgagc caccgctcct ggccaacaac 19080
caggcttttt taagacatca ctcagagcct ttaatttgct aatgtgagtt gtgaatctct 19140
gagagaaggc taacggcatg cttgcaactt acttgtccac agacaagcct ttctgcccca 19200
gaagagaaga ccattctagg gtgctaatga gcaaagaggg tgagggtgga atatcggaga 19260
gcagcaggga gtgcagggga acagataggc cagttcaggg agcagagaag gagaagcccc 19320
cccacctcac ctgccctccc cagcagtctc tgttctggtc tctcacaggg tgacagtggt 19380
gggcccctga tgtaccaatc tgaccagtgg catgtggtgg gcatcgttag ttggggctat 19440
ggctgcgggg gcccgagcac cccaggagta tacaccaagg tctcagccta tctcaactgg 19500
atctacaatg tctggaaggt aaggtacctt tgccctaccc actgtgcctt ccctccagtc 19560
ctctacctgg ggggtgccaa tccatcctca ggtttgattt aaatggttct gacaactctt 19620
tacatcccaa ataactttcc ctccaagcaa gggacagcct gagattgcac tattaaggct 19680
gaaattcctt aggtcagaga tttctgataa atgcaaatac cttagggaat agaacacacc 19740
aagcctttct ttctcttttc tgacagaatg agactatcag atcctttcta gagagaagat 19800
tctgataagg aagagagtgg aaaggctcat gagacctcct ggccctctgc agggtaggga 19860
gagaagcaaa gtgtttcaga aaaggaagac tcacgttaca catgtcacca ctttgtccag 19920
tttcagataa tctgactttc tcttcatcgg tctctcttat tctaggctga gctgtaacgc 19980
tgccgtcccc cacatccaga agctgcttcc cttcagacct acctacggca tgacccctca 20040
aagtcagata tgggacaaga gcctccttga acaaactc 20078
<210> 13
<211> 15159
<212> DNA
<213> Artificial Sequence
<220>
<223> Recombinant polynucleotide
<400> 13
ccacccgcac acactacagt cgagataact tcgtataatg tatgctatac gaagttatgc 60
tagtaactat aacggtccta aggtagcgag ctagccaagt ctgtgtgcta ccaagtagca 120
aaactgagcc tggaactcac acatgcgtgt ctgagagccc agcactatcg ccaggaaaac 180
ccagcgtctc cctgctcaag cctgaccctc agccctctct gcctctccct gcacttgcct 240
tccagtcaag gtgattctgg ataaatacta cttcctctgc gggcagcctc tccacttcat 300
cccgaggaag cagctgtgtg acggagagct ggactgtccc ttgggggagg acgaggagca 360
ctgtgtcaag agcttccccg aagggcctgc agtggcaggt gagtgcaggg tctgaggcac 420
aagagaagtg ggcccagcag gaggtctgct caggccccca cggcccactg catagtatct 480
gccccctact tgtcactttt catccttgtt gtataaggtt ctttgtttgt ttgtttgttg 540
ttgttttgag gcagagtgct ctgtggccca agatggagtg cagtgtcttg gtctcggctc 600
actgcaacct ctgcctccca gtttcaagtg attcttctgc ctcagcctca tgagtagctg 660
ggattacagg tgccagccac cacgcctggc taatttttat atttttagta gagacggggt 720
tttgccacat tggtcaggct gatcttgaac tcctgacctc aggtgatctg cccgcctcag 780
cctcccaaag tgctgggatt acaggcgtga gccaccgtgc ccagctgtgt aagtttcttg 840
agagcaggac cctgtcttgt ctacctttaa atcctagtac ttaacacaca gcaaacagta 900
actatttgat gaccaaatgt gagccagaaa ggacaggaaa ttgtaactga ggctgcccca 960
tgcgtgctgc gcctggtgga tttcaggcag agggctagac tgggtgacct tggggcattc 1020
ctcctttcta tgaaatttgt tatttcaagg agactagaaa agagacttct cagccacttc 1080
gccagctatt ggtccttcta ttcattagtg tttgctgaga catgctatgt gacaggactg 1140
agccaggtcc tttcaatgga taggagatgt tttgagcata aaatccacgt tctctcttgg 1200
gctgggctct tctaccttct tccccctggt gcttgggctc tgaagaaaaa aagataggta 1260
ggagatgagt gatggggctt ctgagggcag ggctgagtga ctttctgtgt atttgctctt 1320
tctttatcag aagtcaaatg cccacaggca cctgtcatcc tactgccagt aggacttctc 1380
actcaacctt cccctctgac cttacttgga gaaggactta ggtccctctc tcagacattt 1440
ccccaggctg ggcaagttgt gtggaccatg gatgggtatg tggtccatac aatttaaaca 1500
agctgtatat ggtcgctggg tagagtgacc acataattga tcatcaaaac tgatacctgt 1560
aagagcaaaa gggggcacta ttaaccattg ggtcagggca acaggtcaaa atggagacct 1620
accctgggac ttctggtcac actagctact gtcaaaatgg ggcccaaata gacaaagcca 1680
aatggaagaa attcccttga cattgaaagt gttggggctc tgtggcaccc ccagttctag 1740
gttgggggag cttgggctgg tctcatgatg agttctgagg gggatgggcc agttgggccc 1800
cccgttccat ctaactcagg ttcctttcct cccagtccgc ctctccaagg accgatccac 1860
actgcaggtg ctggactcgg ccacagggaa ctggttctct gcctgtttcg acaacttcac 1920
agaagctctc gctgagacag cctgtaggca gatgggctac agcaggtaac caacctgggc 1980
ctctctcctt tttccctcct tcctccttcc tcctcttcct cctttccttc ctcccttctt 2040
ctctctttcc taaaaattac gggcattgga gccaggcaga atggcttttg aatcccagca 2100
tttcacttat aagcaacatg aagttaaatt tcctaagcct caggttcctc aggagttaat 2160
tgggggaact aatgccaacc tcataggata gttttgcaat gccagtgaga gaatgtgtgc 2220
tgccctccaa cacacacaca cacacttcta gcgtctatgc agtcctctcc tttcctttac 2280
tcctcaacct tcactccttt gtgctggctt tgcaagaaac tgttcctgcc cagtaataca 2340
aaagctaagt taacttattc aaagtttcgt tagttaagat ttagcttaag tgagcctagt 2400
ttcagtgggg ccccatcttc agcaatccca gctctctctg caaatttcaa aagcagttcc 2460
aaatctggag tggatgaaaa ggtgtaagat gatagtaaga gtaatttgca ttctatatat 2520
ttatattcac ttgattttgg cagaaaacca aaaagatagt tattatatct tatatataga 2580
tatatattat atctatttca taaataggct caaacaaagt aagtaacttg ctagggtact 2640
agctgggagg tagagggcta gaatttgagc ccaagacccc taattcttgc gcattaggag 2700
ttcccacatt gtttctgttt ctagactgag taattcttta ttctcatgta ggacatcatc 2760
tctaagggaa ggggctaatg agatggttga tcactcagag agtttagctg gagaggatgg 2820
aaaagaaccc atacattcag ttgcagattg agatagccta tctctggcag gcctcagatt 2880
tcttcaggat tctaacagac tggacccaga gactaggcca aacaaacaaa caaacaaaaa 2940
ctctactagg cagacatcac caaccaatca cagaactctc tcccatggat ccctaataca 3000
gcctcaaagt ccttttcagt aaatgctcca ggcagccatt acaaatcaat cagaattatt 3060
tgcctttctc ttctctgctc aacgggcttc tgctgctctc tactttccat agggggcaac 3120
ttccattacc ctctagaaag cacaccccac caccttcatt tcaaggagag tgaggaactc 3180
atgcccagca cctgctattc tcccctcttc ctgcagccac ggagcccagc ctcgctgcag 3240
ccagccctgc ctccccactg tagtccagtc aactgctgca tcagccgttc ctggcacagc 3300
aggctgagcc ttgattatga aacctgggtg tctccagggg ttcttaagat gataggctcc 3360
tggaatttct gtccttttgg agctcagtaa ggcaccaaac cacctgagtc ttgtgcttca 3420
caaaatcaaa gttcatcaga atcattcatt gggatggaat tggtgaacag aagttaactt 3480
tcctgggaat gtccatttcc accatattcc gtccttctag gtctcagact tctctacttt 3540
ctttcctctc tctagatcgg aggcccttct tgtcctagaa ccataggcat ttcaagatgt 3600
gggagaccct agggatcatc tagtccacgc atcttttttt tttttttttg acagagtctc 3660
actctgtcac ccaggctgga gtgcaatggc accatctctg cttactgcaa cctccacctc 3720
ccaggttcaa gtgattcttt cgcctcagcc tcccaagtag ctgggattac aggcacgcac 3780
catcatgccc agctaatttt tatatttttg tagagaccga gtttcaccat gttggccagg 3840
ctggtcttga actcctgacc tcaggtgatc cacccacctc ggcctcccaa agtgctggga 3900
ttacaggcgt gagccactgc acccagcccc gtgcatcttt ttatagaggg ggaaactgag 3960
gcttggagag acccagaaaa agaatatgac ctgcccaagg ccacacatca aactagtgcc 4020
agagccaggg acagaaccta gatcatgagg actcttaaaa tgcactctag tcctcccagg 4080
tctgagactt gggtccttcc aggaagtgcc agcattcctg cctgagaatg tgccaatcca 4140
ccagtattgc caatgactca gccctccatg gagagcttct actaacatta ctagcatagt 4200
tagggatgga aggaaaagat ttagaagagg cagattcagt aaaggaacaa tcagagagat 4260
ggaattaatc aaggaaggct tcctggagga ggaaaaactt caacccaagg tttgaaagta 4320
gcaagcatgg attagcaggg agaaagaggg agagtggtcc agttgagaga aacgtttgtc 4380
tggattcata tgaagacaga tctagtcctg ttctattaaa tatctctaag ggggccaaaa 4440
acataccccc gctatcaaag tcagaccaga tgctttgttt ggagaacgaa atatccacat 4500
tccaactccc tcccaggtga gaagggagct aacctgagcc cctatgcctc tttgtttccc 4560
tgctgtgaac cagaagacat tgctgggata tttgaaatag ggacagagct gggaatatgg 4620
aaaggagacc cctaacattt ctccagggct ctgggttctg gatttggatt ccccacccaa 4680
gaaagcaagt tacatcagca atgcactgag ggttgagtcc tgggatgcca agggtcggtt 4740
ctttattgta tagcaaagca ggccccatct tcactgacta agaccatctc cactccctgg 4800
ccactcccca ccaagcattc tctgccactc tttctcctga aagtgggggc caactctacc 4860
atcttgttct aaccccctgc cccagctcac aactctctct ccctcttgat gtgagcagca 4920
aacccacttt cagagctgtg gagattggcc cagaccagga tctggatgtt gttgaaatca 4980
cagaaaacag ccaggagctt cgcatgcgga actcaagtgg gtaagtgagg ggacaccttc 5040
tggcctacag aaggccccca catggacgct gctcttcagg ttgcaaccag ctcacctgga 5100
accccaagca gccaggggaa tgtaagcaga catcaggaag aactcctagc cagatggatc 5160
attcaatgcc aagagctata gactcacatt ttggagaggt tttctgtgtt gacttgtttt 5220
taatacaatg gacagctgga caaagtgtgt tgtcctactc agagccagag ggatggataa 5280
tgtgaccttt ccatcaatct ggatagtaaa tagtttttgc tactgctgta ggttttctaa 5340
taaattgccc aataggcaag attccaaagt cactttgtcc ttccctacca cttacccagc 5400
cagagctccc caccttcttg atgctccagg gaagaggctc catggccctt gtgggtggcc 5460
tgttcctgag cctcgccacc ctgtgttaga gcagagcatc cagatgaaat ctgtcacact 5520
gtggcaaagt ggctcagaga ggaggctggc ttcctagcat tcagggacgt tgctgagggc 5580
cgcttattca ccgaaaataa atcttgaaaa ggacagggct ggtagcagaa tgatccttta 5640
cctaaaattc tatcaaaatc ccattcttcc atttggaaag cccacagtgt cacagactct 5700
gttccgggct ctgtcctctt ccctcttggg tcccaggagc ccaggctggg ctttgaagca 5760
ggcagggccc agcacacagt aggtactcag cagtgggggt gttgaatcca atcaaacgga 5820
agtgtcaatg caggaaatgc aatggatgtc aatgcagtct ccaaatgttc cccactgtgc 5880
agcttccaca ttcccgaggt attgggaggg gacttgaatt aacagcttcg ggaggcctga 5940
gtccctgcct cccagctgag gaagaagctt aaatcacagg gcgctgtgtc tgtcttccag 6000
gccctgtctc tcaggctccc tggtctccct gcactgtctt ggtgagtacc cccaatctct 6060
gagggtttgg ggcctgggcc agcaatgagc agggaggaag accttcatct tcactcctaa 6120
atttctggga ctccaagttt cattctgcct tggtctacag cccttgggct tgtcggtcaa 6180
tgccccctcg agttgttggt ggccttgggc aggtcacatt ctttttctgg gtctttccaa 6240
gccccagttt cccccttcta ccatctgtgc atggctccat gacctaagtg gagacctggg 6300
agagagtgtt aggaagaccg aaaagggcag gacggggcct ccactgcctc ccatccctgg 6360
tccgggccca catagccttc tttgtcacaa tcagctcagg tatccaagat cagattaccc 6420
acattcatta tttgagcaac tattcattga acagttagaa tatgtctcac tctgtcagtt 6480
gctggctaga agtagaaagt accagatgag tgaaataatt ggccactatc cttggtagct 6540
gatgactaag taagagagag atgcaagaca acatgtggaa aatgccaaac tgagtagcag 6600
tcacagttga catgctgcag agagagctgg ccgggggtca gaagacctgg gcaccagtcc 6660
tgttcatttc cagtgtggcc tcgagtcatt cacctgacct ccctgaagtt cattttccca 6720
agaagttgtt tagtccaact gcccatcaag gatctttagg gacccttcta gctctaacag 6780
aggagatcag aaaagaaaac aagcaatgtg gctcagctca tcctacaagc ttcatagaga 6840
actgagactg gcctggaagc atagccagaa attagaacgc ctaagggaag aaggtcacaa 6900
cgctgcctct gcaatttagg agtgtatatg ctttcctgca ggatgttgag agtttcattc 6960
attatcgtat gccccctacc ccggccccac aatacctagt gcgtgggatc tgacacgtgg 7020
tggctggtca atgaatgaat gaatgaatgg tcacaccatc tgaggttctg cactgagtag 7080
ccctgaaggc ttgaagcagc ataagtgaca ggtcctccct tgaggggcct ctgttttacc 7140
aataagccaa gacctaagct caacaacact gaaagggtgg ccaataccca ggacagcctg 7200
tgggaattcc agagaaaggg agattcccag ggactggggg cccaggctaa acactgaaaa 7260
atgcatctgt aggctcaagg aggaaaagcc catgtctgtc tgtcttgccc accactctct 7320
cccagcaccc agcactgccc caggacagag agcacttgac acaagttggt tagattaatg 7380
aatgatttag agttcagtgg tccccaacct ttttggcaca agagactggt tgcatggaag 7440
acaatttttc cgcaaaccaa gagggggata gagagcatta gattctctct tttttttttt 7500
tttgagacca agtctggctc ttgtcactca gcctggagta aagtgttgcg atctcggctc 7560
actgcaacct ccgcctcctg gattcaagcg attctcctgc ctcagccccc taaatagctg 7620
ggattacagg cacccgtcac cagcccagct gggactatag gcatgtgcca ccatgcccgg 7680
ctaatttttg tatttttagt agagacggcg tttcaccatg ttggccaggc tagtctcgaa 7740
ctcctgacct caggtgatct gcccgcctga gcctcccaaa gtgctgggat tacaggcatg 7800
agctgcctca cccagcctaa agtctcataa ggaacgtaca gcatagatcc ctcacatgtg 7860
cagttcacaa taaggttgtg ctcctacaag aatctaacgc cacctctgat ctgacaggag 7920
gtgaagctca ggtggtcatg ctcgcttgtc cctgccactc acttcctaat gtacagccag 7980
gttcctaaca ggccacgaac cagtgggaag ggcatctttt tggatcaaaa acagaattac 8040
tttttagaga actacaagca gatcaatttg gctagacaga gactttatat gaaacagcag 8100
gaggctgcta ggaggagtgg aaactctact ttgccctcaa gggagatccc gaagggcttt 8160
gcaggagcgg gcaaggtggc atgaagaaag cagtgtttga aatcaggtgg tatttgaaaa 8220
gcccagccct tccccttaga atggcccttc taccatctgt gcatggctcc acaaccgtgg 8280
tggtggctgc cagaagaatt ggaaaggcag agcatgggtg gagagggggg acctgagggc 8340
tttacaggag ttccgggggt ggtgagggtg tgaaagccag gtcagtcagt aggaagacag 8400
gatgtcagat tgagagactc ccctggccgg ggaaacagac ttggagaagg gggagttttg 8460
gatgagacag tccacttccg agtcacaaaa tagcttgtgg gtgtctgttt actgttactc 8520
agtgggagtg gctggggaca cgccacctgg gcagggcttt cgtaattctg catcacttgt 8580
gaaggtcaca gattcccagc acaacggaca cacccatgtt catagtctga actcctaaac 8640
acatcttaaa ccaaaataaa aaaaaaagaa agaaagaaag aaaaaggaga gggaggtttg 8700
aggaaagcct atggtctggg acactcaata cctcccatga atatctcata ttgggctggt 8760
cctctctcca ctctggcccc agccataagg gccctgctta gagcagattt tgggtgctga 8820
gtggaggcag cctcatcccc aacagcctga cttcctgcct cctccctgcc tctgcctgtg 8880
tccagcctgt gggaagagcc tgaagacccc ccgtgtggtg ggtgtggagg aggcctctgt 8940
ggattcttgg ccttggcagg tcagcatcca gtacgacaaa cagcacgtct gtggagggag 9000
catcctggac ccccactggg tcctcacggc agcccactgc ttcaggtaag accccagctg 9060
taaggaggtc tctggggacc aaggccagtc agggaccaga gagcttgggg tcctgtctcc 9120
tggcaccgtc cttctcttca ctctcccact agagacgttt tccaggttgt ggtggcccca 9180
atgagacaat ggccatgatg ccctttgtta ggcttttggg tgtctgagca gagggtgctg 9240
gtcaccaagc atggcctctt cctggtggga caccagcaga tacccagagt cctcacccca 9300
cccccatatc gttcaagcta caaaagctct tcccacctgc ctcaacttcc aagaactcac 9360
tctctttttg cttgtttcca ggaagttgtt ccagggtcta gagtcatagc cacgtcctca 9420
ttatgtctgg aaactttaaa aaaattaaag agcataggtt cctttcagtc cacagagaag 9480
cctggcctta cctcagggaa gggctactcc cagaccccct tcactttttt tttttttttt 9540
tttttttttt tttttgagac agagtcttgc tctgttgctt aggctggagc gcagcagcat 9600
gatcttggct cactgcaacc tccgcctcct gagttcaagc aattctcctg cctcagcttc 9660
ccaagtagct gggactatag gcatgggcca ccatgcccgg ctaatttttg tatttttggt 9720
agagacaggg tttcaccatg ttggccaggc tgatctctaa ctcctgacct caagtgatct 9780
gcccacctca gcctcccaaa ctgctgggat tacaggcatg agccagggca tccggctttt 9840
atttattcat tcattcaata tctaatgagc acctaccagg taccaaacac cagatgatgc 9900
gcccaagttc attagacccc accgctgtct tcaaggcact catgatctag gccagcgttt 9960
tttaaccact tttttttttt ttttttttga gattctggtg agagctataa attctttcct 10020
ggaaaaacat ctctgcacac taagctgtgc ctggcattgg gaaaaagaaa gcacgtaatg 10080
taactgacag catgagtaac acagtgagaa aggttggagg agagagcgcc aggacctcag 10140
aactcaggca ttagaggagc cccttcccca gccctccttg aggtttcgtt gggcaggttt 10200
cactgaggaa aaagggtcaa atcccttttt cgaatttgac ttcttgtaag tgccagaaga 10260
ctgccccttc tccaccatcc ctgcctcacc atcatctttc ctcccaaggc agtgacatcc 10320
agcaccccga tccctagggc cctggggacc cagcctttgg caaagtctcc tcaggcttgg 10380
atcaggcctg aacccagctg tctctacccc caggaaacat accgatgtgt tcaactggaa 10440
ggtgcgggca ggctcagaca aactgggcag cttcccatcc ctggctgtgg ccaagatcat 10500
catcattgaa ttcaacccca tgtaccccaa agacaatgac atcgccctca tgaagctgca 10560
gttcccactc actttctcag gtgagaagca gggcccaagg ccactcaagc ctcttacatc 10620
agttttcacg cccactctgc tattagctca ctgaccgccc ttggcacata atgtctcctc 10680
tcaagtcctc agcttgccca tttgtctcta atacgtcagc ctaacatcac tgatgccatg 10740
aggcctcctc aagctgtcag ctaacacctc cactccattc cctgccagag attcttccaa 10800
ggcctgtctt ccctatgtgg agcccctcga gtgagaactg gagtttcatc caatcttgga 10860
gttttaggag accttttaaa aagattatcg agctaattcc ccaccactga ccaacacgca 10920
agagcctgct cagtatccct gccaaggagt cattgtgccc ctgtttgctc tcctccaggg 10980
gcagggaacc cattacctgt gaggcagccc acagagtctt tgaacagctc tgttggatgc 11040
cttgtgctta tactgaaatg tatttagatc aggattccca actgtggggt ccacaagaca 11100
ctggcccctt ggagaagaga ggattccatt gtcaaataag tttggggaac attttcatac 11160
tacagctccc ttcttggaac acattagttt attaaaggta ggagaagttt ttaaaataat 11220
ctgttttatt gcgtttaacc tacatttttt aaatttattt gaccacagaa tccttttttc 11280
atgctacttc tattagcatc ccatagaaca agtgttctag agaccctggt gtgacccctt 11340
tcagagagct taactgccag gctctcctga gccctggtgt gtgtttcaag atttgtgcct 11400
gggaattgtt ttaatcaggt atggcaaggt gacagataca gacacagcta tctttgaaag 11460
aagagtttat tatttataat tcctgagaga aagggacata ccccaccccc caacacaggg 11520
acacccgggg aagcagctgg gtccaccagg aggcaggagt gaggggaagg catggcccag 11580
agccacctgt ggcttccatg ggcaggtctg gccaaggtag ggtaggcaag attgagcatg 11640
ctcaggattg gatagtgtgg acaattctct aggctataga tgtcagcctc tggttgtcta 11700
gtatctgtcc ctggggtgat ttagggcagg gaaaatattg gcttggtgtc tgagagtcag 11760
ataaaggaag tggttgggga tatgggcttt gggttggctg gtttgcctat taaaggcgtg 11820
cccaaagcca agttgtttac tatctgcagg aattagctaa cccagtctct cccagaccag 11880
caagatcccc ataatcataa agcatcataa tttacagaaa attaacactt atgatgaata 11940
aaagatctcc ttcttcctct gtgctcctgg caggcacagt caggcccatc tgtctgccct 12000
tctttgatga ggagctcact ccagccaccc cactctggat cattggatgg ggctttacga 12060
agcagaatgg aggtaagtcc tgggtgcagg accacagggc aggagatgcc cttgtatgag 12120
ggagcagctt ccagaagtaa tgggaaggag gaccaccctt cagagaaacc catcctggag 12180
gaccaagcac caaggcgcca ggcagaaagc aaagtggttt ggcaatccag ggctggggga 12240
tagaaggcaa ggatgggaat gtgagtgttt ttaccctccc agggaagatg tctgacatac 12300
tgctgcaggc gtcagtccag gtcattgaca gcacacggtg caatgcagac gatgcgtacc 12360
agggggaagt caccgagaag atgatgtgtg caggcatccc ggaagggggt gtggacacct 12420
gccaggtggg gcctccaaga atcatgggga gttctaagaa tagggtttag gtcctagaga 12480
gatgagaaaa cccagaggct gcatgcccta caggaagcct tgcatatcat gggcactcaa 12540
tgtgtgatga tgggaggaag agagggaggg aaggaaagga tagtcagata aaagtgtacc 12600
aatagatgag tgggtggatg gatggatgca gacaagcaga gagatttcaa atgtctcttt 12660
cacattcgaa gatgatgtta ctggcctggc atggtggctc acgcttgtaa tcccagcact 12720
ttgggaggct gaggcgggca ggtgatttga ggtcaggaat tcaagaccag cctggccaac 12780
atggtgaaat cccatctcta ctaaaaagaa tacaaaaatt agctgggcgt ggtggcacgt 12840
gcctgtaatc ccagctactt gggaggctga ggcaggagaa ttgcttgaac ccaggaggca 12900
gaggttgcag taagctgaga ttgcgccact gcactccagc ctgggtgacc cagcaagact 12960
ccatctgaaa acaacaacaa caacaaagat gacattactc atccacccca cccacccttc 13020
tcactagcta cagaatgatt agccccttga ggtcaggaat cccaggtcta ttttctctgt 13080
gactctcccc aagctgctga actacactag gaaagaatta ccgcctgcag aatgctggaa 13140
gcacatctgt gtgtgccctc accccggcct cattggccat caggactgct tagcaatccc 13200
tgtagacctt cttcctcccc catacttcca gaggatcttc tgaactattt tcttttttta 13260
ttttttcttt tatgtttttt aacagagaca gggtcactat gttgcccagt ctggtctcaa 13320
actcctgggt tcaagggatt ctcccacctc agctttccaa aatgctggga ttacaggcat 13380
gagccatcgt gcttggcctg aaccattttc attaaaaccc ctaccctact ctcacctcca 13440
tttccagtca ttaaattcct tcatttaaga ggcatctctt agtcatcgca tgtgtgccat 13500
gaacatggta gtctttggag acccctcagg gagctcacag tggttggggg aaaggggggc 13560
attaaacaga catttaagct atagttttgg gttcagaggg aggaagcccc aggggctaaa 13620
acagctgata aggactccca gataagtgca cttttcacta tctggcattt tcttgttttg 13680
ttatttgctt gttcactgtc tctcacccca tttgatccta agctttctga gggcagggat 13740
ctttgttttt tttcatcagt tggatcccaa ttgcttagaa cactacctgg cacaaaatag 13800
gcactctata agtgattaca caaattttgg aacgactagg ttaaacaatg ataaccaggc 13860
tttttttttt ttttttgaga ctgagtctca ctctgttgcc caggctagag tgaagtggtt 13920
tgatctcggc tcactgcagc ctccgcctct gggttcgaat gattctccac ctcagcctcc 13980
tgagtagctg ggattacagg tgcctgccac tatgcccagc taatttttgt atttgtagta 14040
gagacgggtt tcaccatgtt ggccaggctg gtcttgaact cctgacctca agtgattcac 14100
ccgcctcagc ctcccaaggt gctgggatta caggtgtgag ccaccgctcc tggccaacaa 14160
ccaggctttt ttaagacatc actcagagcc tttaatttgc taatgtgagt tgtgaatctc 14220
tgagagaagg ctaacggcat gcttgcaact tacttgtcca cagacaagcc tttctgcccc 14280
agaagagaag accattctag ggtgctaatg agcaaagagg gtgagggtgg aatatcggag 14340
agcagcaggg agtgcagggg aacagatagg ccagttcagg gagcagagaa ggagaagccc 14400
ccccacctca cctgccctcc ccagcagtct ctgttctggt ctctcacagg gtgacagtgg 14460
tgggcccctg atgtaccaat ctgaccagtg gcatgtggtg ggcatcgtta gttggggcta 14520
tggctgcggg ggcccgagca ccccaggagt atacaccaag gtctcagcct atctcaactg 14580
gatctacaat gtctggaagg taaggtacct ttgccctacc cactgtgcct tccctccagt 14640
cctctacctg gggggtgcca atccatcctc aggtttgatt taaatggttc tgacaactct 14700
ttacatccca aataactttc cctccaagca agggacagcc tgagattgca ctattaaggc 14760
tgaaattcct taggtcagag atttctgata aatgcaaata ccttagggaa tagaacacac 14820
caagcctttc tttctctttt ctgacagaat gagactatca gatcctttct agagagaaga 14880
ttctgataag gaagagagtg gaaaggctca tgagacctcc tggccctctg cagggtaggg 14940
agagaagcaa agtgtttcag aaaaggaaga ctcacgttac acatgtcacc actttgtcca 15000
gtttcagata atctgacttt ctcttcatcg gtctctctta ttctaggctg agctgtaacg 15060
ctgccgtccc ccacatccag aagctgcttc ccttcagacc tacctacggc atgacccctc 15120
aaagtcagat atgggacaag agcctccttg aacaaactc 15159
<210> 14
<211> 435
<212> PRT
<213> Artificial Sequence
<220>
<223> Recombinant protein
<400> 14
Met Glu Ser Asp Ser Gly Gln Pro Leu Asn Asn Arg Asp Ile Val Pro
1 5 10 15
Phe Arg Lys Pro Arg Arg Pro Gln Glu Thr Phe Lys Lys Val Gly Ile
20 25 30
Pro Ile Ile Ala Val Leu Leu Ser Leu Ile Ala Leu Val Ile Val Ala
35 40 45
Leu Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Leu Cys Gly Gln
50 55 60
Pro Leu His Phe Ile Pro Arg Lys Gln Leu Cys Asp Gly Glu Leu Asp
65 70 75 80
Cys Pro Leu Gly Glu Asp Glu Glu His Cys Val Lys Ser Phe Pro Glu
85 90 95
Gly Pro Ala Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr Leu Gln
100 105 110
Val Leu Asp Ser Ala Thr Gly Asn Trp Phe Ser Ala Cys Phe Asp Asn
115 120 125
Phe Thr Glu Ala Leu Ala Glu Thr Ala Cys Arg Gln Met Gly Tyr Ser
130 135 140
Ser Lys Pro Thr Phe Arg Ala Val Glu Ile Gly Pro Asp Gln Asp Leu
145 150 155 160
Asp Val Val Glu Ile Thr Glu Asn Ser Gln Glu Leu Arg Met Arg Asn
165 170 175
Ser Ser Gly Pro Cys Leu Ser Gly Ser Leu Val Ser Leu His Cys Leu
180 185 190
Ala Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val Gly Val Glu Glu
195 200 205
Ala Ser Val Asp Ser Trp Pro Trp Gln Val Ser Ile Gln Tyr Asp Lys
210 215 220
Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His Trp Val Leu Thr
225 230 235 240
Ala Ala His Cys Phe Arg Lys His Thr Asp Val Phe Asn Trp Lys Val
245 250 255
Arg Ala Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala Val Ala
260 265 270
Lys Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp Asn Asp
275 280 285
Ile Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly Thr Val
290 295 300
Arg Pro Ile Cys Leu Pro Phe Phe Asp Glu Glu Leu Thr Pro Ala Thr
305 310 315 320
Pro Leu Trp Ile Ile Gly Trp Gly Phe Thr Lys Gln Asn Gly Gly Lys
325 330 335
Met Ser Asp Ile Leu Leu Gln Ala Ser Val Gln Val Ile Asp Ser Thr
340 345 350
Arg Cys Asn Ala Asp Asp Ala Tyr Gln Gly Glu Val Thr Glu Lys Met
355 360 365
Met Cys Ala Gly Ile Pro Glu Gly Gly Val Asp Thr Cys Gln Gly Asp
370 375 380
Ser Gly Gly Pro Leu Met Tyr Gln Ser Asp Gln Trp His Val Val Gly
385 390 395 400
Ile Val Ser Trp Gly Tyr Gly Cys Gly Gly Pro Ser Thr Pro Gly Val
405 410 415
Tyr Thr Lys Val Ser Ala Tyr Leu Asn Trp Ile Tyr Asn Val Trp Lys
420 425 430
Ala Glu Leu
435
<210> 15
<211> 2046
<212> DNA
<213> Mus musculus
<400> 15
cagaaacaag gacctcttca ttattcaaga gtaaaatgta taggccaaga ccaatgctat 60
caccgtcaag attcttcact ccctttgcag tagctttcgt tgtcataata acggtagggc 120
tcctggccat gatggcaggt ctacttattc actttttagc ttttgacaag aaagcttact 180
tttatcatag cagctttcaa atcctaaacg ttgaatacac tgaggcttta aactcaccag 240
ctacacacga atacagaacc ttgagtgaaa gaattgaggc tatgattact gatgaatttc 300
gaggatcaag tctaaaaagt gagtttatca ggacacatgt tgtcaaacta agaaaagaag 360
ggactggtgt ggttgcggat gttgtcatga aatttcgatc tagtaaacgt aacaacagaa 420
aggtaatgaa aaccagaatt caatctgtgc tacgaagact cagcagctct ggaaacttgg 480
aaatagcccc ttcgaatgag ataacatcac tcactgacca ggatacagaa aatgttttga 540
ctcaagaatg tggagcacgt ccagacctta taacactgtc agaagagaga atcattggag 600
gcatgcaagc tgagcccggt gactggccct ggcaagtcag tctacagctc aataatgtcc 660
accactgtgg aggtgccctg atcagtaaca tgtgggtcct gacagcagct cattgcttca 720
aaagctatcc taatcctcaa tattggacag ccacctttgg ggtttctaca atgagcccta 780
ggctgagagt gagagtaagg gctattttag cccacgacgg gtacagctcc gtaactcgtg 840
acaatgacat cgcagttgta caacttgaca gatctgtcgc cttttccaga aatatccata 900
gggtatgtct cccagcagca acccaaaata tcatccctgg ttctgtcgca tatgttacag 960
gatggggatc tctcacatat ggaggcaacg cagtcacaaa tctacggcaa ggagaggtca 1020
gaataataag ttcagaggaa tgcaatacgc cagctggtta cagtggaagt gtcttgccag 1080
gaatgctgtg tgctggaatg cgttcagggg ccgtggatgc atgccagggt gattcaggtg 1140
gcccgctagt acaagaagac tcaaggcggc tttggtttgt tgtgggcatt gtgagctggg 1200
gatatcagtg tggcctccca aataagccag gcgtgtatac tcgagtgaca gcctaccgca 1260
actggatcag acagcagacg ggaatctagt gcaaccgagg aaaaaacgtg ccatgaggtc 1320
tctgtatcca agtgtgactg actcggatgc catggcttca catttcaact gcaaaggaga 1380
ctggaaatgc cccttctgaa cgtcccatta cataaatatg gtttaactgt ttagtatttc 1440
tttgtcggta cagattttta ctttcttgag gaaaaaaaaa acatgaacat ggctaagtaa 1500
gaattatgtt aggctagtaa caggaagaca tttattacat gggtggtcag gtgtagtagt 1560
gagaagtcag gtaagttaag tcaataattt acagaaaata atgtcaggta gtcctaacgt 1620
taaatatgtg aggccacaga acaaatagtg ttagaactga agccatccca agtatttaac 1680
atttgttttc aagtgaaact aagaaacaga cttacatata gttttaatgg tgaattttca 1740
ttttaaatat tttatctaca tagaaaagac atatctcctt catgaagaag ctgaggtgat 1800
gaatcaacac agcctcttca gctatgtttg caaccacaag atttgtggga aagaaatccc 1860
tactaccaac ttcctactgt tggcattatt ttttagagta acacgacgca caatagcaaa 1920
atttaagtaa caaattaaaa gttaatgatg aagaagaagt aaagagtttg tttgcaaaga 1980
caaaaattaa acagattaat atcaataaat ctggagacag aagggtctca gattcatatt 2040
ctctct 2046
<210> 16
<211> 417
<212> PRT
<213> Mus musculus
<400> 16
Met Tyr Arg Pro Arg Pro Met Leu Ser Pro Ser Arg Phe Phe Thr Pro
1 5 10 15
Phe Ala Val Ala Phe Val Val Ile Ile Thr Val Gly Leu Leu Ala Met
20 25 30
Met Ala Gly Leu Leu Ile His Phe Leu Ala Phe Asp Lys Lys Ala Tyr
35 40 45
Phe Tyr His Ser Ser Phe Gln Ile Leu Asn Val Glu Tyr Thr Glu Ala
50 55 60
Leu Asn Ser Pro Ala Thr His Glu Tyr Arg Thr Leu Ser Glu Arg Ile
65 70 75 80
Glu Ala Met Ile Thr Asp Glu Phe Arg Gly Ser Ser Leu Lys Ser Glu
85 90 95
Phe Ile Arg Thr His Val Val Lys Leu Arg Lys Glu Gly Thr Gly Val
100 105 110
Val Ala Asp Val Val Met Lys Phe Arg Ser Ser Lys Arg Asn Asn Arg
115 120 125
Lys Val Met Lys Thr Arg Ile Gln Ser Val Leu Arg Arg Leu Ser Ser
130 135 140
Ser Gly Asn Leu Glu Ile Ala Pro Ser Asn Glu Ile Thr Ser Leu Thr
145 150 155 160
Asp Gln Asp Thr Glu Asn Val Leu Thr Gln Glu Cys Gly Ala Arg Pro
165 170 175
Asp Leu Ile Thr Leu Ser Glu Glu Arg Ile Ile Gly Gly Met Gln Ala
180 185 190
Glu Pro Gly Asp Trp Pro Trp Gln Val Ser Leu Gln Leu Asn Asn Val
195 200 205
His His Cys Gly Gly Ala Leu Ile Ser Asn Met Trp Val Leu Thr Ala
210 215 220
Ala His Cys Phe Lys Ser Tyr Pro Asn Pro Gln Tyr Trp Thr Ala Thr
225 230 235 240
Phe Gly Val Ser Thr Met Ser Pro Arg Leu Arg Val Arg Val Arg Ala
245 250 255
Ile Leu Ala His Asp Gly Tyr Ser Ser Val Thr Arg Asp Asn Asp Ile
260 265 270
Ala Val Val Gln Leu Asp Arg Ser Val Ala Phe Ser Arg Asn Ile His
275 280 285
Arg Val Cys Leu Pro Ala Ala Thr Gln Asn Ile Ile Pro Gly Ser Val
290 295 300
Ala Tyr Val Thr Gly Trp Gly Ser Leu Thr Tyr Gly Gly Asn Ala Val
305 310 315 320
Thr Asn Leu Arg Gln Gly Glu Val Arg Ile Ile Ser Ser Glu Glu Cys
325 330 335
Asn Thr Pro Ala Gly Tyr Ser Gly Ser Val Leu Pro Gly Met Leu Cys
340 345 350
Ala Gly Met Arg Ser Gly Ala Val Asp Ala Cys Gln Gly Asp Ser Gly
355 360 365
Gly Pro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Val Val Gly
370 375 380
Ile Val Ser Trp Gly Tyr Gln Cys Gly Leu Pro Asn Lys Pro Gly Val
385 390 395 400
Tyr Thr Arg Val Thr Ala Tyr Arg Asn Trp Ile Arg Gln Gln Thr Gly
405 410 415
Ile
<210> 17
<211> 2800
<212> DNA
<213> Homo sapiens
<400> 17
atttgagtgg gaatctcaaa gcagttgagt aggcagaaaa aagaacctct tcattaagga 60
ttaaaatgta taggccagca cgtgtaactt cgacttcaag atttctgaat ccatatgtag 120
tatgtttcat tgtcgtcgca ggggtagtga tcctggcagt caccatagct ctacttgttt 180
actttttagc ttttgatcaa aaatcttact tttataggag cagttttcaa ctcctaaatg 240
ttgaatataa tagtcagtta aattcaccag ctacacagga atacaggact ttgagtggaa 300
gaattgaatc tctgattact aaaacattca aagaatcaaa tttaagaaat cagttcatca 360
gagctcatgt tgccaaactg aggcaagatg gtagtggtgt gagagcggat gttgtcatga 420
aatttcaatt cactagaaat aacaatggag catcaatgaa aagcagaatt gagtctgttt 480
tacgacaaat gctgaataac tctggaaacc tggaaataaa cccttcaact gagataacat 540
cacttactga ccaggctgca gcaaattggc ttattaatga atgtggggcc ggtccagacc 600
taataacatt gtctgagcag agaatccttg gaggcactga ggctgaggag ggaagctggc 660
cgtggcaagt cagtctgcgg ctcaataatg cccaccactg tggaggcagc ctgatcaata 720
acatgtggat cctgacagca gctcactgct tcagaagcaa ctctaatcct cgtgactgga 780
ttgccacgtc tggtatttcc acaacatttc ctaaactaag aatgagagta agaaatattt 840
taattcataa caattataaa tctgcaactc atgaaaatga cattgcactt gtgagacttg 900
agaacagtgt cacctttacc aaagatatcc atagtgtgtg tctcccagct gctacccaga 960
atattccacc tggctctact gcttatgtaa caggatgggg cgctcaagaa tatgctggcc 1020
acacagttcc agagctaagg caaggacagg tcagaataat aagtaatgat gtatgtaatg 1080
caccacatag ttataatgga gccatcttgt ctggaatgct gtgtgctgga gtacctcaag 1140
gtggagtgga cgcatgtcag ggtgactctg gtggcccact agtacaagaa gactcacggc 1200
ggctttggtt tattgtgggg atagtaagct ggggagatca gtgtggcctg ccggataagc 1260
caggagtgta tactcgagtg acagcctacc ttgactggat taggcaacaa actgggatct 1320
agtgcaacaa gtgcatccct gttgcaaagt ctgtatgcag gtgtgcctgt cttaaattcc 1380
aaagctttac atttcaactg aaaaagaaac tagaaatgtc ctaatttaac atcttgttac 1440
ataaatatgg tttaacaaac actgtttaac ctttctttat tattaaaggt tttctatttt 1500
ctccagagaa ctatatgaat gttgcatagt actgtggctg tgtaacagaa gaaacacact 1560
aaactaatta caaagttaac aatttcatta cagttgtgct aaatgcccgt agtgagaaga 1620
acaggaacct tgagcatgta tagtagagga acctgcacag gtctgatggg tcagaggggt 1680
cttctctggg tttcactgag gatgagaagt aagcaaactg tggaaacatg caaaggaaaa 1740
agtgatagaa taatattcaa gacaaaaaga acagtatgag gcaagagaaa taatatgtat 1800
ttaaaatttt tggttactca atatcttata cttagtatga gtcctaaaat taaaaatgtg 1860
aaactgttgt actatacgta taacctaacc ttaattattc tgtaagaaca tgcttccata 1920
ggaaatagtg gataattttc agctatttaa ggcaaaagct aaaatagttc actcctcaac 1980
tgagacccaa agaattatag atatttttca tgatgaccca tgaaaaatat cactcatcta 2040
cataaaggag agactatatc tattttatag agaagctaag aaatatacct acacaaactt 2100
gtcaggtgct ttacaactac atagtacttt ttaacaacaa aataataatt ttaagaatga 2160
aaaatttaat catcgggaag aacgtcccac tacagacttc ctatcactgg cagttatatt 2220
tttgagcgta aaagggtcgt caaacgctaa atctaagtaa cgaattgaaa gtttaaagag 2280
ggggaagagt tggtttgcaa aggaaaagtt taaatagctt aatatcaata gaatgatcct 2340
gaagacagaa aaaactttgt cactcttcct ctctcatttt ctttctctct ctctcccctt 2400
ctcatacaca tgcctccccc accaaagaat ataatgtaaa ttaaatccac taaaatgtaa 2460
tggcatgaaa atctctgtag tctgaatcac taatattcct gagtttttat gagctcctag 2520
tacagctaaa gtttgcctat gcatgatcat ctatgcgtca gagcttcctc cttctacaag 2580
ctaactccct gcatctgggc atcaggactg ctccatacat ttgctgaaaa cttcttgtat 2640
ttcctgatgt aaaattgtgc aaacacctac aataaagcca tctactttta gggaaaggga 2700
gttgaaaatg caaccaactc ttggcgaact gtacaaacaa atctttgcta tactttattt 2760
caaataaatt ctttttaaaa taaaaaaaaa aaaaaaaaaa 2800
<210> 18
<211> 418
<212> PRT
<213> Homo sapiens
<400> 18
Met Tyr Arg Pro Ala Arg Val Thr Ser Thr Ser Arg Phe Leu Asn Pro
1 5 10 15
Tyr Val Val Cys Phe Ile Val Val Ala Gly Val Val Ile Leu Ala Val
20 25 30
Thr Ile Ala Leu Leu Val Tyr Phe Leu Ala Phe Asp Gln Lys Ser Tyr
35 40 45
Phe Tyr Arg Ser Ser Phe Gln Leu Leu Asn Val Glu Tyr Asn Ser Gln
50 55 60
Leu Asn Ser Pro Ala Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile
65 70 75 80
Glu Ser Leu Ile Thr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln
85 90 95
Phe Ile Arg Ala His Val Ala Lys Leu Arg Gln Asp Gly Ser Gly Val
100 105 110
Arg Ala Asp Val Val Met Lys Phe Gln Phe Thr Arg Asn Asn Asn Gly
115 120 125
Ala Ser Met Lys Ser Arg Ile Glu Ser Val Leu Arg Gln Met Leu Asn
130 135 140
Asn Ser Gly Asn Leu Glu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu
145 150 155 160
Thr Asp Gln Ala Ala Ala Asn Trp Leu Ile Asn Glu Cys Gly Ala Gly
165 170 175
Pro Asp Leu Ile Thr Leu Ser Glu Gln Arg Ile Leu Gly Gly Thr Glu
180 185 190
Ala Glu Glu Gly Ser Trp Pro Trp Gln Val Ser Leu Arg Leu Asn Asn
195 200 205
Ala His His Cys Gly Gly Ser Leu Ile Asn Asn Met Trp Ile Leu Thr
210 215 220
Ala Ala His Cys Phe Arg Ser Asn Ser Asn Pro Arg Asp Trp Ile Ala
225 230 235 240
Thr Ser Gly Ile Ser Thr Thr Phe Pro Lys Leu Arg Met Arg Val Arg
245 250 255
Asn Ile Leu Ile His Asn Asn Tyr Lys Ser Ala Thr His Glu Asn Asp
260 265 270
Ile Ala Leu Val Arg Leu Glu Asn Ser Val Thr Phe Thr Lys Asp Ile
275 280 285
His Ser Val Cys Leu Pro Ala Ala Thr Gln Asn Ile Pro Pro Gly Ser
290 295 300
Thr Ala Tyr Val Thr Gly Trp Gly Ala Gln Glu Tyr Ala Gly His Thr
305 310 315 320
Val Pro Glu Leu Arg Gln Gly Gln Val Arg Ile Ile Ser Asn Asp Val
325 330 335
Cys Asn Ala Pro His Ser Tyr Asn Gly Ala Ile Leu Ser Gly Met Leu
340 345 350
Cys Ala Gly Val Pro Gln Gly Gly Val Asp Ala Cys Gln Gly Asp Ser
355 360 365
Gly Gly Pro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Ile Val
370 375 380
Gly Ile Val Ser Trp Gly Asp Gln Cys Gly Leu Pro Asp Lys Pro Gly
385 390 395 400
Val Tyr Thr Arg Val Thr Ala Tyr Leu Asp Trp Ile Arg Gln Gln Thr
405 410 415
Gly Ile
<210> 19
<211> 38992
<212> DNA
<213> Artificial Sequence
<220>
<223> Recombinant polynucleotide
<400> 19
gagggagggt ggtgctttgc taatggtgaa ttactaactc ctcaataaag aatattattt 60
gaaataattt ttgaaatttc ataattactt tgggttcttt cttaatgata aataaataat 120
agtatattac aaacatacat taatatttcc tgaatgaata caccacaaat ctcccttaaa 180
atatagcaag aataaaaatt atactatttc tgacaatttt taatttctca aataataata 240
ccactctgat ttttaaacat ctacaccact ctggctttgc caatcttttt aaaaattgaa 300
aagataataa ttttatcata attacactga agcatagaac tttttctttc aaggaaagca 360
aatttttgaa attctataat ataacctccc ataatcctga ataaattaaa ggttcaacaa 420
cttagtaaag taagactgac cttccctttt atttcttttt cagatcaaaa atcttacttt 480
tataggagca gttttcaact cctaaatgtt gaatataata gtcagttaaa ttcaccagct 540
acacaggaat acaggacttt gagtggaaga attgaatctc tggtaagtta atatttgtct 600
ttgctcttta ttccattata aaatgaatat gataataaac ctaatgtttt gtaatatatt 660
ttcagttgct aagtgctcta catattttcc ttccttgaat ggtgaaacat gtgtttctct 720
ctgcttttat ccagttagtt tactcatata ctggttctta ttcacatctt tgtcatgagt 780
aaaaagtgtt agaaaggcca cgagtaaata tgcattttat ttgtttatga attcaaatac 840
taaaagtttt ttatttgttt aattaagcat tgacattgtc tttttaaatt cttttcattt 900
taccttcttc cctcttcctt atccaactaa agacgcaaag caggaggtgt taaaaaacag 960
gtttaccata tcagcagtaa catagtttgg acaacattac actttggttc aatgatagac 1020
atagaagttt gaacagaaat atgcaaagca agtttgagct ctaacttgaa gagagcctct 1080
gggtgcctgc caggaaacct cacgagtgga cccttaacat tcatgtgtca ccacaaacta 1140
ggggctgccc tttagttttg accagtctca gtgtcactca cttaccctta ccttttcaaa 1200
aaaaagtcct aagaatataa agtaattcaa tggttctaca attttagcat gtaactgagt 1260
cacctggcag ggttgctttg gtgagctcaa gataaaattt tatcagcatt tctacatttt 1320
ctggaatatt ccttaatcca ggcttttaat cccttggtgc ttttctgaac cactgcaatg 1380
agcttctaac tgttctcact gtgtgcaggc tcttttcctt ctaatctaat ttacacactt 1440
ctgaacacaa atctctcaca gcctgtttcc ttcatgttac ctccagctca agactttttg 1500
cctacaaaat aaaattcaaa cttgttagct aagcaccttc tcatgtctat gctttggctc 1560
atatttcagc catcgtgtgc cccacttatt cttatagcca acctgaaaag ccatctttta 1620
taagaaacta cctctgctct ccatgattgg atataattaa tcctccttcc acatcacctc 1680
gccacaaaat tgtatctgtg ttgatctcat gccacatacc tgtatgtatt ttatattata 1740
aatatttgca gacttgttta atttgccatg ttagactaag ttccatgaag acagctccat 1800
atccattcca tttttatata tccacaacat ttggtcgggt tgatgcttaa taaatgttta 1860
ttgaaggaac aggagtctcc cacttctgac ataatgaact tatttccccc agtgttaacc 1920
ctacatctgg ttcctgtcca agagtctctt cccaaatcat tctgattcaa ctgttcattc 1980
tgatctcatt aaacatttaa atgatatatc taacttcgct tgctttattc tatgctcatc 2040
ctgcagtctc ctcataactt ggtttcaatg atgcttgctt ctagagaaaa aaatgtatta 2100
aataagctta tgattcagtc ctccagctgt gatggttctc actgaacatt agctcagtgg 2160
ttttcgaagt atggtctcta gcataaccta gaaacttgtt agaaatgcaa attcttgggc 2220
tcaccaagac atactaaatc aaaaattctg acattggggc ctagaaatct gtgttttaac 2280
aagcctgcca gtgcagcctg gtcccttttc ttctcggagc cccactcaaa gctttcagtg 2340
ctcatctccc accaatgaca gggtcctcta tggaaaccgg caggacggtt tccaactcta 2400
actacgtttt agagtttgct tcctagggct atccaggcac caagtatcac aggttagttt 2460
cccagggaag cagactctga gacttgcatg cagggagtgt ctctggggtg ctctcaacca 2520
acaccttcag gaagagaagg aagcagcatt gggcagaggc atagtcaaac tacagtgctg 2580
ttggcacaga agactgaagg gagtcagagc cagggggtag aggtgggccc ttagcatcca 2640
tccttcacca ttaggtgtga gttgccccac ctccttgatg gtgtaacctc agtcccaagg 2700
tgggtgggag tgcagcagag cagcccctac aagggccaaa ccagagatac accaggcgcc 2760
agaagtgctg ccagggaata gagaggaaag gatgggctta aggtaggatc cacagaactt 2820
ggcaatggat tagaagacag gatgagaagt gacaggttaa cactaacaca gaaatgtcta 2880
acttcggtag ataatggtgc cattggctag aagaggaaac cgaaatgaaa gcaggttgtt 2940
cagggagaca aaagttcact gtggacatct cagcagagtg attcagtggg gaaaggaatg 3000
gatgcccaga ccacctcaga ggaagatcta agctggagcc agcaataaag atacaagatg 3060
aacaatccct aacgaactgc tcctcagcca tgctccccag acacgctgct tcagatttat 3120
agtccgggtg aggctaggag gtgcgcctcc ctcagtggag gacagcaaag caccagtggc 3180
tccagggagt taaaatcttt tgataatttt tgttctagca tctgtctgca gagctgtctc 3240
tcagccattg cctgccttta cacaggagtg cagtccgaaa ttgggagatg agtgaaattt 3300
attatgccta gagatctgga tccccagttg tttgggagta tattttctga accacttgtt 3360
ggtttaagta atgcagattt attgatgcca cttctcttga atctgtgact ctggacccac 3420
catctaagtg aatgtgcaga gggaacggaa tggctgcaat agatctccat taaaaccagt 3480
gcatcctccc agacacatac agtagtaggg aggtgagtca atgtcaggac agcaccagct 3540
cccgcttcgg tacatttcca aagttctcag tctgtgtaca aaggtttgct ctggggcagc 3600
agaaatagcc ctgggcaggt agtcaaaggc ctggtttgat ttcctccact tccaggcaag 3660
tcactcgaag gctcacaggc tttttcctca cctgccacat gggtccagtg agatctactg 3720
agctgtaaat aatgaaatga gtgtgtgtgc agtcatctat aagttgtaaa gtactagaaa 3780
atggtgaaac tttgggattt gggctattta aggctgaatg ctaaaaatgt caggcattgt 3840
ggagaaagga atttaaatat aagattgatt gactgggatt taaagacaaa tgaaggcaca 3900
cacgcaagtg cacacccaca ctgacactgc acagctcccg ttggaggcat atcctgacca 3960
tgcagacctg gggctctgcc tgtccaagtg cactccttta ctacataaac cctccttctc 4020
ttttggggct gtcaccccac cagagctggc accgagccct tgctgctgcg cttccctggg 4080
gtgtcagctt ttgacagggt gtttcctccc tctgcaggag ccttaacatc ccttggactt 4140
ccttcccccc acccaccccc agcagtttta tctcttccta actcgggacc ctttttttcc 4200
cacacaaagt ttattgtcag ttgctggttt catctgtttg agcggctgca acaaaatacc 4260
atagactggg tggcatatgc acgacaaaaa tttatttctc acaggagaag tcaaagatta 4320
atgcaccagc agatctggtg tctgaggggc caccttctgg tttgtagatg atgctttcta 4380
gttaaaacac ctatttaaca cactattaaa cactaagtgt gttaaatagt gcagttgatg 4440
tatttgtcat gtcaccttta tcatacacta aatccttctt tgtctttttt tctgtactct 4500
aatctctttc tgtaagtaat ctttgcttgc agcagtagga tatttagagt actgtggctt 4560
gacaatatat ttagtatttc aagatttcca tgaaattctt ctgatgtatg agttccctag 4620
ttaatcttac atatgtatcc ctttgtaaaa acactttgaa catttaaaat gatacatgaa 4680
tagtactcta atacaatgcc ataaaaatta taaatcattt gtatagactg gtaagtaaag 4740
attgtgagat taagaaacgc atcaaaggcc attgagctgg aaagtggtat aatgagaatt 4800
caaaccaggg tctcttgact caaaatctaa ggatcatacc atttctcatg ataatatgag 4860
tattattgtt atctctatcc catagacaaa gtgttaacac tgaatgagca gtgaaatagt 4920
ctcagaattt tttattttat ttagcaattc acttgtcatt tctggtcctc agtttattca 4980
cgagtaaaat aaaatagttg gactagataa tttctatagt acattcttac acaaaaaatc 5040
tatgattttg ttatttttaa tgtgatatac tcatggcact cattcacctc attttcccag 5100
cctgcctcac tggtcattac ttctctgtgt tctttacagg ctccccctcc tctacactgc 5160
cattaaatat tgaaacacct caaagcttta cttatgtcca cctctcctct gacactatca 5220
ttctgtctag atgatcccat acatacatgc ccattacttc aacctgtatt tatacgccaa 5280
tgattcacta tatttccagc ctagacattc ttttgtactc tagttaccag cttgatatcc 5340
ttacatggct gtttcaaaac aactcaaata tattatctct caaaatcaaa ctcatgatgt 5400
ccccacacca tcctagcttt ccaccaacaa tacctatccc tattaatagc aataccattt 5460
attcagttat ccaaatcaaa aacctagaat tcatccttaa aattctacta tcattccaaa 5520
tatcctatcc atcagcagcc actgtattct taatcccctg tatttccttc aaatccattc 5580
acctctctcc atatccattg ctgcatgact atccaagcca tcgcctctac cctagggtac 5640
caaaatagca acaaacctaa tctgttcatt tgcattattt tttctccaaa actgattatc 5700
tatatgtagc aagacagatt gttctcaaat tgcaaatccc actatattat cctcttgctt 5760
caaacacttc catggtttcc cattgtttat gataaaacca aatgcttcaa gttcgaagac 5820
cggcatgatt gggaatttcc tgtcacccta gcctacttgc tctccatggt acagttgcac 5880
tggctttctt tcattcctta agtacaacct gtttcctccc acctcaggac tgtgcatgtg 5940
ccattcattc tgctgaggag cctttttcct tccacttcaa tcagctaagt ctgattcttc 6000
ctgacaatct cagctcaata agcatttcct ctaagaaatg tctctaatat cattaattgg 6060
ctcaggtccc tctactgtat tgctgcactt ttcacagtta taattttact taattatgaa 6120
tgattatttg attaggtcta tttccatcca ttagacataa gcttcatgat ggccagatta 6180
ctgttttcta tccatcgttg tattccaata cctgacagaa ggagggcggg aggtggtggc 6240
acacaagaga tgctcaaaaa caattgttga ataagtaaat gaatgaggcc atttagaaat 6300
aacgaaagta cctgtttaca aagtacatgt atcaaaacta tgaatgcatt ctacttacat 6360
ggttttctcc aaataaaaca aaagacttca atcaggatta atacctggga taaactgagt 6420
cattaaatct ctcctttgcc atcaggagtg acattgaaac aaatgtctgc aaacaacaaa 6480
tacttttttc ccaaaatata ttgaatggca tttccataaa caaactagaa catgggagga 6540
gaaagaaagc aatattaatt taaaattaat cttatcacat aacttatacc atcagggatt 6600
tcgggtaaaa ttcctttcag gcacatccat ttaacaagaa ttgattgtta ctgaaagcct 6660
agaagagaat ttggcacata cttggtgttc aaatatttgt tgactgagtg aataaatgat 6720
gcaagtgtct aagaaacaca aaataaggac atgattacag tcacggtgga gttcacagtc 6780
atctccaaaa tgaggatatg catcccaggg aggaccaaca attcattgga gtgctgaaat 6840
aaaatactca aaggtcattt tacatgtatt ttttctctaa attacttttc ttaagacaca 6900
gaaaacaaaa aaagaaactt agctttgtta ctttctaaca aatagttaaa tcattaaaca 6960
ggattgacac tagcatcctt gtttggtctt atgccttagg ggaacatgaa atgtgtgaag 7020
acattctgag atctgaggga agggtagaca gtaatacagt gggactgacc aggcttcagc 7080
acacctttac ctcctctcag cagatttcag tgatgagcag tttacaacta gattgaaaga 7140
ttatattatc tagttctaaa agaaaactaa gcctcccaaa agcaacaagg gaactgagag 7200
gaatcctgca aaacaaaaac aaattttaaa acttgcactt tgtaataacc ctaatatgta 7260
atcacagtaa tgaacagtaa gataatgaca gaactgacat atttccttat ctattaaagc 7320
catattaaca ggtaaagcaa tgccagtcag tggtacactt cttagaagat atttaataca 7380
tactagacac atacacacac acaacatttt ccttcaaggt gtatgtatca gaaaatcact 7440
ttttaaggcc ggatgcagtg gctcaggcct gtaatcccag cactttggga ggccgacgtg 7500
ggcggatcat ctgaggtcag gagttcaaga ccagcctgcc caacatggcg aaaccccatc 7560
tctacaaaaa tacaaaaatt agccagggat gatggtggat gcttgtagtc ccagctactc 7620
aagaggcaga ggcaggagaa tcacttgaac ctgggaggca gaggttgcag tgagccaaga 7680
tcacccattg cactccagcc tgggcaacag agtgagactc tgtctcaaaa aaaaaaaaat 7740
cactttttag ataaaattca tgctatagag agaagactat gaaaatatgt ttagcaatgt 7800
gtccatcatt aggtgattga gtttcctttt gttttgtttt actgaaaatc atataaagta 7860
tgttatctgt aaaagttctc tgacatgcac acataaaaat ttgggagaaa agattaacta 7920
taatgtttaa tagattttgt acacatttct ttaaaaatat ataaaacaca acacctttca 7980
attggtttgc aagaataacc aattgacatc atggaaaatg gaaattcact tgctgaattt 8040
taacaaaaat ttgcatgatg agtgagactg acaacttagt gtcatgattt aatgaattat 8100
gccaatggta aacttcatgc acatggggcc aggtaattat gtggaaactt tttcaatgct 8160
taaagccaag tattgaaatt aaacttagaa tcagaccttt gaaccatttt atgacaatgt 8220
tcaaaaatta taaattctat ccacttatat tataatatta aaaatatcat tacaaaaaaa 8280
acctgtgttt attttataac tcagcctttt taatttctaa tttcataaat atattataat 8340
ggatattgtt agtaatgtag tattattaca tgtatataat ttataagtaa atatacatgt 8400
tttggctact catgcataaa atgtttcacc cataggagca cataatcaga aatgtctgga 8460
gaccattata gtaatagata gatcatattg ccacatattt tatctcctcc ttgacaactg 8520
agctttccag atcttctggt gaaacgaaag agaaagttgt aacagaagag tgattaaaat 8580
gacaaaagca ttacttctat tacttctatt ctaataatat gagcaaagct ataactatca 8640
agtaataatg cactaaagaa ggtgattaat ctgatatatt cacaggcaac taataagacc 8700
tttctattgc agccatgaaa aatatgtgac aattatagat atcctgtgtg cagtgtttca 8760
acctttatgt gacctgttct actaacagat ttagtgatgt tcactttgtt agaattttct 8820
tacacatgcc ataacttgct tcagtctttt gattatgaat attatggata ttaaggattc 8880
tagactattc tagatttaaa aaataatatt gtcacctcaa tcagaaggga aatattaaat 8940
agttctcatt ttttcaatgt ttactcagtt tttgtccaat gtaatgaaag tgtcagcagt 9000
acaggttaca aaataaaatg tgtattaaag taaactcatt tgaacaggtt aataattgta 9060
gagggaggga aaaggctaaa agattgaatg taaaacttat gaaaagtaga tacatcgtct 9120
ctatgatttg cagtagtcaa ctgcatacag atgaatcatt ttaatacacg ttaactactt 9180
tccttttaca gatggagaaa ctgagaggaa gaaagtttat atggttcatt aaactttgtg 9240
atgcaagcta aactaacctg tctctgtatt ttccatctac tgcccttatc actatctcat 9300
tagaatactc ttcaagcatc tccttactga ttttcttacc aagcatttgt taagttctaa 9360
tgagagttgg tagtaacatt ttcacccact ctgtgaaata tgaaatctta ttcataggcc 9420
tcttctttta ttcttgtatt tgcatatcaa ccaattaatc aacttgcttt ctttatgttg 9480
cttattatct tagtccttac taaattgcct cttaatgttg tccacataac agaaatgtta 9540
aggtggatac ttaacatttt agtccagtct agccggtgcc agtgcaatgc caaatcatga 9600
attaaaatat aattacaaga accacttatc aaattttaac aattccttca gctttgtgac 9660
agttttttct acttcgatta aagtcaagta aaattaaagt taaatatttt tattaaaata 9720
tctcctttaa cattccatat taataaacat attaaagctc atgcttctaa gtagattact 9780
agaagttact ttatcgaatt acagcaatgg ttaattctag atcatagaat ttagaatgac 9840
tttttgcctt cttctttttt ttcctttttt ttaaacagag tcttgctctg ttgtccaggc 9900
tggagtgtac tggcgcgatc ttgactcact gcgacctctg ccctgcaggt tcaagtgatt 9960
ctcctgcccc agcctcttaa gtagttggga ttacaggtgc ctgccaccac acctggctaa 10020
tttttttttt gtatttttag gagagacagg gtttcaccat gttggccaga ctggtctcga 10080
actcctgacc tcaagtgatc cacttgcctc agcctcccaa agtgctggga ttacaggtgt 10140
gagccactgt gcctggcctg actttttgct ttcttcttaa tacttactag tatttcttga 10200
atttttaaaa aagaaacata aagtactttg ataaaaccaa cagtctcatt gttcttaaaa 10260
ttgttcaaag gttctctgga aaaaaaaaag aaaattatca tttggttaag aatcatgttg 10320
gtctgacatc aatcatccta taggagtgaa tattgaaaaa gtaagatata ttgtggtata 10380
atcgagattg cataaatttt accatttttg agaagaatct gctccaaatc ctggcttaat 10440
gtaatatcca gcatgctact taattttctt gtcttcacct tttcatatcc acatccacct 10500
aggtgccacc tcacagtata agccagcata atccattctt ctcaatgaaa ccacaataca 10560
tctgaccctg catctcagga gaactgtatc agccacagca cttccagttg actatgaatc 10620
tgaatgttat gcctcaggag aaacatcctt gctgggactg agtagtgatt caaggagata 10680
gttatgattc agtcaagaaa ttaataatta gtgttatttt tattattgag acagagtctc 10740
gttctgtagc ccaggctgga gtacagtggc atgatctcgg ctcactgcaa cctctacctc 10800
cccggttcaa gtgattctcc tgcctcagcc tcccaaataa ctgggacagc aggcacttgc 10860
caccacgcct agctaatttt ttgtattttt agtagagacg gagtttcacc gtgttagcca 10920
ggatggtctc gatctcctga cctcaaggtc cacctgcctc agcctcccaa agtgctggga 10980
ttacaggcgt gagccactgc gcccggccat aaattattaa ctgagccagg cacagtggta 11040
cacacttata gtcccagata ctcaggagac tgaggttgga gtatcctttt ttatgttatt 11100
ttatttttaa ttattatggg tacataatag gtgtacatac ccatggagta caagtcatgt 11160
tctgatacag acacataatg tttaataatc acatcagggt aattgggata tccatcacct 11220
caagcattta tctttctttg tgttaggaac attccacctc cactcttgga ataggcaccc 11280
tgttgtgcta ttaaatacga ggtcttattc atttcatcta actatatttt tctacccatt 11340
aaccatcacc tcttttcccc tcttccccac tacctttcct gtgaggctgc aggattctta 11400
agcacaacag ttagaggcca gcctggacaa catagtgaga ctcaatttct aaaaaataaa 11460
aaagaaatta ccaactaatg ctaaaaaaat agtctctgat gcttaggtat gaattagaaa 11520
tgaccaaaaa aaaaaaaaaa aaaaagactg ccctttgctt ccttctcccc ttctcttcaa 11580
gttttccatt gctactcatt ttagtctggt ttaatcaggt ttcatccatt aaaagcaatt 11640
gttgggatca cacattttga gttgtgtcag tggacttccc tcatgctggc atgattcctg 11700
ccccaagccc ttagtaaaag ccaccaagcc atataacata atctctcatt gagtaaaaca 11760
tctgatgtgt ttagaatgac ttctagcaaa aaaccagcct gtccagcatc atctctgtat 11820
aacagataaa ggaataggta ctgcatcaaa aggttataga acctgcccaa atcaatccca 11880
tgtgttttgc aatggaatta ggttgaacta aagtgaaaat tcagttttct actcctcatt 11940
aacatgtctc atgttgcaag gttgagagga aggagaagaa gaactgtatt tacagagaga 12000
ttccccctct ctttctttct acagattact aaaacattca aagaatcaaa tttaagaaat 12060
cagttcatca gagctcatgt tgccaaactg aggtgagtgg aactgtagaa aaaatattta 12120
agtatagata caatgtggca tacttgactt tttgtcacag aatgaatagt aaatgacatg 12180
ttcagataag ttgttgtaat attatgaaaa tagtatttta gtcagcttaa aaaccaatgc 12240
caaaaaagcc aaacatatga tctatttagc tactaatgta aataaccata ttatatctat 12300
tcttattggg aagaggaaga aggggtggag agagagttgg ggtgaaggta cagtaacaag 12360
gccatcctat tgtaaaactc cagtggatat cattcacagt gcagcctatg taaacagtcc 12420
ctcctggagt tgtacaatgc tgtggtttgg gtgtatccat ccaagatcaa gacactatga 12480
ccaacatcaa aagtggcttt ttggttttat ctgcctgatg tgctataata aaagggtatt 12540
atggccaaat ccaaggcatg tctatcatga attaataata ggaggagtag cagcatgcat 12600
gctagttatt tgccattcct gccttagtta aatatgatgt gataaaacca gcctttccaa 12660
ctgaaatagt cacctttact gactctcccg caaatgtctc aaatgaccac attgctctag 12720
tctttaaata atatgcaata gttctttggt agaagaggaa ttatactaat tctttctcaa 12780
atactagcat cacaagaaaa ttaattcttg ttctctggag agtcacctag taagtatctg 12840
gagcacagat gtctggtcag gtaagttttg atgaggagtt aaagggataa gaagagtcca 12900
tgagaagggt attttccaaa acacctttcg gtcaattcag tgcacattca cttagtactt 12960
tcttgtcagt atctgtatca gccactaatg ttcaaaagtg agtaagccct gaaaacctgt 13020
aggactacat gagccttctg ccttttctct ccttttgttc acttcccact tatcactcaa 13080
tcctctgcaa cctggcttca ataccaccat aaaatatcaa ctgctcttgc cgattcaaca 13140
atgacatcca gataacaaaa tccaaagaaa ccacatcagt cctattcttg gacctttcaa 13200
cagtatttgg tcctgttggc ctgtcactcc ttgaaatagg actatccctt ggtttgcatg 13260
gccttgtata ccctgatttt ccccttacct ccctagctat tccttcttag tttcctttac 13320
taggtcttac ttctttgtat attccttaaa tgttgctgaa catcaggctg tgctctaggc 13380
ctctcatctt ctcaggtcac actctctcct ttccttggcc ttcactgcca cccatatgct 13440
gagtgctctc aaagttgtat ctctaggcca gtcctctttt gcctccaaac atgaatatat 13500
gcagccatct acttggtacc atcacatgga taattctcat gatctcttcc agtatgactg 13560
cttctttatt tttttctggg ctctttttta gcattgcttt acatggaact ttatcatgtc 13620
tctcaacctc tattttatct tttatctatg tatgtagagt ctgtgtaatt tcttcatctc 13680
ttttagataa ctaatatctc ttcagctttg acttgtattc tgtgtaaccc atttattgcg 13740
ttttcaattt caatgagtat gttttcctat ctgcaagttc tatttgtttc ttttgagaat 13800
cttcctggtc ttttaaacac atttcttatt ttaatttttg ggggtaccta gtagttgtat 13860
gtatttttgg agtacatgag atgttttgat acaagcaaac aatgcataat aatcacattg 13920
tgtaaaatgg ggtatccatc ccctcaagca tttatccttt gtgttacaaa caatccaatt 13980
atattctttt agttattttt aaatgtacaa ttaaattatt attgaccata gtgactctgt 14040
tgtgctatca gatactaggt gatcttttaa aaataatgtt ttctacttaa tctcattttt 14100
atgattccct cttttacgtc atttgtcatt tcaaatacag tcacttgtct gttgattcta 14160
ttatgtgaag tttttgagga taatcttttt gttactttga ttccaccttg gtatggtttg 14220
gctgtgcccc cactaaaatc tcatcttgaa ctctggttcc cataataccc acatgttgtg 14280
ggagggacct tgtgggaggt gattagatta tagggacgtt tccccccttt gctctgttct 14340
ttttcctgcc accatgtaag aaagatgtgt ttgcttcccc ttctgccatg attgtaaatt 14400
tcctgaggcc tccgcagcca tgcaggacct cttttctttg taaattaccc agtctccggc 14460
ggttctttat agctccgtga gaaaaaacta atacacacct catgatgtat tgtttaccac 14520
tgaaattgta tgcttaaatt taatctcact tgggaccctg tacaacctag acttaacata 14580
tctacctcca gagcagttac atctgtcaga cattctagag gaatcagcag cacatggact 14640
ttgttgttgt taatttgttg tcgggggagg ggggagggat agcattagga gatacaccta 14700
atgctaaatg acgagttaat gggtgcagca caccaacatg gcacatgtat acatatgtaa 14760
caaacctgca cgttgtgcac atatacccta aaacttaaag tataataata ataaaattaa 14820
aaaaaaaaag gttctgggag tattcaggta gtattaatga agattcagac atcgtgcagc 14880
caggcccatg cttatgaatt ttcaggtgat acttcttttt cttttttctt aatttaaagc 14940
tggatctcgg aaacagataa atttattttt ttatgacatg acgagcattt ttttcattct 15000
agttcatgct gttattgggt gtttagttct ttgagactcc tggccttttt ctaaaacctc 15060
aagttcaact tcctattttg cactggccca aggtcccatc tccagtctct atgtaaatgc 15120
taaacataag cctgtggaat attctagtct caccacatac tattcacatt cttctttgtt 15180
tttggtcttc caggattttc cttacttttc tatgaaccca gtcttgcatt tgaaatggaa 15240
tttattatat attatctatc ctttctattt gttttatgca gaaagtgttt tctaaaatta 15300
tttaggcttc catattgcta gacatggaag ttgtaattat ttgttcagtg cctgtttcta 15360
catctaaact gcaagaccca tatggcaact gtgaatctta gtcccagcta atttctgaag 15420
cttagaatag tgcctagcac aagaagttgt ttatctaaca tttttaaaaa taaatattaa 15480
attcatatct ggaatgaata ttaagttaga gctggtcatt gaggtgagag gaggaagcca 15540
agagagaata tgagagcctc aaagccaaat atctttaatg tactttttca gaaaagaaga 15600
cagccaatgt caggtggagg aactggttta tgaggtaact ttcctggaag aaaatagaaa 15660
ttactgaggt tttagataat ccaaatattt aatcaagtca ccaaggttta ttgtggggaa 15720
tctttattat taattaaaat gagtgatgaa atcttaatat acgacaaaag ttaaaatttg 15780
cttttgcagg cagatgaatg gtctaggtat caaaaaatta agttgagtct ctaactcaca 15840
caaatttaca accctatcac tttatgaatt tgtttaggag attattttta ataacactgg 15900
tgaagtctaa gaatagctaa aatttatagt acacttattg tgtgctattg actcttcttt 15960
gaagttttgc atatagtgat tcatctaatc ttcataaccc attttacatg tgaagaaact 16020
tagatataga aagattaaga aacttacata acttatccaa agttacacag taaaactctg 16080
gcattataac ttcaaaatca gctatcctac agtgagtaca gtgttctgtg cattgaaatc 16140
aaataagtga gatagcatcg tgatatagta ttacgtatgc aaacactgtt acagagatct 16200
gtctaaagtt aaattccaca aatgaattct ttaaaagggt ttaatcaaga agaatatata 16260
aacaggatgg tgaaaaattg tcatattatt tgttttttaa aatatcttta tgatttacag 16320
gcaagatggt agtggtgtga gagcggatgt tgtcatgaaa tttcaattca ctagaaataa 16380
caatggagca tcaatgaaaa gcagaattga gtctgtttta cgacaaatgc tgaataactc 16440
tggaaacctg gaaataaacc cttcaactga gataacatgt aagtataatt tttcataaac 16500
aattttattt caatatatcc ctcaagttta ccaattcaaa ttcatatttt aattgagagg 16560
ctgacttttc tttctttgaa actaaactgt gaaaacaatc cattaaaaag ctaaatatac 16620
catatagctc cctaacgtaa atcattctaa gacttaaaga atcatttggc atttatatag 16680
taaattttat ttgctaaaaa ttctcattaa ttatccctgc aacattcctt atgagtgatg 16740
ttactgtcag atgtcattag tggataggcc ataggagggg tacatagatg ctcaaggtca 16800
gagaactatt taattaatga tccacctcag aggcttcttc atttttcttt gtaacattta 16860
tcacaattga aattacaaag ttatctgtgt aaattttgta ttgtttggct tcatcctaca 16920
ctgtaatcat cctaaaagaa agaaccagtc aaccttcttc atcctactac cctcctacca 16980
cccagtctcc atcatataac acatattcaa taaataattc ttgcatgact gaaagaaaag 17040
aaataatata tgcatagaat ttaaggacat tcctccaagt tggttacatt ctgctagttt 17100
aataagccat tatttcttct cgatgagctc aagattaaaa ggattttgat gattcccata 17160
ctagactggt aggtaccagt tacagatgta ctaactgtta aatattgaaa tgctttccta 17220
tttgttggta aacaattact gcatcaggcc cacaaagttg tcttccgaga tgtttcaaat 17280
ccactgcccc tgctgctaaa gagttatgct tagcaaagca aagcactcta agacactgct 17340
ccaactccat ggcctgattg catcttttat gactggccaa tgctcacgca ctgcagtttg 17400
ttaggtagtt gaatattacc tctgcttcca cacattaagg aatgctcccg aacgcacttc 17460
ccaagtgttt atttatttat cattatacta gacaatatgg tgatacgatg gtcacagaat 17520
agcggtttcc acctccagag cccataatct agttgaaggg aaagatattc caacacaaga 17580
gtgttgacaa tcaagataga atatgatcaa gggcccagtg tgaggcccag gcaatgatca 17640
ctgcaggaat ctggggaaga aagagaccag cgtgcttggg atatctagca aaagtttcat 17700
gaaggagaat ggactttgac tttgaaatat gggtaggatt tacatatttt gagatgagaa 17760
aaagaaagtt cccagagaag gaaagcatga aaaggcaaac agtctgtact gaacgcgatg 17820
ctttgacaga ataatgaaga aagggacctg ctggaatgat tgatcagtgt tcatcattca 17880
caccatcatc atcaaaacac ttatttaatg agaacttact gttttttagg catggcttta 17940
atgccctata tgaatttttt tcttgattaa tccttacaac aaacatatcc catagatagt 18000
tttattgtcc cccttagaaa agataaattg cctaggctga cacagtcagt atatgaggca 18060
gtcaggattc aaactaagtc tgtttgttca aaaaattaag aatggccagc tttttaaaat 18120
tttctgtctc cagaagtatg atttggctcc actgaagttt gcaaaacaaa tgtgataccc 18180
aaaccttgtg aaacttttag tgggaaataa ctttgcataa gtcggtttga gagagcgtgg 18240
aaacctgtct tgaaaagttt taatttaact tgcaggaaat aaaaatgatg ggtttctcaa 18300
ttaaaaattt caatcaagga aggatatgag ctaacataac atttttttaa aaagatcagt 18360
ctggtaaggt agaggtgcat aaactgaaaa ggagcaaaag tggtggaatt cagttagaaa 18420
attattgtaa ctgtactgat gtcaaatgat gaaaccatga actaaagtag taccaaaagg 18480
agtgaggagg atggaataat tcaaaagata gaggacagat gtgcagaacc tggagattat 18540
aagatgtgaa aggaggagtt tgagaaaatt tcagattttg gaagtggtgt cattttacta 18600
aaaggatata ataagtagca aattttggat aaagttgggt cccactgagt ttgagatggc 18660
tgttggacat gcagagaaaa ctgtcttgta tgctgttctt aaattgaaat agacagacct 18720
ttaccctctg atactgacat attttccttt ccaggctcac cctccatttc cctaaacaca 18780
acacatgcac tagctctcct tactttattg ctccacaaac atcttacacc tccaagcatt 18840
tgtgcccact gtaccttcta tctggaatct cttttgtcct cttgtgtgcc tgaaaaattc 18900
ctttcagatc ttcaaaatac agtgcagatg ctatttcttc tagctcaaat attatctcct 18960
ccatataatt taattactct cttttttctt ttctctactt tgcacttaca tttatttgaa 19020
tgattgcttg attaatttct acctgtaaat tatgtgaggg caggtcctct atattttgct 19080
cgcagttaaa tctgcagcac ttattataga gtggtatcat tagagtaata tacatatatt 19140
tgaggacatg ataaattaac ttcccctata gtatttatca cattgcatct caatgacttg 19200
cttatgtttc tgttttccca tataaattga gtaacttgaa aaaagagata tctattaagt 19260
atttaatgag aaattaaagt acaaacttta gtatgcataa caacaaattg ggaaaaggtt 19320
gtaaacaaag agatttgtag ggcccatgag ttagagatcg tttcagcagg tctgaaagga 19380
agcctaggaa tctgcatttt agaggaccac ctcccaaccc caacaagtaa ttctgcttct 19440
tgttgtctgg gtactgtact ttaagaaatt atggtgaaat gatatcagcc tttattgtat 19500
ttatcttatt ctcatttttt aatactagca cttactgacc aggctgcagc aaattggctt 19560
attaatggta agttttaata ttattttgta actgtaattt gccaaatcat aaagagtaaa 19620
agtgcaagtc ttttgtgtac ttttggccaa ggcagtatct atcaagttga tgtctttgtt 19680
cttagttcgc tcaggtggtg ttgaaacaag acagtgctga tcccaagtgt cccatggagt 19740
ggactttagg tttccccttt ccttttagaa aaaggaagaa gttgtagtgg aggactaccc 19800
actctgcact caaaattgcc ctcatgaaaa tttctttggc agctttgaga accttttact 19860
gccctggttc taaggtggca tttctgtaga cttacaaatt atgtttgatg acaccgttta 19920
tgtagcttct cctaaccacc agagtagctt gctttgttgt gaattcaggt taatcacaaa 19980
gtataataaa aaagaattgt cagaagtctt cccagctttg ggtctataac ctgaaggaaa 20040
agtcactact cttcaacatc atcctatgta ctctcaggct aggatagcag aaatgcaatc 20100
cctagaaaac agcaacttac ttctctgacc aaaaaaatgc agttaaaaat tagttcaatg 20160
tacctggtag ctggcctatc ttaggtactt cagtgatttt acaaagtgat ggtagtccta 20220
tgggtgtttt tcagcttcac tacgtattta attcatgctt attgttaatg aaactgtgat 20280
aagcaattta ctagggtatt tgtttgggag atgccacaaa ggaacacatg tatctcttaa 20340
tggaagcctg gtcctccttt atccaggaaa tttgctagga aaaaaaagcc tttaggtggt 20400
tgtgctatta aaccagggca ctacttaaaa gccagcccag caatagttgt gtgatttacc 20460
attaatttct tagtaataga ccacacaaaa gaagaaaatt atgggaatgc gagttgagag 20520
gaattgggtg atcagcctac cccagcccgt ttcagctctg gccagtagac tattcacgag 20580
ctctttgaaa acatttaaat aaaccttatt tagatactag aaaccctctg tcaccctcaa 20640
gaatattctg tggtatagcg actcctttat gagggcatgt ttggtaatac agcatcagtc 20700
ttggaggtgg actggattct acaaggtgaa ctgcagtcac taaggagtct tttggatgag 20760
accagttttc ctccaacttc aatgtgtgca tgaacctcac atcaaaatgt agctttagat 20820
ttgtcccatg atgtggttcc aagaatcagc acttctaata agtttccagg ggatgcccat 20880
gctgcaggcc cacaaaccac actgagcata gcaagactat tgagaaaaag gaaatttccc 20940
aggagtctgt ggcctgagct ggcacatcca ataatgacct atcttaacct caactcatga 21000
ggaattccag ggaactctga agctgctcaa aatttgaagc ctatatgcca actaaattca 21060
gaaatgttct ccaaaatgct atctataagc aacagtagtc acaaatgcat tgtagaaata 21120
tatcgatcat gctttttgga aaatccagca tgtcctgagg aagaatgtat aagacataaa 21180
agtcataaat tatggaaaga ctcttcagct tcttccaaat gtaaaggaat catgatcttc 21240
ccagcacatt aatgcccttt ctcattagaa tgtggggccg gtccagacct aataacattg 21300
tctgagcaga gaatccttgg aggcactgag gctgaggagg gaagctggcc gtggcaagtc 21360
agtctgcggc tcaataatgc ccaccactgt ggaggcagcc tgatcaataa catgtggatc 21420
ctgacagcag ctcactgctt cagaaggtga ggccaccact acctacccat ctgggaacaa 21480
ttagaataga caggtcatga agactgcacc ctctacccta ggattgaatt gagccagaaa 21540
taattcaatg caaaaaaatc agtaagaatt ttcttcctat tcatgaaagg aaaaggattt 21600
ttccccttta gcatgctaat ttagtgctat ttctctgttt caggtaataa tatattagca 21660
cagtaaagaa caaagattta tatgtcagaa tgttttttaa atcctagcta taaaagctta 21720
agaaatttac taaatctcca taagctttat tttttttcca aattaaggga caacactgtt 21780
atctgtgact tagtgttact ggtagcattg agtacactaa tgtaaacata cgttaaatgt 21840
tagcgaaacg aattgctgtg gaagatttgc acattatatc atgggagctg atggctaacc 21900
tagagactgc cccatgccat taatttattc attcataaag attattgagt atctagtatg 21960
agcacagtgt tatatattgt agaagctact agtataaaca aagtattgcc tctgccttca 22020
aagagcttac actcgaatgt tggaatcaga atgcacaaaa ataatgatca attacaatga 22080
gtagcataaa taaaattaat gtaggcaact tacaagaatt cttaattgag gtgactaaac 22140
tattgccaac actagggtga tatgctacca gtggcgagta ggttgcataa acttacctta 22200
ttggtaaaaa gaaaagttca cattgctcat aaaagaagga ttttagattt cagcataact 22260
aaaatctgtt tcaaacctgc cttgttactg gggcatcgca gaccacaaca gttgttggga 22320
acttaactca aaaagttcac ccagaaaaat aatggagatt tgaactcgtg tgcccctgac 22380
catatcaatt ttcttctcag actcttactc taaactggac ctccttatca cacacacaaa 22440
gccttccata ggcagatcaa tccagtctta tttctcaaag catgtacctt gagcttcaga 22500
taaacagcat tgttctcttc ccctggactc ttcctacatt tccctaccta tgagtatctg 22560
atcaatctgc ttatccttga aatgttaata tatttaccac atctctattt gaattttatg 22620
aaatttttga taatttctaa gtagtttttt cagatttata ggcactactt catggtacag 22680
tgactgttac aaacgtattt gttaaattta gaaggaataa agatttaaaa gactagggta 22740
gttactgaac taaagtttta ggaaatccca aattatttca aatttttctt atggtaattt 22800
tatgacttaa tatttttata tgcagtgaac aaatttgaaa ctttaaaaga tactcccaga 22860
attatcagtt ttctgatgta gattggcaaa tttattacta tatcccaaat aacccaagag 22920
acaaaattca caaaaacatt tcaattttca ttgccacttg aaaggccaaa aagcagaaat 22980
ggcacgcatt gatttcaatc gtactcttga gtgtgggaac caggaattaa aatacctgga 23040
cttatcaggc acttagcata accaagaacg gaatagaaac ctccctggat tctaagccct 23100
attcagtccc aatcaccaaa aaccaagtaa acgatatcac tataatgaaa gccacagtta 23160
taaatatcga caacgattac caaaggaatc catggaactt tgaattttgc caccccacat 23220
ccttctattc attaccatga ttgatccact aaagctaaca gactctgtga accttgtatt 23280
ggacccctcc ctaaagacct gattgtcact gagaaccatc agtgaggatt tgtttggggc 23340
atgaccagcc ttacatcaaa gtacatagaa gtgatgaggt cttatcaaag aggattattg 23400
aattatcacc tcttctatgt agctttccct gatactctct ttcctctcca ttgagttcca 23460
cagaaatttt tttatctgcc tttaacagtt gtcctcatga tttgtgatat ttgacttacc 23520
tcttgtcagt ttccttcact agtgtagagt tcctcaaaga aagagaccat aattacttat 23580
atttttattc ctggagactc atactattcc ttatacaaag tagacactta acaatggctt 23640
gttgaactat aattaatgaa aataatagct accttcatga aagttcactt tgtgccaaac 23700
actatagttg acataataca tttgtctcat taatacttaa caattgtgtg agaaggtatc 23760
accaatcaca ttttatatgt aaataaaccc cagagctatt aattaacttg tcataaataa 23820
cacttttcat atgtggcata gccaagattt aaatataaat gttactggtt ccaaaatgat 23880
gctctaattc acttgctgga aagaaggaaa ggaagaaaat aaacgagtgg aaggaagaga 23940
gggagggaag agagaaaagg aaggaaagaa aaaagagtct cttcagaacc ttcactgtaa 24000
agactccgag caaaagaagt tgaatataaa aacaacatag gtttgtttgt tttctaatat 24060
tttttcttca aaatttttaa ctcaggttca ctcttacaca aactactgtg tcttataaaa 24120
gtatttccgg tcatagaatt tttattttct gtattaactc cactatctaa tctccataaa 24180
actcctaaat tggtattatc ggtaacattt tgtttttact caacccttag gaacaatgtt 24240
aagttaatca gccctccaca tcacagatcc ttattttcat cagtctgtac aaggcatttc 24300
tctcatttta attttttttc ctcctgtcat ccctggattt cactttcact gccctccttc 24360
cacccatatg cctcatacta atatattcga aatatacatg tcttaaaggt acatgcacgc 24420
acctacaaaa cctatagtgt ttttttgtat gtatatgtct ttaatttaaa taagtagcat 24480
tgtgtaaaag tctaatattg tttcttactg ttttcactca attcttggaa ttttcatctg 24540
atgcactgct gcatagcacc ccatggtatg cagccaccat atttccttca tccaattagg 24600
ttgcatgacc taccttccca ttgccacaaa gagtacacac aaaatatttg tacttatctt 24660
tctgtaaacc ttcaggaatt tcagaagcac acatgcaggc tgctaaatat accagaatac 24720
tttccagcca cttaaatctt taccagtatt gcaaaagagg ccccatttcc ctccacatca 24780
acatttagta ttattctttt gtttaagttt tatcaatctt ttaaatgtac acaagatgct 24840
catttttata attttaattt ctcagattac tagtttgagt atcttttcat atatctaaga 24900
gctgttttga tctcccctac catgaactgc cactaatatt ctttgcctat tttacaatgg 24960
tttttctgct tatttattac tggtttacag acttttaaaa tatattctac aaaaatttta 25020
gacattaaac attaccaata ttttcccatg gttcctcatc catctggtaa acttgtctat 25080
ggtatatcta attttgattt aatagaattc attctatttt taccttttag tttgtgtttt 25140
tgttgtttag ccaaaaagtc cccattccta ggtcataaag gtaatgtcct tttttttttt 25200
ttaacgctac tgttctctct ctgtctcccc ctatgtatat aggtgcacat atacttgtac 25260
acacatacat atacctatat atgaggggag ttcgataagt ttatggaaaa taaaattaaa 25320
agataaaata aaaaattata aactttattt ctcaacataa gctccttcaa gttcaagaca 25380
cttttgtaag caataatacc agccatatcg tccatcccta aagaactgag ggtcctgaga 25440
atttaactat gtcaatgcag tcttttttac attacttttt tacagtactt attgatgaaa 25500
aatgggtgcc ttttaaagat tgttttaaga ttagggaaca aaaataagtc agaggaagtc 25560
aaatcaggac tgaaaggtgg atgcctagtg atttattgct gaaactttca taaaactaac 25620
cttatttgat gagaggaatg agcatgagca tggttgtgat ggagaagaac tctggtggag 25680
ctttcctgga cactttttct actaaagctt tggctaactt tcttactctc ataagaagaa 25740
gatgttattt ttcactgacc ctttagaagg tcaacaagca aaatgccttc agcatcccaa 25800
atgtctgttg tcatgacttt tgttcttgac tagtctggtt ttgctttgac tggaccactt 25860
ctacctcttt atagccattg ctttgatggt gctttgtctt caagattgta ttagtaaagc 25920
catatttcat cttctgttac aattcttcaa agaaatactt cagaatcttg atctgacatg 25980
tttaaaattt ctattggaag ctctgacctt gggtgcagct gatctgggcg aaacagtttt 26040
ggcatccatc aagtagaaag tttgctcaac tttagttttt cagtcagaat tgtataagct 26100
gaaccagttg agatgtctat ggtgttgtct attgtttctc acagttaatt gttggtcctc 26160
tttgagacat gaacaagatg aaatttttcc tagcaaactg atgtggatga tctgttgctg 26220
cgggcttcac cctcaacaac atctctttct ttcttgaaac aaattatcca ttagtaaact 26280
gatgattggg ggagatgctg tccccataaa ctttttgtaa ggcataaata atttcaccat 26340
tcttccagtt tcaccataaa tttgacgttt ttttgcttca attttagcag cattcatgtt 26400
gctttgataa gagctctttt caaattcatg tcttattcct cttagtgcct caaactagat 26460
cttgttcagt atgacaagtt agtatgagtt tatctgcatg caaaaatctt tgaaatccat 26520
gcatagtttg tttataatat acattttcaa tgaacttttg aagaccccat acatacatat 26580
gtatatatat gcacacacac acacacacac acaccaaaat cttcaaccat tatcagactt 26640
agtgcagaaa aattattcat ccattaacaa gataagaatg ccccttatca tcactactat 26700
ttaaatggag ctcctggcta aaggaaaaga cagggattga aaaaaattag ttaaatctaa 26760
aatgtttatt atttcaggtt tcttagttgc ttaaatggga agggaggtat ggacaaaaga 26820
gaaatcaaag atatttgtgt tatgctactt atcattaaag tatcagaata acttcattgg 26880
aatagaaaaa caccaagatc accccacgat atgttttcta aaatcttctc catttcttta 26940
gacaagtgac catgtattcg gccagtgaag aattaaactc acttgccagc ttataatgca 27000
ggaaaatata gcaaagagat gtggatccaa tagtttctag atagtggtac aggatggcta 27060
agatgaattt atatatctga aatgttcaca aattccctac tcatatagca tgttttcata 27120
atgttttagc aactctaatc ctcgtgactg gattgccacg tctggtattt ccacaacatt 27180
tcctaaacta agaatgagag taagaaatat tttaattcat aacaattata aatctgcaac 27240
tcatgaaaat gacattgcac ttgtgagact tgagaacagt gtcaccttta ccaaagatat 27300
ccatagtgtg tgtctcccag ctgctaccca gaatattcca cctggctcta ctgcttatgt 27360
aacaggatgg ggcgctcaag aatatgctgg taagtgtctc ggaaaaaaaa attaacaata 27420
gaaatgtctt atatttgcta ttaggtaatt ttttaaatta ggaaacatct ggaataggtg 27480
tttctattct tctacagaca gaaccattct atattctgct cagcccaagc tctggctacc 27540
cctgagtctc cttagcaaag caaagcaatg ctccagaaac tatgggaatt ctcaaatata 27600
gtaataggaa aatgtaaaag aaagttatga agacacgagt tctttaataa tccagagatt 27660
ctataagatt caaatagctt ccctataaac aataaaaaag attttgtttg tttgtttgtt 27720
tgcttgtttt ttagagacaa agactttctc agactggagt gcagtggtgc aatcatggct 27780
tactgcagcc tcaaactctg gtcttaagaa atcctcttgc ttcagcctcc caagtagcta 27840
gaattataaa taagtgtgta ccaccatacc cagctttttt tttttttttc tacagacagg 27900
ttcttgctct gttgcccagg ctggtctgga attcctgccc tcaagccatc ctcctgcctt 27960
gttggcctcc caaagcaatg ggaggattta gattagacat tgtatgaggg cttaataatc 28020
cttaaggtat taactgccct ttaaagtatt ctgggatatg gcaaaaactc gatgtgtata 28080
taaacattgg tcatatttgt ttattgaatg aataaaatgg aaactaaaat gaggacaatg 28140
cacaagagct actagaacca gtaagagtat cagcgaagga gtggaagggt agcattgaca 28200
atttccctgg gcttttaccc atgttgtaga ttgtctctcc aaggaataat acaaagcctt 28260
aatagtccta gaacacattc tattgtgttc ttatggccca aagtaaattg gtgtagtaga 28320
taacatttgc accagtcatg aaaaactatt ggtgtcattc tgagagtaca tcaatataaa 28380
atagactagt tctttagcct tgaaactaga ctggtttctc ttttgctgct aggttaaagg 28440
ttattcaata tgtaatcttc caatccaaaa tctgtcagtg gataatttaa aagcttttag 28500
tcaattttaa gatatttgtt ttcttaaaat tttaaggggc actgtgtcac aaagctaaag 28560
aaaaaaaaga aaaaaaaact gatctgtgaa aggggttatc ctcatctact tggggaattt 28620
tggctgcgaa gaaactccaa agtaaatctt tagaagcctt cattgttaaa tatgaaataa 28680
tgtttggagt acatttattt cttctcaaat ttattatagg gtcaataatg tacacatctt 28740
gaagtccatt tttttcctgc ttttataaca aacaggccac acagttccag agctaaggca 28800
aggacaggtc agaataataa gtaatgatgt atgtaatgca ccacatagtt ataatggagc 28860
catcttgtct ggaatgctgt gtgctggagt acctcaaggt ggagtggacg catgtcaggt 28920
aagctcaaga caatctcatc catgtcatca tccaagaagt gtataagcac ttcctagtat 28980
gtgataatgt gatagacata agtgtaacag ttacaataca cagccctgtt cctctaaaat 29040
ttataatcta gattttagaa ataaattttt ttatgaatga agtttatcta tcatgaaagc 29100
attaactctg agaggccaaa ttacagagta gttaaccatc caaagctcaa gaatcagaaa 29160
gacctcgatt tgaattcctt aacctctatt accaagtctc taactaaaag ctggggataa 29220
tcataatagc acctaacttt ttgggtacta agaaaagtta aatgaagact aaatatatca 29280
ggcacatggt aaacaacaaa gaaatctcat ctatttcact attattaatg tagaccatgg 29340
tcactcgtgt taataacttt aacctcaacc ttttaactgc tgtgaaggat taaataaaaa 29400
attaatcact atattataaa aattaattga tatataataa atgaatttta agagatacgt 29460
aataattcat ggactccttg aagatagaaa atttatacaa aatcctagta atttgagtca 29520
caaaagctcc tacaataatg aaacagtatg aatgaaaaag aaaagaaata actattatat 29580
ttggatctag cccataattt ttaaccaaat gcacaaaaac aaacaacaaa tatgaaattc 29640
tcactgtaaa gtgattaaaa tcaaatttga attctaaaat tttaaattaa attatctaaa 29700
cataattgat gcagttatat gttttaatag gttttgttca catatctgaa atccaactcc 29760
acacagtagc aggaacagct ggtgtcagaa attaaatatt cttttagtct ggagttttaa 29820
aaaatcaatc tgtttacttg agtaatttgt tgctgttttc atgggtgaat tgtatacaga 29880
aggataagaa ttattcttcg catcaaaagg tcactgactt tcatatttag tgctcatggt 29940
ctttaaaaag tggataaaaa gtagttctca catttcatgg aaagccccca atccatgagc 30000
acatttccca aaatgaaaca tttttatcaa ctgcaagttg tgtgtaggtg gagatttgtt 30060
tttcaattgt caagatactg ttaattaccc agtcctttat ctccttttgg tggagatgtc 30120
tctgtgctag gaaacccttc ttgctctcct tcctgtttct cttttactac tggccctgaa 30180
acaacaaatt ctcaagtttc atgacagctt tccaaagaat ccatcaatca aataagcaac 30240
acaactcgac actgacaatt ccagacctac taagagcatt aattaagact taaaaataaa 30300
catgagtttt aaaagggtgt tattcattat tttcccattt ataacgtccc ttaccttctg 30360
tccttcagtg catacaaatt attatcttcc ttgaagccca gttcaagccg tacctcacca 30420
tgataccttc catgtatatt ccactctagg cctcactgat ttttaactga aatactataa 30480
tgcatagttc acacttaaaa aaaaaaaaaa aacacagcac tttacataag agcttacagg 30540
atcctatttg ttttatccat tcttttgttc atttttacaa tcattaattc aaaggaatta 30600
tattaattac tttctatgca cccgacgttg tgttaacaca acaatactat ccctgcattc 30660
agcaagtcta tggtctacaa gagaggacac aaattcaaat gtctgtagtc aagcagtgaa 30720
gctggctaga tatggaaaaa ttacaagtcc ctcttgcttt aacatttgct tgcccacatt 30780
tggtcagaca tcatgcaaaa taatttctca ctatagaaaa aaaaacacta caaaaacaat 30840
aatataaaga actgagaact ggttaactga agcatgcata tgtcatctaa aagaagcagg 30900
tgacgaccag cttcatgaag tacttgccat gcatattggc acttcacaca ctgacccttc 30960
tccccaccta gaccagtaat taaacaggta tggatgagct agctactaag agcagccaac 31020
tgaatagctg actaacttag aagcacactt ggtaataata gctgactttt attagtactg 31080
actatactat atgctaagct gtactcaaag tgctttgagt tttaaactga tacaaacatt 31140
atatgaggaa acagaggtac agagagctat tcaccagctt accaaaggtc acatagctgg 31200
taagtggagg acttaaaccc agactatcta gtttcagaac ccacagactt aatccatcgt 31260
gcagaacata agacatactc catctgtctc cccaactagg ttattatgtg cacaaatatt 31320
tattggttgg ttggttcatt attatgactg ggtggtaagt atgtcattag gagtgttttg 31380
cttatgacta tataaatttc ttcaccaaaa gaagactttc tgatgatata ctatgcatca 31440
gacaccacgc agggtgctaa ggttaggaag ataagtgaga cttctagaaa ctcattcatt 31500
caacaaatat ctcctaaggg ctagaagctt aggtttcagc agtgaacaga ataggtatgt 31560
tctctttcgt gttggacctt atagtatatc tgggaaaaca gacattgaat aaatatcaca 31620
aatgcaagtg agtgtttcag agacatgcag ctgctacatc aaaacaaaac agaacaaaac 31680
aaacaaacaa aaactgacca gtgggattaa gtgtaaatag gcacacaaat gcacaaatat 31740
gcttttataa aatagtgaag cagtgacaga gacacacaca agatataaag acacaatgaa 31800
gaacaattga gcccaaagct ggaaagggtg agagtgtgaa ggaaaaaggt tgatcagaga 31860
agttttcccg aaggagagaa agcctggatg attaggaggc aaccactcgg tgactgaggg 31920
aaatctgaaa aatgtatttg tcatcttctc agacttgctg aaggaatgac ttgggtactt 31980
tgaggatttc agtaattttt ccatgacttg gtataatatt tcaaaaggaa ataggctgac 32040
tttatttgta taatgaatgt gactccttcc tcgactgcca tagaaataaa ctccttaata 32100
ttttgggttt gtctttgcac ttaagtaatc agtcattctg tttttttaca gggtgactct 32160
ggtggcccac tagtacaaga agactcacgg cggctttggt ttattgtggg gatagtaagc 32220
tggggagatc agtgtggcct gccggataag ccaggagtgt atactcgagt gacagcctac 32280
cttgactgga ttaggcaaca aactgggatc tagtgcaaca agtgcatccc tgttgcaaag 32340
tctgtatgca ggtgtgcctg tcttaaattc caaagcttta catttcaact gaaaaagaaa 32400
ctagaaatgt cctaatttaa catcttgtta cataaatatg gtttaacaaa cactgtttaa 32460
cctttcttta ttattaaagg ttttctattt tctccagaga actatatgaa tgttgcatag 32520
tactgtggct gtgtaacaga agaaacacac taaactaatt acaaagttaa caatttcatt 32580
acagttgtgc taaatgcccg tagtgagaag aacaggaacc ttgagcatgt atagtagagg 32640
aacctgcaca ggtctgatgg gtcagagggg tcttctctgg gtttcactga ggatgagaag 32700
taagcaaact gtggaaacat gcaaaggaaa aagtgataga ataatattca agacaaaaag 32760
aacagtatga ggcaagagaa ataatatgta tttaaaattt ttggttactc aatatcttat 32820
acttagtatg agtcctaaaa ttaaaaatgt gaaactgttg tactatacgt ataacctaac 32880
cttaattatt ctgtaagaac atgcttccat aggaaatagt ggataatttt cagctattta 32940
aggcaaaagc taaaatagtt cactcctcaa ctgagaccca aagaattata gatatttttc 33000
atgatgaccc atgaaaaata tcactcatct acataaagga gagactatat ctattttata 33060
gagaagctaa gaaatatacc tacacaaact tgtcaggtgc tttacaacta catagtactt 33120
tttaacaaca aaataataat tttaagaatg aaaaatttaa tcatcgggaa gaacgtccca 33180
ctacagactt cctatcactg gcagttatat ttttgagcgt aaaagggtcg tcaaacgcta 33240
aatctaagta acgaattgaa agtttaaaga gggggaagag ttggtttgca aaggaaaagt 33300
ttaaatagct taatatcaat agaatgatcc tgaagacaga aaaaactttg tcactcttcc 33360
tctctcattt tctttctctc tctctcccct tctcatacac atgcctcccc caccaaagaa 33420
tataatgtaa attaaatcca ctaaaatgta atggcatgaa aatctctgta gtctgaatca 33480
ctaatattcc tgagttttta tgagctccta gtacagctaa agtttgccta tgcatgatca 33540
tctatgcgtc agagcttcct ccttctacaa gctaactccc tgcatctggg catcaggact 33600
gctccataca tttgctgaaa acttcttgta tttcctgatg taaaattgtg caaacaccta 33660
caataaagcc atctactttt agggaaaggg agttgaaaat gcaaccaact cttggcgaac 33720
tgtacaaaca aatctttgct atactttatt tcaaataaat tctttttaaa ataatttccc 33780
tgcctaatta tttatggaag ttatgacttt tgaaggacaa ttcaaaacca tttatttaat 33840
tggttctgca atgaaagaac tgccccatat actctactaa aggcttggca ctttctgctg 33900
ccttttaatc cagcgctata attgaggcaa gcgtccagct tgacacctcg agataacttc 33960
gtataatgta tgctatacga agttatatgc atggcctccg cgccgggttt tggcgcctcc 34020
cgcgggcgcc cccctcctca cggcgagcgc tgccacgtca gacgaagggc gcagcgagcg 34080
tcctgatcct tccgcccgga cgctcaggac agcggcccgc tgctcataag actcggcctt 34140
agaaccccag tatcagcaga aggacatttt aggacgggac ttgggtgact ctagggcact 34200
ggttttcttt ccagagagcg gaacaggcga ggaaaagtag tcccttctcg gcgattctgc 34260
ggagggatct ccgtggggcg gtgaacgccg atgattatat aaggacgcgc cgggtgtggc 34320
acagctagtt ccgtcgcagc cgggatttgg gtcgcggttc ttgtttgtgg atcgctgtga 34380
tcgtcacttg gtgagtagcg ggctgctggg ctggccgggg ctttcgtggc cgccgggccg 34440
ctcggtggga cggaagcgtg tggagagacc gccaagggct gtagtctggg tccgcgagca 34500
aggttgccct gaactggggg ttggggggag cgcagcaaaa tggcggctgt tcccgagtct 34560
tgaatggaag acgcttgtga ggcgggctgt gaggtcgttg aaacaaggtg gggggcatgg 34620
tgggcggcaa gaacccaagg tcttgaggcc ttcgctaatg cgggaaagct cttattcggg 34680
tgagatgggc tggggcacca tctggggacc ctgacgtgaa gtttgtcact gactggagaa 34740
ctcggtttgt cgtctgttgc gggggcggca gttatggcgg tgccgttggg cagtgcaccc 34800
gtacctttgg gagcgcgcgc cctcgtcgtg tcgtgacgtc acccgttctg ttggcttata 34860
atgcagggtg gggccacctg ccggtaggtg tgcggtaggc ttttctccgt cgcaggacgc 34920
agggttcggg cctagggtag gctctcctga atcgacaggc gccggacctc tggtgagggg 34980
agggataagt gaggcgtcag tttctttggt cggttttatg tacctatctt cttaagtagc 35040
tgaagctccg gttttgaact atgcgctcgg ggttggcgag tgtgttttgt gaagtttttt 35100
aggcaccttt tgaaatgtaa tcatttgggt caatatgtaa ttttcagtgt tagactagta 35160
aattgtccgc taaattctgg ccgtttttgg cttttttgtt agacgtgttg acaattaatc 35220
atcggcatag tatatcggca tagtataata cgacaaggtg aggaactaaa ccatgggatc 35280
ggccattgaa caagatggat tgcacgcagg ttctccggcc gcttgggtgg agaggctatt 35340
cggctatgac tgggcacaac agacaatcgg ctgctctgat gccgccgtgt tccggctgtc 35400
agcgcagggg cgcccggttc tttttgtcaa gaccgacctg tccggtgccc tgaatgaact 35460
gcaggacgag gcagcgcggc tatcgtggct ggccacgacg ggcgttcctt gcgcagctgt 35520
gctcgacgtt gtcactgaag cgggaaggga ctggctgcta ttgggcgaag tgccggggca 35580
ggatctcctg tcatctcacc ttgctcctgc cgagaaagta tccatcatgg ctgatgcaat 35640
gcggcggctg catacgcttg atccggctac ctgcccattc gaccaccaag cgaaacatcg 35700
catcgagcga gcacgtactc ggatggaagc cggtcttgtc gatcaggatg atctggacga 35760
agagcatcag gggctcgcgc cagccgaact gttcgccagg ctcaaggcgc gcatgcccga 35820
cggcgatgat ctcgtcgtga cccatggcga tgcctgcttg ccgaatatca tggtggaaaa 35880
tggccgcttt tctggattca tcgactgtgg ccggctgggt gtggcggacc gctatcagga 35940
catagcgttg gctacccgtg atattgctga agagcttggc ggcgaatggg ctgaccgctt 36000
cctcgtgctt tacggtatcg ccgctcccga ttcgcagcgc atcgccttct atcgccttct 36060
tgacgagttc ttctgagggg atccgctgta agtctgcaga aattgatgat ctattaaaca 36120
ataaagatgt ccactaaaat ggaagttttt cctgtcatac tttgttaaga agggtgagaa 36180
cagagtacct acattttgaa tggaaggatt ggagctacgg gggtgggggt ggggtgggat 36240
tagataaatg cctgctcttt actgaaggct ctttactatt gctttatgat aatgtttcat 36300
agttggatat cataatttaa acaagcaaaa ccaaattaag ggccagctca ttcctcccac 36360
tcatgatcta tagatctata gatctctcgt gggatcattg tttttctctt gattcccact 36420
ttgtggttct aagtactgtg gtttccaaat gtgtcagttt catagcctga agaacgagat 36480
cagcagcctc tgttccacat acacttcatt ctcagtattg ttttgccaag ttctaattcc 36540
atcagacctc gacctgcagc ccctagcccg ggcgccagta gcagcaccca cgtccacctt 36600
ctgtctagta atgtccaaca cctccctcag tccaaacact gctctgcatc catgtggctc 36660
ccatttatac ctgaagcact tgatggggcc tcaatgtttt actagagccc acccccctgc 36720
aactctgaga ccctctggat ttgtctgtca gtgcctcact ggggcgttgg ataatttctt 36780
aaaaggtcaa gttccctcag cagcattctc tgagcagtct gaagatgtgt gcttttcaca 36840
gttcaaatcc atgtggctgt ttcacccacc tgcctggcct tgggttatct atcaggacct 36900
agcctagaag caggtgtgtg gcacttaaca cctaagctga gtgactaact gaacactcaa 36960
gtggatgcca tctttgtcac ttcttgactg tgacacaagc aactcctgat gccaaagccc 37020
tgcccacccc tctcatgccc atatttggac atggtacagg tcctcactgg ccatggtctg 37080
tgaggtcctg gtcctctttg acttcataat tcctaggggc cactagtatc tataagagga 37140
agagggtgct ggctcccagg ccacagccca caaaattcca cctgctcaca ggttggctgg 37200
ctcgacccag gtggtgtccc ctgctctgag ccagctcccg gccaagccag caccatgggt 37260
acccccaaga agaagaggaa ggtgcgtacc gatttaaatt ccaatttact gaccgtacac 37320
caaaatttgc ctgcattacc ggtcgatgca acgagtgatg aggttcgcaa gaacctgatg 37380
gacatgttca gggatcgcca ggcgttttct gagcatacct ggaaaatgct tctgtccgtt 37440
tgccggtcgt gggcggcatg gtgcaagttg aataaccgga aatggtttcc cgcagaacct 37500
gaagatgttc gcgattatct tctatatctt caggcgcgcg gtctggcagt aaaaactatc 37560
cagcaacatt tgggccagct aaacatgctt catcgtcggt ccgggctgcc acgaccaagt 37620
gacagcaatg ctgtttcact ggttatgcgg cggatccgaa aagaaaacgt tgatgccggt 37680
gaacgtgcaa aacaggctct agcgttcgaa cgcactgatt tcgaccaggt tcgttcactc 37740
atggaaaata gtgatcgctg ccaggatata cgtaatctgg catttctggg gattgcttat 37800
aacaccctgt tacgtatagc cgaaattgcc aggatcaggg ttaaagatat ctcacgtact 37860
gacggtggga gaatgttaat ccatattggc agaacgaaaa cgctggttag caccgcaggt 37920
gtagagaagg cacttagcct gggggtaact aaactggtcg agcgatggat ttccgtctct 37980
ggtgtagctg atgatccgaa taactacctg ttttgccggg tcagaaaaaa tggtgttgcc 38040
gcgccatctg ccaccagcca gctatcaact cgcgccctgg aagggatttt tgaagcaact 38100
catcgattga tttacggcgc taaggtaaat ataaaatttt taagtgtata atgtgttaaa 38160
ctactgattc taattgtttg tgtattttag gatgactctg gtcagagata cctggcctgg 38220
tctggacaca gtgcccgtgt cggagccgcg cgagatatgg cccgcgctgg agtttcaata 38280
ccggagatca tgcaagctgg tggctggacc aatgtaaata ttgtcatgaa ctatatccgt 38340
aacctggata gtgaaacagg ggcaatggtg cgcctgctgg aagatggcga ttgatctaga 38400
taagtaatga tcataatcag ccatatcaca tctgtagagg ttttacttgc tttaaaaaac 38460
ctcccacacc tccccctgaa cctgaaacat aaaatgaatg caattgttgt tgttaaacct 38520
gccctagttg cggccaattc cagctgagcg tgcctccgca ccattaccag ttggtctggt 38580
gtcaaaaata ataataaccg ggcagggggg atctaagctc tagataagta atgatcataa 38640
tcagccatat cacatctgta gaggttttac ttgctttaaa aaacctccca cacctccccc 38700
tgaacctgaa acataaaatg aatgcaattg ttgttgttaa cttgtttatt gcagcttata 38760
atggttacaa ataaagcaat agcatcacaa atttcacaaa taaagcattt ttttcactgc 38820
attctagttg tggtttgtcc aaactcatca atgtatctta tcatgtctgg aataacttcg 38880
tataatgtat gctatacgaa gttatgctag taactataac ggtcctaagg tagcgagcta 38940
gctgcaaccg aggaaaaaac gtgccatgag gtctctgtat ccaagtgtga ct 38992
<210> 20
<211> 34073
<212> DNA
<213> Artificial Sequence
<220>
<223> Recombinant polynucleotide
<400> 20
gagggagggt ggtgctttgc taatggtgaa ttactaactc ctcaataaag aatattattt 60
gaaataattt ttgaaatttc ataattactt tgggttcttt cttaatgata aataaataat 120
agtatattac aaacatacat taatatttcc tgaatgaata caccacaaat ctcccttaaa 180
atatagcaag aataaaaatt atactatttc tgacaatttt taatttctca aataataata 240
ccactctgat ttttaaacat ctacaccact ctggctttgc caatcttttt aaaaattgaa 300
aagataataa ttttatcata attacactga agcatagaac tttttctttc aaggaaagca 360
aatttttgaa attctataat ataacctccc ataatcctga ataaattaaa ggttcaacaa 420
cttagtaaag taagactgac cttccctttt atttcttttt cagatcaaaa atcttacttt 480
tataggagca gttttcaact cctaaatgtt gaatataata gtcagttaaa ttcaccagct 540
acacaggaat acaggacttt gagtggaaga attgaatctc tggtaagtta atatttgtct 600
ttgctcttta ttccattata aaatgaatat gataataaac ctaatgtttt gtaatatatt 660
ttcagttgct aagtgctcta catattttcc ttccttgaat ggtgaaacat gtgtttctct 720
ctgcttttat ccagttagtt tactcatata ctggttctta ttcacatctt tgtcatgagt 780
aaaaagtgtt agaaaggcca cgagtaaata tgcattttat ttgtttatga attcaaatac 840
taaaagtttt ttatttgttt aattaagcat tgacattgtc tttttaaatt cttttcattt 900
taccttcttc cctcttcctt atccaactaa agacgcaaag caggaggtgt taaaaaacag 960
gtttaccata tcagcagtaa catagtttgg acaacattac actttggttc aatgatagac 1020
atagaagttt gaacagaaat atgcaaagca agtttgagct ctaacttgaa gagagcctct 1080
gggtgcctgc caggaaacct cacgagtgga cccttaacat tcatgtgtca ccacaaacta 1140
ggggctgccc tttagttttg accagtctca gtgtcactca cttaccctta ccttttcaaa 1200
aaaaagtcct aagaatataa agtaattcaa tggttctaca attttagcat gtaactgagt 1260
cacctggcag ggttgctttg gtgagctcaa gataaaattt tatcagcatt tctacatttt 1320
ctggaatatt ccttaatcca ggcttttaat cccttggtgc ttttctgaac cactgcaatg 1380
agcttctaac tgttctcact gtgtgcaggc tcttttcctt ctaatctaat ttacacactt 1440
ctgaacacaa atctctcaca gcctgtttcc ttcatgttac ctccagctca agactttttg 1500
cctacaaaat aaaattcaaa cttgttagct aagcaccttc tcatgtctat gctttggctc 1560
atatttcagc catcgtgtgc cccacttatt cttatagcca acctgaaaag ccatctttta 1620
taagaaacta cctctgctct ccatgattgg atataattaa tcctccttcc acatcacctc 1680
gccacaaaat tgtatctgtg ttgatctcat gccacatacc tgtatgtatt ttatattata 1740
aatatttgca gacttgttta atttgccatg ttagactaag ttccatgaag acagctccat 1800
atccattcca tttttatata tccacaacat ttggtcgggt tgatgcttaa taaatgttta 1860
ttgaaggaac aggagtctcc cacttctgac ataatgaact tatttccccc agtgttaacc 1920
ctacatctgg ttcctgtcca agagtctctt cccaaatcat tctgattcaa ctgttcattc 1980
tgatctcatt aaacatttaa atgatatatc taacttcgct tgctttattc tatgctcatc 2040
ctgcagtctc ctcataactt ggtttcaatg atgcttgctt ctagagaaaa aaatgtatta 2100
aataagctta tgattcagtc ctccagctgt gatggttctc actgaacatt agctcagtgg 2160
ttttcgaagt atggtctcta gcataaccta gaaacttgtt agaaatgcaa attcttgggc 2220
tcaccaagac atactaaatc aaaaattctg acattggggc ctagaaatct gtgttttaac 2280
aagcctgcca gtgcagcctg gtcccttttc ttctcggagc cccactcaaa gctttcagtg 2340
ctcatctccc accaatgaca gggtcctcta tggaaaccgg caggacggtt tccaactcta 2400
actacgtttt agagtttgct tcctagggct atccaggcac caagtatcac aggttagttt 2460
cccagggaag cagactctga gacttgcatg cagggagtgt ctctggggtg ctctcaacca 2520
acaccttcag gaagagaagg aagcagcatt gggcagaggc atagtcaaac tacagtgctg 2580
ttggcacaga agactgaagg gagtcagagc cagggggtag aggtgggccc ttagcatcca 2640
tccttcacca ttaggtgtga gttgccccac ctccttgatg gtgtaacctc agtcccaagg 2700
tgggtgggag tgcagcagag cagcccctac aagggccaaa ccagagatac accaggcgcc 2760
agaagtgctg ccagggaata gagaggaaag gatgggctta aggtaggatc cacagaactt 2820
ggcaatggat tagaagacag gatgagaagt gacaggttaa cactaacaca gaaatgtcta 2880
acttcggtag ataatggtgc cattggctag aagaggaaac cgaaatgaaa gcaggttgtt 2940
cagggagaca aaagttcact gtggacatct cagcagagtg attcagtggg gaaaggaatg 3000
gatgcccaga ccacctcaga ggaagatcta agctggagcc agcaataaag atacaagatg 3060
aacaatccct aacgaactgc tcctcagcca tgctccccag acacgctgct tcagatttat 3120
agtccgggtg aggctaggag gtgcgcctcc ctcagtggag gacagcaaag caccagtggc 3180
tccagggagt taaaatcttt tgataatttt tgttctagca tctgtctgca gagctgtctc 3240
tcagccattg cctgccttta cacaggagtg cagtccgaaa ttgggagatg agtgaaattt 3300
attatgccta gagatctgga tccccagttg tttgggagta tattttctga accacttgtt 3360
ggtttaagta atgcagattt attgatgcca cttctcttga atctgtgact ctggacccac 3420
catctaagtg aatgtgcaga gggaacggaa tggctgcaat agatctccat taaaaccagt 3480
gcatcctccc agacacatac agtagtaggg aggtgagtca atgtcaggac agcaccagct 3540
cccgcttcgg tacatttcca aagttctcag tctgtgtaca aaggtttgct ctggggcagc 3600
agaaatagcc ctgggcaggt agtcaaaggc ctggtttgat ttcctccact tccaggcaag 3660
tcactcgaag gctcacaggc tttttcctca cctgccacat gggtccagtg agatctactg 3720
agctgtaaat aatgaaatga gtgtgtgtgc agtcatctat aagttgtaaa gtactagaaa 3780
atggtgaaac tttgggattt gggctattta aggctgaatg ctaaaaatgt caggcattgt 3840
ggagaaagga atttaaatat aagattgatt gactgggatt taaagacaaa tgaaggcaca 3900
cacgcaagtg cacacccaca ctgacactgc acagctcccg ttggaggcat atcctgacca 3960
tgcagacctg gggctctgcc tgtccaagtg cactccttta ctacataaac cctccttctc 4020
ttttggggct gtcaccccac cagagctggc accgagccct tgctgctgcg cttccctggg 4080
gtgtcagctt ttgacagggt gtttcctccc tctgcaggag ccttaacatc ccttggactt 4140
ccttcccccc acccaccccc agcagtttta tctcttccta actcgggacc ctttttttcc 4200
cacacaaagt ttattgtcag ttgctggttt catctgtttg agcggctgca acaaaatacc 4260
atagactggg tggcatatgc acgacaaaaa tttatttctc acaggagaag tcaaagatta 4320
atgcaccagc agatctggtg tctgaggggc caccttctgg tttgtagatg atgctttcta 4380
gttaaaacac ctatttaaca cactattaaa cactaagtgt gttaaatagt gcagttgatg 4440
tatttgtcat gtcaccttta tcatacacta aatccttctt tgtctttttt tctgtactct 4500
aatctctttc tgtaagtaat ctttgcttgc agcagtagga tatttagagt actgtggctt 4560
gacaatatat ttagtatttc aagatttcca tgaaattctt ctgatgtatg agttccctag 4620
ttaatcttac atatgtatcc ctttgtaaaa acactttgaa catttaaaat gatacatgaa 4680
tagtactcta atacaatgcc ataaaaatta taaatcattt gtatagactg gtaagtaaag 4740
attgtgagat taagaaacgc atcaaaggcc attgagctgg aaagtggtat aatgagaatt 4800
caaaccaggg tctcttgact caaaatctaa ggatcatacc atttctcatg ataatatgag 4860
tattattgtt atctctatcc catagacaaa gtgttaacac tgaatgagca gtgaaatagt 4920
ctcagaattt tttattttat ttagcaattc acttgtcatt tctggtcctc agtttattca 4980
cgagtaaaat aaaatagttg gactagataa tttctatagt acattcttac acaaaaaatc 5040
tatgattttg ttatttttaa tgtgatatac tcatggcact cattcacctc attttcccag 5100
cctgcctcac tggtcattac ttctctgtgt tctttacagg ctccccctcc tctacactgc 5160
cattaaatat tgaaacacct caaagcttta cttatgtcca cctctcctct gacactatca 5220
ttctgtctag atgatcccat acatacatgc ccattacttc aacctgtatt tatacgccaa 5280
tgattcacta tatttccagc ctagacattc ttttgtactc tagttaccag cttgatatcc 5340
ttacatggct gtttcaaaac aactcaaata tattatctct caaaatcaaa ctcatgatgt 5400
ccccacacca tcctagcttt ccaccaacaa tacctatccc tattaatagc aataccattt 5460
attcagttat ccaaatcaaa aacctagaat tcatccttaa aattctacta tcattccaaa 5520
tatcctatcc atcagcagcc actgtattct taatcccctg tatttccttc aaatccattc 5580
acctctctcc atatccattg ctgcatgact atccaagcca tcgcctctac cctagggtac 5640
caaaatagca acaaacctaa tctgttcatt tgcattattt tttctccaaa actgattatc 5700
tatatgtagc aagacagatt gttctcaaat tgcaaatccc actatattat cctcttgctt 5760
caaacacttc catggtttcc cattgtttat gataaaacca aatgcttcaa gttcgaagac 5820
cggcatgatt gggaatttcc tgtcacccta gcctacttgc tctccatggt acagttgcac 5880
tggctttctt tcattcctta agtacaacct gtttcctccc acctcaggac tgtgcatgtg 5940
ccattcattc tgctgaggag cctttttcct tccacttcaa tcagctaagt ctgattcttc 6000
ctgacaatct cagctcaata agcatttcct ctaagaaatg tctctaatat cattaattgg 6060
ctcaggtccc tctactgtat tgctgcactt ttcacagtta taattttact taattatgaa 6120
tgattatttg attaggtcta tttccatcca ttagacataa gcttcatgat ggccagatta 6180
ctgttttcta tccatcgttg tattccaata cctgacagaa ggagggcggg aggtggtggc 6240
acacaagaga tgctcaaaaa caattgttga ataagtaaat gaatgaggcc atttagaaat 6300
aacgaaagta cctgtttaca aagtacatgt atcaaaacta tgaatgcatt ctacttacat 6360
ggttttctcc aaataaaaca aaagacttca atcaggatta atacctggga taaactgagt 6420
cattaaatct ctcctttgcc atcaggagtg acattgaaac aaatgtctgc aaacaacaaa 6480
tacttttttc ccaaaatata ttgaatggca tttccataaa caaactagaa catgggagga 6540
gaaagaaagc aatattaatt taaaattaat cttatcacat aacttatacc atcagggatt 6600
tcgggtaaaa ttcctttcag gcacatccat ttaacaagaa ttgattgtta ctgaaagcct 6660
agaagagaat ttggcacata cttggtgttc aaatatttgt tgactgagtg aataaatgat 6720
gcaagtgtct aagaaacaca aaataaggac atgattacag tcacggtgga gttcacagtc 6780
atctccaaaa tgaggatatg catcccaggg aggaccaaca attcattgga gtgctgaaat 6840
aaaatactca aaggtcattt tacatgtatt ttttctctaa attacttttc ttaagacaca 6900
gaaaacaaaa aaagaaactt agctttgtta ctttctaaca aatagttaaa tcattaaaca 6960
ggattgacac tagcatcctt gtttggtctt atgccttagg ggaacatgaa atgtgtgaag 7020
acattctgag atctgaggga agggtagaca gtaatacagt gggactgacc aggcttcagc 7080
acacctttac ctcctctcag cagatttcag tgatgagcag tttacaacta gattgaaaga 7140
ttatattatc tagttctaaa agaaaactaa gcctcccaaa agcaacaagg gaactgagag 7200
gaatcctgca aaacaaaaac aaattttaaa acttgcactt tgtaataacc ctaatatgta 7260
atcacagtaa tgaacagtaa gataatgaca gaactgacat atttccttat ctattaaagc 7320
catattaaca ggtaaagcaa tgccagtcag tggtacactt cttagaagat atttaataca 7380
tactagacac atacacacac acaacatttt ccttcaaggt gtatgtatca gaaaatcact 7440
ttttaaggcc ggatgcagtg gctcaggcct gtaatcccag cactttggga ggccgacgtg 7500
ggcggatcat ctgaggtcag gagttcaaga ccagcctgcc caacatggcg aaaccccatc 7560
tctacaaaaa tacaaaaatt agccagggat gatggtggat gcttgtagtc ccagctactc 7620
aagaggcaga ggcaggagaa tcacttgaac ctgggaggca gaggttgcag tgagccaaga 7680
tcacccattg cactccagcc tgggcaacag agtgagactc tgtctcaaaa aaaaaaaaat 7740
cactttttag ataaaattca tgctatagag agaagactat gaaaatatgt ttagcaatgt 7800
gtccatcatt aggtgattga gtttcctttt gttttgtttt actgaaaatc atataaagta 7860
tgttatctgt aaaagttctc tgacatgcac acataaaaat ttgggagaaa agattaacta 7920
taatgtttaa tagattttgt acacatttct ttaaaaatat ataaaacaca acacctttca 7980
attggtttgc aagaataacc aattgacatc atggaaaatg gaaattcact tgctgaattt 8040
taacaaaaat ttgcatgatg agtgagactg acaacttagt gtcatgattt aatgaattat 8100
gccaatggta aacttcatgc acatggggcc aggtaattat gtggaaactt tttcaatgct 8160
taaagccaag tattgaaatt aaacttagaa tcagaccttt gaaccatttt atgacaatgt 8220
tcaaaaatta taaattctat ccacttatat tataatatta aaaatatcat tacaaaaaaa 8280
acctgtgttt attttataac tcagcctttt taatttctaa tttcataaat atattataat 8340
ggatattgtt agtaatgtag tattattaca tgtatataat ttataagtaa atatacatgt 8400
tttggctact catgcataaa atgtttcacc cataggagca cataatcaga aatgtctgga 8460
gaccattata gtaatagata gatcatattg ccacatattt tatctcctcc ttgacaactg 8520
agctttccag atcttctggt gaaacgaaag agaaagttgt aacagaagag tgattaaaat 8580
gacaaaagca ttacttctat tacttctatt ctaataatat gagcaaagct ataactatca 8640
agtaataatg cactaaagaa ggtgattaat ctgatatatt cacaggcaac taataagacc 8700
tttctattgc agccatgaaa aatatgtgac aattatagat atcctgtgtg cagtgtttca 8760
acctttatgt gacctgttct actaacagat ttagtgatgt tcactttgtt agaattttct 8820
tacacatgcc ataacttgct tcagtctttt gattatgaat attatggata ttaaggattc 8880
tagactattc tagatttaaa aaataatatt gtcacctcaa tcagaaggga aatattaaat 8940
agttctcatt ttttcaatgt ttactcagtt tttgtccaat gtaatgaaag tgtcagcagt 9000
acaggttaca aaataaaatg tgtattaaag taaactcatt tgaacaggtt aataattgta 9060
gagggaggga aaaggctaaa agattgaatg taaaacttat gaaaagtaga tacatcgtct 9120
ctatgatttg cagtagtcaa ctgcatacag atgaatcatt ttaatacacg ttaactactt 9180
tccttttaca gatggagaaa ctgagaggaa gaaagtttat atggttcatt aaactttgtg 9240
atgcaagcta aactaacctg tctctgtatt ttccatctac tgcccttatc actatctcat 9300
tagaatactc ttcaagcatc tccttactga ttttcttacc aagcatttgt taagttctaa 9360
tgagagttgg tagtaacatt ttcacccact ctgtgaaata tgaaatctta ttcataggcc 9420
tcttctttta ttcttgtatt tgcatatcaa ccaattaatc aacttgcttt ctttatgttg 9480
cttattatct tagtccttac taaattgcct cttaatgttg tccacataac agaaatgtta 9540
aggtggatac ttaacatttt agtccagtct agccggtgcc agtgcaatgc caaatcatga 9600
attaaaatat aattacaaga accacttatc aaattttaac aattccttca gctttgtgac 9660
agttttttct acttcgatta aagtcaagta aaattaaagt taaatatttt tattaaaata 9720
tctcctttaa cattccatat taataaacat attaaagctc atgcttctaa gtagattact 9780
agaagttact ttatcgaatt acagcaatgg ttaattctag atcatagaat ttagaatgac 9840
tttttgcctt cttctttttt ttcctttttt ttaaacagag tcttgctctg ttgtccaggc 9900
tggagtgtac tggcgcgatc ttgactcact gcgacctctg ccctgcaggt tcaagtgatt 9960
ctcctgcccc agcctcttaa gtagttggga ttacaggtgc ctgccaccac acctggctaa 10020
tttttttttt gtatttttag gagagacagg gtttcaccat gttggccaga ctggtctcga 10080
actcctgacc tcaagtgatc cacttgcctc agcctcccaa agtgctggga ttacaggtgt 10140
gagccactgt gcctggcctg actttttgct ttcttcttaa tacttactag tatttcttga 10200
atttttaaaa aagaaacata aagtactttg ataaaaccaa cagtctcatt gttcttaaaa 10260
ttgttcaaag gttctctgga aaaaaaaaag aaaattatca tttggttaag aatcatgttg 10320
gtctgacatc aatcatccta taggagtgaa tattgaaaaa gtaagatata ttgtggtata 10380
atcgagattg cataaatttt accatttttg agaagaatct gctccaaatc ctggcttaat 10440
gtaatatcca gcatgctact taattttctt gtcttcacct tttcatatcc acatccacct 10500
aggtgccacc tcacagtata agccagcata atccattctt ctcaatgaaa ccacaataca 10560
tctgaccctg catctcagga gaactgtatc agccacagca cttccagttg actatgaatc 10620
tgaatgttat gcctcaggag aaacatcctt gctgggactg agtagtgatt caaggagata 10680
gttatgattc agtcaagaaa ttaataatta gtgttatttt tattattgag acagagtctc 10740
gttctgtagc ccaggctgga gtacagtggc atgatctcgg ctcactgcaa cctctacctc 10800
cccggttcaa gtgattctcc tgcctcagcc tcccaaataa ctgggacagc aggcacttgc 10860
caccacgcct agctaatttt ttgtattttt agtagagacg gagtttcacc gtgttagcca 10920
ggatggtctc gatctcctga cctcaaggtc cacctgcctc agcctcccaa agtgctggga 10980
ttacaggcgt gagccactgc gcccggccat aaattattaa ctgagccagg cacagtggta 11040
cacacttata gtcccagata ctcaggagac tgaggttgga gtatcctttt ttatgttatt 11100
ttatttttaa ttattatggg tacataatag gtgtacatac ccatggagta caagtcatgt 11160
tctgatacag acacataatg tttaataatc acatcagggt aattgggata tccatcacct 11220
caagcattta tctttctttg tgttaggaac attccacctc cactcttgga ataggcaccc 11280
tgttgtgcta ttaaatacga ggtcttattc atttcatcta actatatttt tctacccatt 11340
aaccatcacc tcttttcccc tcttccccac tacctttcct gtgaggctgc aggattctta 11400
agcacaacag ttagaggcca gcctggacaa catagtgaga ctcaatttct aaaaaataaa 11460
aaagaaatta ccaactaatg ctaaaaaaat agtctctgat gcttaggtat gaattagaaa 11520
tgaccaaaaa aaaaaaaaaa aaaaagactg ccctttgctt ccttctcccc ttctcttcaa 11580
gttttccatt gctactcatt ttagtctggt ttaatcaggt ttcatccatt aaaagcaatt 11640
gttgggatca cacattttga gttgtgtcag tggacttccc tcatgctggc atgattcctg 11700
ccccaagccc ttagtaaaag ccaccaagcc atataacata atctctcatt gagtaaaaca 11760
tctgatgtgt ttagaatgac ttctagcaaa aaaccagcct gtccagcatc atctctgtat 11820
aacagataaa ggaataggta ctgcatcaaa aggttataga acctgcccaa atcaatccca 11880
tgtgttttgc aatggaatta ggttgaacta aagtgaaaat tcagttttct actcctcatt 11940
aacatgtctc atgttgcaag gttgagagga aggagaagaa gaactgtatt tacagagaga 12000
ttccccctct ctttctttct acagattact aaaacattca aagaatcaaa tttaagaaat 12060
cagttcatca gagctcatgt tgccaaactg aggtgagtgg aactgtagaa aaaatattta 12120
agtatagata caatgtggca tacttgactt tttgtcacag aatgaatagt aaatgacatg 12180
ttcagataag ttgttgtaat attatgaaaa tagtatttta gtcagcttaa aaaccaatgc 12240
caaaaaagcc aaacatatga tctatttagc tactaatgta aataaccata ttatatctat 12300
tcttattggg aagaggaaga aggggtggag agagagttgg ggtgaaggta cagtaacaag 12360
gccatcctat tgtaaaactc cagtggatat cattcacagt gcagcctatg taaacagtcc 12420
ctcctggagt tgtacaatgc tgtggtttgg gtgtatccat ccaagatcaa gacactatga 12480
ccaacatcaa aagtggcttt ttggttttat ctgcctgatg tgctataata aaagggtatt 12540
atggccaaat ccaaggcatg tctatcatga attaataata ggaggagtag cagcatgcat 12600
gctagttatt tgccattcct gccttagtta aatatgatgt gataaaacca gcctttccaa 12660
ctgaaatagt cacctttact gactctcccg caaatgtctc aaatgaccac attgctctag 12720
tctttaaata atatgcaata gttctttggt agaagaggaa ttatactaat tctttctcaa 12780
atactagcat cacaagaaaa ttaattcttg ttctctggag agtcacctag taagtatctg 12840
gagcacagat gtctggtcag gtaagttttg atgaggagtt aaagggataa gaagagtcca 12900
tgagaagggt attttccaaa acacctttcg gtcaattcag tgcacattca cttagtactt 12960
tcttgtcagt atctgtatca gccactaatg ttcaaaagtg agtaagccct gaaaacctgt 13020
aggactacat gagccttctg ccttttctct ccttttgttc acttcccact tatcactcaa 13080
tcctctgcaa cctggcttca ataccaccat aaaatatcaa ctgctcttgc cgattcaaca 13140
atgacatcca gataacaaaa tccaaagaaa ccacatcagt cctattcttg gacctttcaa 13200
cagtatttgg tcctgttggc ctgtcactcc ttgaaatagg actatccctt ggtttgcatg 13260
gccttgtata ccctgatttt ccccttacct ccctagctat tccttcttag tttcctttac 13320
taggtcttac ttctttgtat attccttaaa tgttgctgaa catcaggctg tgctctaggc 13380
ctctcatctt ctcaggtcac actctctcct ttccttggcc ttcactgcca cccatatgct 13440
gagtgctctc aaagttgtat ctctaggcca gtcctctttt gcctccaaac atgaatatat 13500
gcagccatct acttggtacc atcacatgga taattctcat gatctcttcc agtatgactg 13560
cttctttatt tttttctggg ctctttttta gcattgcttt acatggaact ttatcatgtc 13620
tctcaacctc tattttatct tttatctatg tatgtagagt ctgtgtaatt tcttcatctc 13680
ttttagataa ctaatatctc ttcagctttg acttgtattc tgtgtaaccc atttattgcg 13740
ttttcaattt caatgagtat gttttcctat ctgcaagttc tatttgtttc ttttgagaat 13800
cttcctggtc ttttaaacac atttcttatt ttaatttttg ggggtaccta gtagttgtat 13860
gtatttttgg agtacatgag atgttttgat acaagcaaac aatgcataat aatcacattg 13920
tgtaaaatgg ggtatccatc ccctcaagca tttatccttt gtgttacaaa caatccaatt 13980
atattctttt agttattttt aaatgtacaa ttaaattatt attgaccata gtgactctgt 14040
tgtgctatca gatactaggt gatcttttaa aaataatgtt ttctacttaa tctcattttt 14100
atgattccct cttttacgtc atttgtcatt tcaaatacag tcacttgtct gttgattcta 14160
ttatgtgaag tttttgagga taatcttttt gttactttga ttccaccttg gtatggtttg 14220
gctgtgcccc cactaaaatc tcatcttgaa ctctggttcc cataataccc acatgttgtg 14280
ggagggacct tgtgggaggt gattagatta tagggacgtt tccccccttt gctctgttct 14340
ttttcctgcc accatgtaag aaagatgtgt ttgcttcccc ttctgccatg attgtaaatt 14400
tcctgaggcc tccgcagcca tgcaggacct cttttctttg taaattaccc agtctccggc 14460
ggttctttat agctccgtga gaaaaaacta atacacacct catgatgtat tgtttaccac 14520
tgaaattgta tgcttaaatt taatctcact tgggaccctg tacaacctag acttaacata 14580
tctacctcca gagcagttac atctgtcaga cattctagag gaatcagcag cacatggact 14640
ttgttgttgt taatttgttg tcgggggagg ggggagggat agcattagga gatacaccta 14700
atgctaaatg acgagttaat gggtgcagca caccaacatg gcacatgtat acatatgtaa 14760
caaacctgca cgttgtgcac atatacccta aaacttaaag tataataata ataaaattaa 14820
aaaaaaaaag gttctgggag tattcaggta gtattaatga agattcagac atcgtgcagc 14880
caggcccatg cttatgaatt ttcaggtgat acttcttttt cttttttctt aatttaaagc 14940
tggatctcgg aaacagataa atttattttt ttatgacatg acgagcattt ttttcattct 15000
agttcatgct gttattgggt gtttagttct ttgagactcc tggccttttt ctaaaacctc 15060
aagttcaact tcctattttg cactggccca aggtcccatc tccagtctct atgtaaatgc 15120
taaacataag cctgtggaat attctagtct caccacatac tattcacatt cttctttgtt 15180
tttggtcttc caggattttc cttacttttc tatgaaccca gtcttgcatt tgaaatggaa 15240
tttattatat attatctatc ctttctattt gttttatgca gaaagtgttt tctaaaatta 15300
tttaggcttc catattgcta gacatggaag ttgtaattat ttgttcagtg cctgtttcta 15360
catctaaact gcaagaccca tatggcaact gtgaatctta gtcccagcta atttctgaag 15420
cttagaatag tgcctagcac aagaagttgt ttatctaaca tttttaaaaa taaatattaa 15480
attcatatct ggaatgaata ttaagttaga gctggtcatt gaggtgagag gaggaagcca 15540
agagagaata tgagagcctc aaagccaaat atctttaatg tactttttca gaaaagaaga 15600
cagccaatgt caggtggagg aactggttta tgaggtaact ttcctggaag aaaatagaaa 15660
ttactgaggt tttagataat ccaaatattt aatcaagtca ccaaggttta ttgtggggaa 15720
tctttattat taattaaaat gagtgatgaa atcttaatat acgacaaaag ttaaaatttg 15780
cttttgcagg cagatgaatg gtctaggtat caaaaaatta agttgagtct ctaactcaca 15840
caaatttaca accctatcac tttatgaatt tgtttaggag attattttta ataacactgg 15900
tgaagtctaa gaatagctaa aatttatagt acacttattg tgtgctattg actcttcttt 15960
gaagttttgc atatagtgat tcatctaatc ttcataaccc attttacatg tgaagaaact 16020
tagatataga aagattaaga aacttacata acttatccaa agttacacag taaaactctg 16080
gcattataac ttcaaaatca gctatcctac agtgagtaca gtgttctgtg cattgaaatc 16140
aaataagtga gatagcatcg tgatatagta ttacgtatgc aaacactgtt acagagatct 16200
gtctaaagtt aaattccaca aatgaattct ttaaaagggt ttaatcaaga agaatatata 16260
aacaggatgg tgaaaaattg tcatattatt tgttttttaa aatatcttta tgatttacag 16320
gcaagatggt agtggtgtga gagcggatgt tgtcatgaaa tttcaattca ctagaaataa 16380
caatggagca tcaatgaaaa gcagaattga gtctgtttta cgacaaatgc tgaataactc 16440
tggaaacctg gaaataaacc cttcaactga gataacatgt aagtataatt tttcataaac 16500
aattttattt caatatatcc ctcaagttta ccaattcaaa ttcatatttt aattgagagg 16560
ctgacttttc tttctttgaa actaaactgt gaaaacaatc cattaaaaag ctaaatatac 16620
catatagctc cctaacgtaa atcattctaa gacttaaaga atcatttggc atttatatag 16680
taaattttat ttgctaaaaa ttctcattaa ttatccctgc aacattcctt atgagtgatg 16740
ttactgtcag atgtcattag tggataggcc ataggagggg tacatagatg ctcaaggtca 16800
gagaactatt taattaatga tccacctcag aggcttcttc atttttcttt gtaacattta 16860
tcacaattga aattacaaag ttatctgtgt aaattttgta ttgtttggct tcatcctaca 16920
ctgtaatcat cctaaaagaa agaaccagtc aaccttcttc atcctactac cctcctacca 16980
cccagtctcc atcatataac acatattcaa taaataattc ttgcatgact gaaagaaaag 17040
aaataatata tgcatagaat ttaaggacat tcctccaagt tggttacatt ctgctagttt 17100
aataagccat tatttcttct cgatgagctc aagattaaaa ggattttgat gattcccata 17160
ctagactggt aggtaccagt tacagatgta ctaactgtta aatattgaaa tgctttccta 17220
tttgttggta aacaattact gcatcaggcc cacaaagttg tcttccgaga tgtttcaaat 17280
ccactgcccc tgctgctaaa gagttatgct tagcaaagca aagcactcta agacactgct 17340
ccaactccat ggcctgattg catcttttat gactggccaa tgctcacgca ctgcagtttg 17400
ttaggtagtt gaatattacc tctgcttcca cacattaagg aatgctcccg aacgcacttc 17460
ccaagtgttt atttatttat cattatacta gacaatatgg tgatacgatg gtcacagaat 17520
agcggtttcc acctccagag cccataatct agttgaaggg aaagatattc caacacaaga 17580
gtgttgacaa tcaagataga atatgatcaa gggcccagtg tgaggcccag gcaatgatca 17640
ctgcaggaat ctggggaaga aagagaccag cgtgcttggg atatctagca aaagtttcat 17700
gaaggagaat ggactttgac tttgaaatat gggtaggatt tacatatttt gagatgagaa 17760
aaagaaagtt cccagagaag gaaagcatga aaaggcaaac agtctgtact gaacgcgatg 17820
ctttgacaga ataatgaaga aagggacctg ctggaatgat tgatcagtgt tcatcattca 17880
caccatcatc atcaaaacac ttatttaatg agaacttact gttttttagg catggcttta 17940
atgccctata tgaatttttt tcttgattaa tccttacaac aaacatatcc catagatagt 18000
tttattgtcc cccttagaaa agataaattg cctaggctga cacagtcagt atatgaggca 18060
gtcaggattc aaactaagtc tgtttgttca aaaaattaag aatggccagc tttttaaaat 18120
tttctgtctc cagaagtatg atttggctcc actgaagttt gcaaaacaaa tgtgataccc 18180
aaaccttgtg aaacttttag tgggaaataa ctttgcataa gtcggtttga gagagcgtgg 18240
aaacctgtct tgaaaagttt taatttaact tgcaggaaat aaaaatgatg ggtttctcaa 18300
ttaaaaattt caatcaagga aggatatgag ctaacataac atttttttaa aaagatcagt 18360
ctggtaaggt agaggtgcat aaactgaaaa ggagcaaaag tggtggaatt cagttagaaa 18420
attattgtaa ctgtactgat gtcaaatgat gaaaccatga actaaagtag taccaaaagg 18480
agtgaggagg atggaataat tcaaaagata gaggacagat gtgcagaacc tggagattat 18540
aagatgtgaa aggaggagtt tgagaaaatt tcagattttg gaagtggtgt cattttacta 18600
aaaggatata ataagtagca aattttggat aaagttgggt cccactgagt ttgagatggc 18660
tgttggacat gcagagaaaa ctgtcttgta tgctgttctt aaattgaaat agacagacct 18720
ttaccctctg atactgacat attttccttt ccaggctcac cctccatttc cctaaacaca 18780
acacatgcac tagctctcct tactttattg ctccacaaac atcttacacc tccaagcatt 18840
tgtgcccact gtaccttcta tctggaatct cttttgtcct cttgtgtgcc tgaaaaattc 18900
ctttcagatc ttcaaaatac agtgcagatg ctatttcttc tagctcaaat attatctcct 18960
ccatataatt taattactct cttttttctt ttctctactt tgcacttaca tttatttgaa 19020
tgattgcttg attaatttct acctgtaaat tatgtgaggg caggtcctct atattttgct 19080
cgcagttaaa tctgcagcac ttattataga gtggtatcat tagagtaata tacatatatt 19140
tgaggacatg ataaattaac ttcccctata gtatttatca cattgcatct caatgacttg 19200
cttatgtttc tgttttccca tataaattga gtaacttgaa aaaagagata tctattaagt 19260
atttaatgag aaattaaagt acaaacttta gtatgcataa caacaaattg ggaaaaggtt 19320
gtaaacaaag agatttgtag ggcccatgag ttagagatcg tttcagcagg tctgaaagga 19380
agcctaggaa tctgcatttt agaggaccac ctcccaaccc caacaagtaa ttctgcttct 19440
tgttgtctgg gtactgtact ttaagaaatt atggtgaaat gatatcagcc tttattgtat 19500
ttatcttatt ctcatttttt aatactagca cttactgacc aggctgcagc aaattggctt 19560
attaatggta agttttaata ttattttgta actgtaattt gccaaatcat aaagagtaaa 19620
agtgcaagtc ttttgtgtac ttttggccaa ggcagtatct atcaagttga tgtctttgtt 19680
cttagttcgc tcaggtggtg ttgaaacaag acagtgctga tcccaagtgt cccatggagt 19740
ggactttagg tttccccttt ccttttagaa aaaggaagaa gttgtagtgg aggactaccc 19800
actctgcact caaaattgcc ctcatgaaaa tttctttggc agctttgaga accttttact 19860
gccctggttc taaggtggca tttctgtaga cttacaaatt atgtttgatg acaccgttta 19920
tgtagcttct cctaaccacc agagtagctt gctttgttgt gaattcaggt taatcacaaa 19980
gtataataaa aaagaattgt cagaagtctt cccagctttg ggtctataac ctgaaggaaa 20040
agtcactact cttcaacatc atcctatgta ctctcaggct aggatagcag aaatgcaatc 20100
cctagaaaac agcaacttac ttctctgacc aaaaaaatgc agttaaaaat tagttcaatg 20160
tacctggtag ctggcctatc ttaggtactt cagtgatttt acaaagtgat ggtagtccta 20220
tgggtgtttt tcagcttcac tacgtattta attcatgctt attgttaatg aaactgtgat 20280
aagcaattta ctagggtatt tgtttgggag atgccacaaa ggaacacatg tatctcttaa 20340
tggaagcctg gtcctccttt atccaggaaa tttgctagga aaaaaaagcc tttaggtggt 20400
tgtgctatta aaccagggca ctacttaaaa gccagcccag caatagttgt gtgatttacc 20460
attaatttct tagtaataga ccacacaaaa gaagaaaatt atgggaatgc gagttgagag 20520
gaattgggtg atcagcctac cccagcccgt ttcagctctg gccagtagac tattcacgag 20580
ctctttgaaa acatttaaat aaaccttatt tagatactag aaaccctctg tcaccctcaa 20640
gaatattctg tggtatagcg actcctttat gagggcatgt ttggtaatac agcatcagtc 20700
ttggaggtgg actggattct acaaggtgaa ctgcagtcac taaggagtct tttggatgag 20760
accagttttc ctccaacttc aatgtgtgca tgaacctcac atcaaaatgt agctttagat 20820
ttgtcccatg atgtggttcc aagaatcagc acttctaata agtttccagg ggatgcccat 20880
gctgcaggcc cacaaaccac actgagcata gcaagactat tgagaaaaag gaaatttccc 20940
aggagtctgt ggcctgagct ggcacatcca ataatgacct atcttaacct caactcatga 21000
ggaattccag ggaactctga agctgctcaa aatttgaagc ctatatgcca actaaattca 21060
gaaatgttct ccaaaatgct atctataagc aacagtagtc acaaatgcat tgtagaaata 21120
tatcgatcat gctttttgga aaatccagca tgtcctgagg aagaatgtat aagacataaa 21180
agtcataaat tatggaaaga ctcttcagct tcttccaaat gtaaaggaat catgatcttc 21240
ccagcacatt aatgcccttt ctcattagaa tgtggggccg gtccagacct aataacattg 21300
tctgagcaga gaatccttgg aggcactgag gctgaggagg gaagctggcc gtggcaagtc 21360
agtctgcggc tcaataatgc ccaccactgt ggaggcagcc tgatcaataa catgtggatc 21420
ctgacagcag ctcactgctt cagaaggtga ggccaccact acctacccat ctgggaacaa 21480
ttagaataga caggtcatga agactgcacc ctctacccta ggattgaatt gagccagaaa 21540
taattcaatg caaaaaaatc agtaagaatt ttcttcctat tcatgaaagg aaaaggattt 21600
ttccccttta gcatgctaat ttagtgctat ttctctgttt caggtaataa tatattagca 21660
cagtaaagaa caaagattta tatgtcagaa tgttttttaa atcctagcta taaaagctta 21720
agaaatttac taaatctcca taagctttat tttttttcca aattaaggga caacactgtt 21780
atctgtgact tagtgttact ggtagcattg agtacactaa tgtaaacata cgttaaatgt 21840
tagcgaaacg aattgctgtg gaagatttgc acattatatc atgggagctg atggctaacc 21900
tagagactgc cccatgccat taatttattc attcataaag attattgagt atctagtatg 21960
agcacagtgt tatatattgt agaagctact agtataaaca aagtattgcc tctgccttca 22020
aagagcttac actcgaatgt tggaatcaga atgcacaaaa ataatgatca attacaatga 22080
gtagcataaa taaaattaat gtaggcaact tacaagaatt cttaattgag gtgactaaac 22140
tattgccaac actagggtga tatgctacca gtggcgagta ggttgcataa acttacctta 22200
ttggtaaaaa gaaaagttca cattgctcat aaaagaagga ttttagattt cagcataact 22260
aaaatctgtt tcaaacctgc cttgttactg gggcatcgca gaccacaaca gttgttggga 22320
acttaactca aaaagttcac ccagaaaaat aatggagatt tgaactcgtg tgcccctgac 22380
catatcaatt ttcttctcag actcttactc taaactggac ctccttatca cacacacaaa 22440
gccttccata ggcagatcaa tccagtctta tttctcaaag catgtacctt gagcttcaga 22500
taaacagcat tgttctcttc ccctggactc ttcctacatt tccctaccta tgagtatctg 22560
atcaatctgc ttatccttga aatgttaata tatttaccac atctctattt gaattttatg 22620
aaatttttga taatttctaa gtagtttttt cagatttata ggcactactt catggtacag 22680
tgactgttac aaacgtattt gttaaattta gaaggaataa agatttaaaa gactagggta 22740
gttactgaac taaagtttta ggaaatccca aattatttca aatttttctt atggtaattt 22800
tatgacttaa tatttttata tgcagtgaac aaatttgaaa ctttaaaaga tactcccaga 22860
attatcagtt ttctgatgta gattggcaaa tttattacta tatcccaaat aacccaagag 22920
acaaaattca caaaaacatt tcaattttca ttgccacttg aaaggccaaa aagcagaaat 22980
ggcacgcatt gatttcaatc gtactcttga gtgtgggaac caggaattaa aatacctgga 23040
cttatcaggc acttagcata accaagaacg gaatagaaac ctccctggat tctaagccct 23100
attcagtccc aatcaccaaa aaccaagtaa acgatatcac tataatgaaa gccacagtta 23160
taaatatcga caacgattac caaaggaatc catggaactt tgaattttgc caccccacat 23220
ccttctattc attaccatga ttgatccact aaagctaaca gactctgtga accttgtatt 23280
ggacccctcc ctaaagacct gattgtcact gagaaccatc agtgaggatt tgtttggggc 23340
atgaccagcc ttacatcaaa gtacatagaa gtgatgaggt cttatcaaag aggattattg 23400
aattatcacc tcttctatgt agctttccct gatactctct ttcctctcca ttgagttcca 23460
cagaaatttt tttatctgcc tttaacagtt gtcctcatga tttgtgatat ttgacttacc 23520
tcttgtcagt ttccttcact agtgtagagt tcctcaaaga aagagaccat aattacttat 23580
atttttattc ctggagactc atactattcc ttatacaaag tagacactta acaatggctt 23640
gttgaactat aattaatgaa aataatagct accttcatga aagttcactt tgtgccaaac 23700
actatagttg acataataca tttgtctcat taatacttaa caattgtgtg agaaggtatc 23760
accaatcaca ttttatatgt aaataaaccc cagagctatt aattaacttg tcataaataa 23820
cacttttcat atgtggcata gccaagattt aaatataaat gttactggtt ccaaaatgat 23880
gctctaattc acttgctgga aagaaggaaa ggaagaaaat aaacgagtgg aaggaagaga 23940
gggagggaag agagaaaagg aaggaaagaa aaaagagtct cttcagaacc ttcactgtaa 24000
agactccgag caaaagaagt tgaatataaa aacaacatag gtttgtttgt tttctaatat 24060
tttttcttca aaatttttaa ctcaggttca ctcttacaca aactactgtg tcttataaaa 24120
gtatttccgg tcatagaatt tttattttct gtattaactc cactatctaa tctccataaa 24180
actcctaaat tggtattatc ggtaacattt tgtttttact caacccttag gaacaatgtt 24240
aagttaatca gccctccaca tcacagatcc ttattttcat cagtctgtac aaggcatttc 24300
tctcatttta attttttttc ctcctgtcat ccctggattt cactttcact gccctccttc 24360
cacccatatg cctcatacta atatattcga aatatacatg tcttaaaggt acatgcacgc 24420
acctacaaaa cctatagtgt ttttttgtat gtatatgtct ttaatttaaa taagtagcat 24480
tgtgtaaaag tctaatattg tttcttactg ttttcactca attcttggaa ttttcatctg 24540
atgcactgct gcatagcacc ccatggtatg cagccaccat atttccttca tccaattagg 24600
ttgcatgacc taccttccca ttgccacaaa gagtacacac aaaatatttg tacttatctt 24660
tctgtaaacc ttcaggaatt tcagaagcac acatgcaggc tgctaaatat accagaatac 24720
tttccagcca cttaaatctt taccagtatt gcaaaagagg ccccatttcc ctccacatca 24780
acatttagta ttattctttt gtttaagttt tatcaatctt ttaaatgtac acaagatgct 24840
catttttata attttaattt ctcagattac tagtttgagt atcttttcat atatctaaga 24900
gctgttttga tctcccctac catgaactgc cactaatatt ctttgcctat tttacaatgg 24960
tttttctgct tatttattac tggtttacag acttttaaaa tatattctac aaaaatttta 25020
gacattaaac attaccaata ttttcccatg gttcctcatc catctggtaa acttgtctat 25080
ggtatatcta attttgattt aatagaattc attctatttt taccttttag tttgtgtttt 25140
tgttgtttag ccaaaaagtc cccattccta ggtcataaag gtaatgtcct tttttttttt 25200
ttaacgctac tgttctctct ctgtctcccc ctatgtatat aggtgcacat atacttgtac 25260
acacatacat atacctatat atgaggggag ttcgataagt ttatggaaaa taaaattaaa 25320
agataaaata aaaaattata aactttattt ctcaacataa gctccttcaa gttcaagaca 25380
cttttgtaag caataatacc agccatatcg tccatcccta aagaactgag ggtcctgaga 25440
atttaactat gtcaatgcag tcttttttac attacttttt tacagtactt attgatgaaa 25500
aatgggtgcc ttttaaagat tgttttaaga ttagggaaca aaaataagtc agaggaagtc 25560
aaatcaggac tgaaaggtgg atgcctagtg atttattgct gaaactttca taaaactaac 25620
cttatttgat gagaggaatg agcatgagca tggttgtgat ggagaagaac tctggtggag 25680
ctttcctgga cactttttct actaaagctt tggctaactt tcttactctc ataagaagaa 25740
gatgttattt ttcactgacc ctttagaagg tcaacaagca aaatgccttc agcatcccaa 25800
atgtctgttg tcatgacttt tgttcttgac tagtctggtt ttgctttgac tggaccactt 25860
ctacctcttt atagccattg ctttgatggt gctttgtctt caagattgta ttagtaaagc 25920
catatttcat cttctgttac aattcttcaa agaaatactt cagaatcttg atctgacatg 25980
tttaaaattt ctattggaag ctctgacctt gggtgcagct gatctgggcg aaacagtttt 26040
ggcatccatc aagtagaaag tttgctcaac tttagttttt cagtcagaat tgtataagct 26100
gaaccagttg agatgtctat ggtgttgtct attgtttctc acagttaatt gttggtcctc 26160
tttgagacat gaacaagatg aaatttttcc tagcaaactg atgtggatga tctgttgctg 26220
cgggcttcac cctcaacaac atctctttct ttcttgaaac aaattatcca ttagtaaact 26280
gatgattggg ggagatgctg tccccataaa ctttttgtaa ggcataaata atttcaccat 26340
tcttccagtt tcaccataaa tttgacgttt ttttgcttca attttagcag cattcatgtt 26400
gctttgataa gagctctttt caaattcatg tcttattcct cttagtgcct caaactagat 26460
cttgttcagt atgacaagtt agtatgagtt tatctgcatg caaaaatctt tgaaatccat 26520
gcatagtttg tttataatat acattttcaa tgaacttttg aagaccccat acatacatat 26580
gtatatatat gcacacacac acacacacac acaccaaaat cttcaaccat tatcagactt 26640
agtgcagaaa aattattcat ccattaacaa gataagaatg ccccttatca tcactactat 26700
ttaaatggag ctcctggcta aaggaaaaga cagggattga aaaaaattag ttaaatctaa 26760
aatgtttatt atttcaggtt tcttagttgc ttaaatggga agggaggtat ggacaaaaga 26820
gaaatcaaag atatttgtgt tatgctactt atcattaaag tatcagaata acttcattgg 26880
aatagaaaaa caccaagatc accccacgat atgttttcta aaatcttctc catttcttta 26940
gacaagtgac catgtattcg gccagtgaag aattaaactc acttgccagc ttataatgca 27000
ggaaaatata gcaaagagat gtggatccaa tagtttctag atagtggtac aggatggcta 27060
agatgaattt atatatctga aatgttcaca aattccctac tcatatagca tgttttcata 27120
atgttttagc aactctaatc ctcgtgactg gattgccacg tctggtattt ccacaacatt 27180
tcctaaacta agaatgagag taagaaatat tttaattcat aacaattata aatctgcaac 27240
tcatgaaaat gacattgcac ttgtgagact tgagaacagt gtcaccttta ccaaagatat 27300
ccatagtgtg tgtctcccag ctgctaccca gaatattcca cctggctcta ctgcttatgt 27360
aacaggatgg ggcgctcaag aatatgctgg taagtgtctc ggaaaaaaaa attaacaata 27420
gaaatgtctt atatttgcta ttaggtaatt ttttaaatta ggaaacatct ggaataggtg 27480
tttctattct tctacagaca gaaccattct atattctgct cagcccaagc tctggctacc 27540
cctgagtctc cttagcaaag caaagcaatg ctccagaaac tatgggaatt ctcaaatata 27600
gtaataggaa aatgtaaaag aaagttatga agacacgagt tctttaataa tccagagatt 27660
ctataagatt caaatagctt ccctataaac aataaaaaag attttgtttg tttgtttgtt 27720
tgcttgtttt ttagagacaa agactttctc agactggagt gcagtggtgc aatcatggct 27780
tactgcagcc tcaaactctg gtcttaagaa atcctcttgc ttcagcctcc caagtagcta 27840
gaattataaa taagtgtgta ccaccatacc cagctttttt tttttttttc tacagacagg 27900
ttcttgctct gttgcccagg ctggtctgga attcctgccc tcaagccatc ctcctgcctt 27960
gttggcctcc caaagcaatg ggaggattta gattagacat tgtatgaggg cttaataatc 28020
cttaaggtat taactgccct ttaaagtatt ctgggatatg gcaaaaactc gatgtgtata 28080
taaacattgg tcatatttgt ttattgaatg aataaaatgg aaactaaaat gaggacaatg 28140
cacaagagct actagaacca gtaagagtat cagcgaagga gtggaagggt agcattgaca 28200
atttccctgg gcttttaccc atgttgtaga ttgtctctcc aaggaataat acaaagcctt 28260
aatagtccta gaacacattc tattgtgttc ttatggccca aagtaaattg gtgtagtaga 28320
taacatttgc accagtcatg aaaaactatt ggtgtcattc tgagagtaca tcaatataaa 28380
atagactagt tctttagcct tgaaactaga ctggtttctc ttttgctgct aggttaaagg 28440
ttattcaata tgtaatcttc caatccaaaa tctgtcagtg gataatttaa aagcttttag 28500
tcaattttaa gatatttgtt ttcttaaaat tttaaggggc actgtgtcac aaagctaaag 28560
aaaaaaaaga aaaaaaaact gatctgtgaa aggggttatc ctcatctact tggggaattt 28620
tggctgcgaa gaaactccaa agtaaatctt tagaagcctt cattgttaaa tatgaaataa 28680
tgtttggagt acatttattt cttctcaaat ttattatagg gtcaataatg tacacatctt 28740
gaagtccatt tttttcctgc ttttataaca aacaggccac acagttccag agctaaggca 28800
aggacaggtc agaataataa gtaatgatgt atgtaatgca ccacatagtt ataatggagc 28860
catcttgtct ggaatgctgt gtgctggagt acctcaaggt ggagtggacg catgtcaggt 28920
aagctcaaga caatctcatc catgtcatca tccaagaagt gtataagcac ttcctagtat 28980
gtgataatgt gatagacata agtgtaacag ttacaataca cagccctgtt cctctaaaat 29040
ttataatcta gattttagaa ataaattttt ttatgaatga agtttatcta tcatgaaagc 29100
attaactctg agaggccaaa ttacagagta gttaaccatc caaagctcaa gaatcagaaa 29160
gacctcgatt tgaattcctt aacctctatt accaagtctc taactaaaag ctggggataa 29220
tcataatagc acctaacttt ttgggtacta agaaaagtta aatgaagact aaatatatca 29280
ggcacatggt aaacaacaaa gaaatctcat ctatttcact attattaatg tagaccatgg 29340
tcactcgtgt taataacttt aacctcaacc ttttaactgc tgtgaaggat taaataaaaa 29400
attaatcact atattataaa aattaattga tatataataa atgaatttta agagatacgt 29460
aataattcat ggactccttg aagatagaaa atttatacaa aatcctagta atttgagtca 29520
caaaagctcc tacaataatg aaacagtatg aatgaaaaag aaaagaaata actattatat 29580
ttggatctag cccataattt ttaaccaaat gcacaaaaac aaacaacaaa tatgaaattc 29640
tcactgtaaa gtgattaaaa tcaaatttga attctaaaat tttaaattaa attatctaaa 29700
cataattgat gcagttatat gttttaatag gttttgttca catatctgaa atccaactcc 29760
acacagtagc aggaacagct ggtgtcagaa attaaatatt cttttagtct ggagttttaa 29820
aaaatcaatc tgtttacttg agtaatttgt tgctgttttc atgggtgaat tgtatacaga 29880
aggataagaa ttattcttcg catcaaaagg tcactgactt tcatatttag tgctcatggt 29940
ctttaaaaag tggataaaaa gtagttctca catttcatgg aaagccccca atccatgagc 30000
acatttccca aaatgaaaca tttttatcaa ctgcaagttg tgtgtaggtg gagatttgtt 30060
tttcaattgt caagatactg ttaattaccc agtcctttat ctccttttgg tggagatgtc 30120
tctgtgctag gaaacccttc ttgctctcct tcctgtttct cttttactac tggccctgaa 30180
acaacaaatt ctcaagtttc atgacagctt tccaaagaat ccatcaatca aataagcaac 30240
acaactcgac actgacaatt ccagacctac taagagcatt aattaagact taaaaataaa 30300
catgagtttt aaaagggtgt tattcattat tttcccattt ataacgtccc ttaccttctg 30360
tccttcagtg catacaaatt attatcttcc ttgaagccca gttcaagccg tacctcacca 30420
tgataccttc catgtatatt ccactctagg cctcactgat ttttaactga aatactataa 30480
tgcatagttc acacttaaaa aaaaaaaaaa aacacagcac tttacataag agcttacagg 30540
atcctatttg ttttatccat tcttttgttc atttttacaa tcattaattc aaaggaatta 30600
tattaattac tttctatgca cccgacgttg tgttaacaca acaatactat ccctgcattc 30660
agcaagtcta tggtctacaa gagaggacac aaattcaaat gtctgtagtc aagcagtgaa 30720
gctggctaga tatggaaaaa ttacaagtcc ctcttgcttt aacatttgct tgcccacatt 30780
tggtcagaca tcatgcaaaa taatttctca ctatagaaaa aaaaacacta caaaaacaat 30840
aatataaaga actgagaact ggttaactga agcatgcata tgtcatctaa aagaagcagg 30900
tgacgaccag cttcatgaag tacttgccat gcatattggc acttcacaca ctgacccttc 30960
tccccaccta gaccagtaat taaacaggta tggatgagct agctactaag agcagccaac 31020
tgaatagctg actaacttag aagcacactt ggtaataata gctgactttt attagtactg 31080
actatactat atgctaagct gtactcaaag tgctttgagt tttaaactga tacaaacatt 31140
atatgaggaa acagaggtac agagagctat tcaccagctt accaaaggtc acatagctgg 31200
taagtggagg acttaaaccc agactatcta gtttcagaac ccacagactt aatccatcgt 31260
gcagaacata agacatactc catctgtctc cccaactagg ttattatgtg cacaaatatt 31320
tattggttgg ttggttcatt attatgactg ggtggtaagt atgtcattag gagtgttttg 31380
cttatgacta tataaatttc ttcaccaaaa gaagactttc tgatgatata ctatgcatca 31440
gacaccacgc agggtgctaa ggttaggaag ataagtgaga cttctagaaa ctcattcatt 31500
caacaaatat ctcctaaggg ctagaagctt aggtttcagc agtgaacaga ataggtatgt 31560
tctctttcgt gttggacctt atagtatatc tgggaaaaca gacattgaat aaatatcaca 31620
aatgcaagtg agtgtttcag agacatgcag ctgctacatc aaaacaaaac agaacaaaac 31680
aaacaaacaa aaactgacca gtgggattaa gtgtaaatag gcacacaaat gcacaaatat 31740
gcttttataa aatagtgaag cagtgacaga gacacacaca agatataaag acacaatgaa 31800
gaacaattga gcccaaagct ggaaagggtg agagtgtgaa ggaaaaaggt tgatcagaga 31860
agttttcccg aaggagagaa agcctggatg attaggaggc aaccactcgg tgactgaggg 31920
aaatctgaaa aatgtatttg tcatcttctc agacttgctg aaggaatgac ttgggtactt 31980
tgaggatttc agtaattttt ccatgacttg gtataatatt tcaaaaggaa ataggctgac 32040
tttatttgta taatgaatgt gactccttcc tcgactgcca tagaaataaa ctccttaata 32100
ttttgggttt gtctttgcac ttaagtaatc agtcattctg tttttttaca gggtgactct 32160
ggtggcccac tagtacaaga agactcacgg cggctttggt ttattgtggg gatagtaagc 32220
tggggagatc agtgtggcct gccggataag ccaggagtgt atactcgagt gacagcctac 32280
cttgactgga ttaggcaaca aactgggatc tagtgcaaca agtgcatccc tgttgcaaag 32340
tctgtatgca ggtgtgcctg tcttaaattc caaagcttta catttcaact gaaaaagaaa 32400
ctagaaatgt cctaatttaa catcttgtta cataaatatg gtttaacaaa cactgtttaa 32460
cctttcttta ttattaaagg ttttctattt tctccagaga actatatgaa tgttgcatag 32520
tactgtggct gtgtaacaga agaaacacac taaactaatt acaaagttaa caatttcatt 32580
acagttgtgc taaatgcccg tagtgagaag aacaggaacc ttgagcatgt atagtagagg 32640
aacctgcaca ggtctgatgg gtcagagggg tcttctctgg gtttcactga ggatgagaag 32700
taagcaaact gtggaaacat gcaaaggaaa aagtgataga ataatattca agacaaaaag 32760
aacagtatga ggcaagagaa ataatatgta tttaaaattt ttggttactc aatatcttat 32820
acttagtatg agtcctaaaa ttaaaaatgt gaaactgttg tactatacgt ataacctaac 32880
cttaattatt ctgtaagaac atgcttccat aggaaatagt ggataatttt cagctattta 32940
aggcaaaagc taaaatagtt cactcctcaa ctgagaccca aagaattata gatatttttc 33000
atgatgaccc atgaaaaata tcactcatct acataaagga gagactatat ctattttata 33060
gagaagctaa gaaatatacc tacacaaact tgtcaggtgc tttacaacta catagtactt 33120
tttaacaaca aaataataat tttaagaatg aaaaatttaa tcatcgggaa gaacgtccca 33180
ctacagactt cctatcactg gcagttatat ttttgagcgt aaaagggtcg tcaaacgcta 33240
aatctaagta acgaattgaa agtttaaaga gggggaagag ttggtttgca aaggaaaagt 33300
ttaaatagct taatatcaat agaatgatcc tgaagacaga aaaaactttg tcactcttcc 33360
tctctcattt tctttctctc tctctcccct tctcatacac atgcctcccc caccaaagaa 33420
tataatgtaa attaaatcca ctaaaatgta atggcatgaa aatctctgta gtctgaatca 33480
ctaatattcc tgagttttta tgagctccta gtacagctaa agtttgccta tgcatgatca 33540
tctatgcgtc agagcttcct ccttctacaa gctaactccc tgcatctggg catcaggact 33600
gctccataca tttgctgaaa acttcttgta tttcctgatg taaaattgtg caaacaccta 33660
caataaagcc atctactttt agggaaaggg agttgaaaat gcaaccaact cttggcgaac 33720
tgtacaaaca aatctttgct atactttatt tcaaataaat tctttttaaa ataatttccc 33780
tgcctaatta tttatggaag ttatgacttt tgaaggacaa ttcaaaacca tttatttaat 33840
tggttctgca atgaaagaac tgccccatat actctactaa aggcttggca ctttctgctg 33900
ccttttaatc cagcgctata attgaggcaa gcgtccagct tgacacctcg agataacttc 33960
gtataatgta tgctatacga agttatgcta gtaactataa cggtcctaag gtagcgagct 34020
agctgcaacc gaggaaaaaa cgtgccatga ggtctctgta tccaagtgtg act 34073
<210> 21
<211> 418
<212> PRT
<213> Artificial Sequence
<220>
<223> Recombinant protein
<400> 21
Met Tyr Arg Pro Arg Pro Met Leu Ser Pro Ser Arg Phe Phe Thr Pro
1 5 10 15
Phe Ala Val Ala Phe Val Val Ile Ile Thr Val Gly Leu Leu Ala Met
20 25 30
Met Ala Gly Leu Leu Ile His Phe Leu Ala Phe Asp Gln Lys Ser Tyr
35 40 45
Phe Tyr Arg Ser Ser Phe Gln Leu Leu Asn Val Glu Tyr Asn Ser Gln
50 55 60
Leu Asn Ser Pro Ala Thr Gln Glu Tyr Arg Thr Leu Ser Gly Arg Ile
65 70 75 80
Glu Ser Leu Ile Thr Lys Thr Phe Lys Glu Ser Asn Leu Arg Asn Gln
85 90 95
Phe Ile Arg Ala His Val Ala Lys Leu Arg Gln Asp Gly Ser Gly Val
100 105 110
Arg Ala Asp Val Val Met Lys Phe Gln Phe Thr Arg Asn Asn Asn Gly
115 120 125
Ala Ser Met Lys Ser Arg Ile Glu Ser Val Leu Arg Gln Met Leu Asn
130 135 140
Asn Ser Gly Asn Leu Glu Ile Asn Pro Ser Thr Glu Ile Thr Ser Leu
145 150 155 160
Thr Asp Gln Ala Ala Ala Asn Trp Leu Ile Asn Glu Cys Gly Ala Gly
165 170 175
Pro Asp Leu Ile Thr Leu Ser Glu Gln Arg Ile Leu Gly Gly Thr Glu
180 185 190
Ala Glu Glu Gly Ser Trp Pro Trp Gln Val Ser Leu Arg Leu Asn Asn
195 200 205
Ala His His Cys Gly Gly Ser Leu Ile Asn Asn Met Trp Ile Leu Thr
210 215 220
Ala Ala His Cys Phe Arg Ser Asn Ser Asn Pro Arg Asp Trp Ile Ala
225 230 235 240
Thr Ser Gly Ile Ser Thr Thr Phe Pro Lys Leu Arg Met Arg Val Arg
245 250 255
Asn Ile Leu Ile His Asn Asn Tyr Lys Ser Ala Thr His Glu Asn Asp
260 265 270
Ile Ala Leu Val Arg Leu Glu Asn Ser Val Thr Phe Thr Lys Asp Ile
275 280 285
His Ser Val Cys Leu Pro Ala Ala Thr Gln Asn Ile Pro Pro Gly Ser
290 295 300
Thr Ala Tyr Val Thr Gly Trp Gly Ala Gln Glu Tyr Ala Gly His Thr
305 310 315 320
Val Pro Glu Leu Arg Gln Gly Gln Val Arg Ile Ile Ser Asn Asp Val
325 330 335
Cys Asn Ala Pro His Ser Tyr Asn Gly Ala Ile Leu Ser Gly Met Leu
340 345 350
Cys Ala Gly Val Pro Gln Gly Gly Val Asp Ala Cys Gln Gly Asp Ser
355 360 365
Gly Gly Pro Leu Val Gln Glu Asp Ser Arg Arg Leu Trp Phe Ile Val
370 375 380
Gly Ile Val Ser Trp Gly Asp Gln Cys Gly Leu Pro Asp Lys Pro Gly
385 390 395 400
Val Tyr Thr Arg Val Thr Ala Tyr Leu Asp Trp Ile Arg Gln Gln Thr
405 410 415
Gly Ile
<210> 22
<211> 257
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 22
agcacccctc tcttccgcag agtctaagaa atcgctgtgt ttagccctcg ccctgggcac 60
tgtcctcacg ggagctgctg tggctgctgt cttgctttgg aagttcagta agtgcaggga 120
gcctcgatcc caccatgtgc tcctgcagtc cccagtgctc tgagccagac cctgctctct 180
gggctattga gacctctgga ggccctccgt gaggttcctc tcttacataa cgaggctgtc 240
tctcttccct tctcttg 257
<210> 23
<211> 190
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 23
ggtcagagga ccaaaggtga ggcaaggcca gacttggtgc tcctgtggtt ctcgagataa 60
cttcgtataa tgtatgctat acgaagttat atgcatggcc tccgcgccgg gttttggcgc 120
ctcccgcggg cgcccccctc ctcacggcga gcgctgccac gtcagacgaa gggcgcagcg 180
agcgtcctga 190
<210> 24
<211> 171
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 24
attgttttgc caagttctaa ttccatcaga cctcgacctg cagcccctag ataacttcgt 60
ataatgtatg ctatacgaag ttatgctagt aactataacg gtcctaaggt agcgagctag 120
ctccacgtgg ctttgtccca gacttccttt gtcttcaaca accttctgca a 171
<210> 25
<211> 177
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 25
ggtcagagga ccaaaggtga ggcaaggcca gacttggtgc tcctgtggtt ctcgagataa 60
cttcgtataa tgtatgctat acgaagttat gctagtaact ataacggtcc taaggtagcg 120
agctagctcc acgtggcttt gtcccagact tcctttgtct tcaacaacct tctgcaa 177
<210> 26
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 26
gccgtgactg tgaccttctc 20
<210> 27
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 27
tggaggagcc acctgatgcc tc 22
<210> 28
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 28
gccttgccct caatggaaac 20
<210> 29
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 29
ggttgcacag caaggaagaa g 21
<210> 30
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 30
ccaggagttc ctgtgagcct accc 24
<210> 31
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 31
tggaatggaa ggagctggag 20
<210> 32
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 32
gtcccacctc ctgcaactg 19
<210> 33
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 33
tgagccttcc catcagcctg gg 22
<210> 34
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 34
ccacaatggc acatgggtct g 21
<210> 35
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 35
ggtgcttgct ccccaaga 18
<210> 36
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 36
cctaaaaggt gttgtaatgg 20
<210> 37
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 37
ggcaataaag aaggaagacg tttt 24
<210> 38
<211> 120
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 38
ccagtcaggg acacacatgc tcacacgccc gcccacccgc acacactaca gtcgagataa 60
cttcgtataa tgtatgctat acgaagttat atgcatggcc tccgcgccgg gttttggcgc 120
<210> 39
<211> 198
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 39
attctagttg tggtttgtcc aaactcatca atgtatctta tcatgtctgg aataacttcg 60
tataatgtat gctatacgaa gttatgctag taactataac ggtcctaagg tagcgagcta 120
gccaagtctg tgtgctacca agtagcaaaa ctgagcctgg aactcacaca tgcgtgtctg 180
agagcccagc actatcgc 198
<210> 40
<211> 100
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 40
taatctgact ttctcttcat cggtctctct tattctaggc tgagctgtaa cgctgccgtc 60
ccccacatcc agaagctgct tcccttcaga cctacctacg 100
<210> 41
<211> 177
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 41
ccagtcaggg acacacatgc tcacacgccc gcccacccgc acacactaca gtcgagataa 60
cttcgtataa tgtatgctat acgaagttat gctagtaact ataacggtcc taaggtagcg 120
agctagccaa gtctgtgtgc taccaagtag caaaactgag cctggaactc acacatg 177
<210> 42
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 42
gagcagggcc atgacacat 19
<210> 43
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 43
accattagat cccagcactg gaca 24
<210> 44
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 44
aaacccttcc cgagagagaa 20
<210> 45
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 45
gaggaacact gtgtcaagga ctt 23
<210> 46
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 46
cctgaaaagc ccggagtggc ag 22
<210> 47
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 47
gggcagagac cacatctga 19
<210> 48
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 48
ggaagccctc tctcgatact tg 22
<210> 49
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 49
ttctaccctg agggcatgca gc 22
<210> 50
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 50
tgggatgtag aaggttgtca ga 22
<210> 51
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 51
ctgagcctgg aactcacaca tg 22
<210> 52
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 52
tctgagagcc cagcactatc gcc 23
<210> 53
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 53
gctgagggtc aggcttgag 19
<210> 54
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 54
tctgcagggt agggagagaa g 21
<210> 55
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 55
tgtttcagaa aaggaagact cacgttaca 29
<210> 56
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 56
gagaccgatg aagagaaagt caga 24
<210> 57
<211> 100
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 57
gaccatttta aggttttgct tggttgtttt ggagggaggg tggtgctttg ctaatggtga 60
attactaact cctcaataaa gaatattatt tgaaataatt 100
<210> 58
<211> 190
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 58
gctgcctttt aatccagcgc tataattgag gcaagcgtcc agcttgacac ctcgagataa 60
cttcgtataa tgtatgctat acgaagttat atgcatggcc tccgcgccgg gttttggcgc 120
ctcccgcggg cgcccccctc ctcacggcga gcgctgccac gtcagacgaa gggcgcagcg 180
agcgtcctga 190
<210> 59
<211> 171
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 59
attgttttgc caagttctaa ttccatcaga cctcgacctg cagcccctag ataacttcgt 60
ataatgtatg ctatacgaag ttatgctagt aactataacg gtcctaaggt agcgagctag 120
ctgcaaccga ggaaaaaacg tgccatgagg tctctgtatc caagtgtgac t 171
<210> 60
<211> 177
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 60
ccagtcaggg acacacatgc tcacacgccc gcccacccgc acacactaca ctcgagataa 60
cttcgtataa tgtatgctat acgaagttat gctagtaact ataacggtcc taaggtagcg 120
agctagctgc aaccgaggaa aaaacgtgcc atgaggtctc tgtatccaag tgtgact 177
<210> 61
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 61
tcctctccag acaagaaagc t 21
<210> 62
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 62
tcatagcagc tttcaaatcc taaacgttga 30
<210> 63
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 63
tcgtgtgtag ctggtgagtt 20
<210> 64
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 64
catgcgatca caggaggaga tc 22
<210> 65
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 65
aattgggccc gaagccagat gc 22
<210> 66
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 66
cggaaggctt ctgtgacttc 20
<210> 67
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 67
gtctcccact tctgacataa tgaac 25
<210> 68
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 68
cccagtgtta accctacatc tggttcc 27
<210> 69
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 69
tgggaagaga ctcttggaca 20
<210> 70
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 70
atgagctcct agtacagcta aagtt 25
<210> 71
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 71
atgcatgatc atctatgcgt cagagc 26
<210> 72
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> synthetic oligonucleotide
<400> 72
tgcccagatg cagggagtta g 21
Claims (67)
- 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss 유전자를 포함하는 설치류로서, 상기 인간화 Tmprss 유전자는 상기 내인성 설치류 Tmprss 유전자의 프로모터에 의해 조절되는 것인, 설치류.
- 제1항에 있어서, 상기 인간화 Tmprss 유전자는 상기 동족 인간 TMPRSS 유전자에 의해 암호화된 상기 인간 TMPRSS 단백질의 세포외 도메인(ectodomain)과 실질적으로 동일한 세포외 도메인을 포함하는 인간화 Tmprss 단백질을 암호화하는, 설치류.
- 제2항에 있어서, 상기 인간화 Tmprss 단백질은 상기 내인성 설치류 Tmprss 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 포함하는, 설치류.
- 제1항에 있어서, 상기 동족 인간 TMPRSS 유전자의 상기 뉴클레오티드 서열은 상기 동족 인간 TMPRSS 유전자에 의해 암호화된 상기 인간 TMPRSS 단백질의 상기 세포외 도메인과 실질적으로 동일한 폴리펩티드를 암호화하는, 설치류.
- 제1항에 있어서, 상기 내인성 설치류 Tmprss 유전자의 상기 뉴클레오티드 서열은 상기 내인성 설치류 Tmprss 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss 단백질의 상기 세포질 및 막관통 부분과 실질적으로 동일한 폴리펩티드를 암호화하는, 설치류.
- 제1항에 있어서, 상기 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 유전자좌에 위치하고, 상기 내인성 설치류 Tmprss 유전자의 게놈 서열을 상기 동족 인간 TMPRSS 유전자의 상기 뉴클레오티드 서열로 대체함으로써 생성되는 것인, 설치류.
- 제1항에 있어서, 상기 인간화 Tmprss 유전자는 인간화 Tmprss2 유전자이고, 상기 내인성 설치류 Tmprss 유전자는 내인성 설치류 Tmprss2 유전자이며, 상기 동족 인간 TMPRSS 유전자는 인간 TMPRSS2 유전자인, 설치류.
- 제7항에 있어서, 상기 인간화 Tmprss2 유전자는 상기 인간 TMPRSS2 유전자에 의해 암호화된 상기 인간 TMPRSS2 단백질의 상기 세포외 도메인과 실질적으로 동일한 세포외 도메인을 포함하는 인간화 Tmprss2 단백질을 암호화하는, 설치류.
- 제8항에 있어서, 상기 인간 TMPRSS2 단백질은 서열 번호 4에 명시된 바와 같은 아미노산 서열과 적어도 85% 동일한 아미노산 서열을 포함하는, 설치류.
- 제8항에 있어서, 상기 인간화 Tmprss2 단백질의 세포외 도메인은 서열 번호 4의 잔기 W106 내지 G492로 이루어진 아미노산 서열과 실질적으로 동일한 아미노산 서열을 포함하는, 설치류.
- 제8항에 있어서, 상기 인간화 Tmprss2 단백질은 상기 내인성 설치류 Tmprss2 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss2 단백질의 상기 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 포함하는, 설치류.
- 제7항에 있어서, 상기 인간 TMPRSS2 유전자의 상기 뉴클레오티드 서열은 상기 인간 TMPRSS2 유전자에 의해 암호화된 상기 인간 TMPRSS2 단백질의 상기 세포외 도메인과 실질적으로 동일한 폴리펩티드를 암호화하는, 설치류.
- 제12항에 있어서, 상기 인간 TMPRSS2 유전자의 뉴클레오티드 서열은 상기 인간화 TMPRSS2 유전자의 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 포함하는, 설치류.
- 제13항에 있어서, 상기 인간 TMPRSS2 유전자의 3' UTR을 추가로 포함하는, 설치류.
- 제7항에 있어서, 상기 내인성 설치류 Tmprss2 유전자의 상기 뉴클레오티드 서열은 상기 내인성 설치류 Tmprss2 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss2 단백질의 상기 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화하는, 설치류.
- 제7항에 있어서, 상기 인간화 Tmprss2 유전자는 상기 내인성 설치류 Tmprss2 유전자의 코딩 엑손 1 내지 2 및 상기 인간 TMPRSS2 유전자의 코딩 엑손 4 내지 코딩 엑손 13을 포함하되, 상기 인간화 Tmprss2 유전자는 상기 내인성 설치류 Tmprss2 유전자에 의해 암호화된 상기 설치류 Tmprss2 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 포함하는 인간화 Tmprss2 단백질, 및 상기 인간 TMPRSS2 유전자에 의해 암호화된 상기 인간 TMPRSS2 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는, 설치류.
- 제16항에 있어서, 상기 인간화 Tmprss2 유전자는 상기 내인성 설치류 Tmprss2 유전자의 코딩 엑손 3의 5' 부분 및 상기 인간 TMPRSS2 유전자의 코딩 엑손 3의 3' 부분을 포함하는 엑손 3을 포함하는, 설치류.
- 제1항에 있어서, 상기 인간화 Tmprss 유전자는 인간화 Tmprss4 유전자이고, 상기 내인성 설치류 Tmprss 유전자는 내인성 설치류 Tmprss4 유전자이며, 상기 동족 인간 TMPRSS 유전자는 인간 TMPRSS4 유전자인, 설치류.
- 제18항에 있어서, 상기 인간화 Tmprss4 유전자는 상기 인간 TMPRSS4 유전자에 의해 암호화된 상기 인간 TMPRSS4 단백질의 상기 세포외 도메인과 실질적으로 동일한 세포외 도메인을 포함하는 인간화 Tmprss4 단백질을 암호화하는, 설치류.
- 제19항에 있어서, 상기 인간 TMPRSS4 단백질은 서열 번호 11에 명시된 바와 같은 아미노산 서열과 적어도 85% 동일한 아미노산 서열을 포함하는, 설치류.
- 제19항에 있어서, 상기 세포외 도메인은 서열 번호 11의 잔기 K54~L437로 이루어진 아미노산 서열과 실질적으로 동일한 아미노산 서열을 포함하는, 설치류.
- 제19항에 있어서, 상기 인간화 Tmprss4 단백질은 상기 내인성 설치류 Tmprss4 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss4 단백질의 상기 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 포함하는, 설치류.
- 제18항에 있어서, 상기 인간 TMPRSS4 유전자의 상기 뉴클레오티드 서열은 상기 인간 TMPRSS4 유전자에 의해 암호화된 상기 인간 TMPRSS4 단백질의 상기 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는, 설치류.
- 제23항에 있어서, 상기 인간 TMPRSS4 유전자의 뉴클레오티드 서열은 상기 인간 TMPRSS4 유전자의 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 포함하는, 설치류.
- 제24항에 있어서, 상기 인간 TMPRSS4 유전자의 정지 코돈 다음에 상기 내인성 설치류 Tmprss4 유전자의 3' UTR이 이어지는, 설치류.
- 제18항에 있어서, 상기 내인성 설치류 Tmprss4 유전자의 뉴클레오티드 서열은 상기 내인성 설치류 Tmprss4 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss4 단백질의 상기 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화하는, 설치류.
- 제18항에 있어서, 상기 인간화 Tmprss4 유전자는 상기 내인성 설치류 Tmprss4 유전자의 코딩 엑손 1 내지 3 및 상기 인간 TMPRSS4 유전자의 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 포함하는, 설치류.
- 제1항에 있어서, 상기 인간화 Tmprss 유전자는 인간화 Tmprss11d 유전자이고, 상기 내인성 설치류 Tmprss 유전자는 내인성 설치류 Tmprss11d 유전자이며, 상기 동족 인간 TMPRSS 유전자는 인간 TMPRSS11D 유전자인, 설치류.
- 제28항에 있어서, 상기 인간화 Tmprss11d 유전자는 상기 동족 인간 TMPRSS11D 유전자에 의해 암호화된 상기 인간 TMPRSS11D 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 포함하는 인간화 Tmprss11d 단백질을 암호화하는, 설치류.
- 제29항에 있어서, 상기 인간 TMPRSS11D 단백질은 서열 번호 18에 명시된 바와 같은 아미노산 서열과 적어도 85% 동일한 아미노산 서열을 포함하는, 설치류.
- 제29항에 있어서, 상기 세포외 도메인은 서열 번호 18의 잔기 A42 내지 I418로 이루어진 아미노산 서열과 실질적으로 동일한 아미노산 서열을 포함하는, 설치류.
- 제29항에 있어서, 상기 인간화 Tmprss11d 단백질은 상기 내인성 설치류 Tmprss11d 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss11d 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 포함하는, 설치류.
- 제28항에 있어서, 상기 인간 TMPRSS11D 유전자의 뉴클레오티드 서열은 상기 인간 TMPRSS11D 유전자에 의해 암호화된 상기 인간 TMPRSS11D 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 암호화하는, 설치류.
- 제33항에 있어서, 상기 인간 TMPRSS11D 유전자의 뉴클레오티드 서열은 상기 인간화 TMPRSS11D 유전자의 코딩 엑손 3 내지 코딩 엑손 10 내의 정지 코돈을 포함하는, 설치류.
- 제34항에 있어서, 상기 인간 TMPRSS11D 유전자의 3' UTR을 추가로 포함하는, 설치류.
- 제28항에 있어서, 상기 내인성 설치류 Tmprss11d 유전자의 뉴클레오티드 서열은 상기 내인성 설치류 Tmprss11d 유전자에 의해 암호화된 상기 내인성 설치류 Tmprss11d 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 암호화하는, 설치류.
- 제28항에 있어서, 상기 인간화 Tmprss11d 유전자는 상기 내인성 설치류 Tmprss11d 유전자의 코딩 엑손 1 내지 코딩 엑손 2 및 상기 인간 TMPRSS11D 유전자의 코딩 엑손 3 내지 코딩 엑손 10을 포함하는, 설치류.
- 제1항에 있어서, 상기 설치류는 마우스 또는 랫트인, 설치류.
- 제1항에 있어서, 상기 설치류는 인간화 Tmprss 유전자에 대해 이형접합체(heterozygous)인, 설치류.
- 제1항에 있어서, 상기 설치류는 인간화 Tmprss 유전자에 대해 동형접합체(homozygous)인, 설치류.
- 제1항에 있어서, 상기 설치류는 동족 내인성 Tmprss 유전자좌에 적어도 2개의 인간화 Tmprss 유전자를 포함하는, 설치류.
- 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss 유전자를 포함하는 게놈을 가진 단리된 설치류 세포 또는 조직으로서, 상기 인간화 Tmprss 유전자는 상기 내인성 설치류 Tmprss 유전자의 프로모터에 의해 조절되는 것인, 단리된 설치류 세포 또는 조직.
- 제42항에 있어서, 상기 인간화 Tmprss 유전자는 인간화 Tmprss2 유전자, 인간화 Tmprss4 유전자, 및 인간화 Tmprss11d 유전자로 이루어지는 군으로부터 선택된 것인, 단리된 설치류 세포 또는 조직.
- 내인성 설치류 Tmprss 유전자의 뉴클레오티드 서열 및 동족 인간 TMPRSS 유전자의 뉴클레오티드 서열을 포함하는 인간화 Tmprss 유전자를 포함하는 게놈을 가진 설치류 배아 줄기 세포로서, 상기 인간화 Tmprss 유전자는 상기 내인성 설치류 Tmprss 유전자의 프로모터에 의해 조절되는 것인, 설치류 배아 줄기 세포.
- 제44항에 있어서, 상기 인간화 Tmprss 유전자는 인간화 Tmprss2 유전자, 인간화 Tmprss4 유전자, 및 인간화 Tmprss11d 유전자로 이루어지는 군으로부터 선택된 것인, 설치류 배아 줄기 세포.
- 제44항의 설치류 배아 줄기 세포로부터 생성된 설치류 배아.
- 설치류 Tmprss 유전자좌에서 동족 설치류 Tmprss 단백질을 암호화하는 설치류 게놈 DNA의 측면에 위치하는 게놈 DNA 서열과 상동인 5' 뉴클레오티드 서열 및 3' 뉴클레오티드 서열이 측면에 위치하는, 인간 TMPRSS 단백질의 세포외 도메인을 암호화하는 인간 게놈 DNA를 포함하는 벡터.
- 인간화 Tmprss 유전자를 포함하는 게놈을 가진 설치류를 제공하는 방법으로서, 상기 방법은:
내인성 Tmprss 유전자의 게놈 서열을 동족 인간 TMPRSS 유전자의 게놈 서열로 대체시켜 인간화 Tmprss 유전자를 형성하기 위해 설치류의 상기 게놈을 변형시키는 것을 포함하는, 방법. - 인간화 Tmprss 유전자를 갖는 설치류를 만드는 방법으로서:
(a) 설치류 배아 줄기 세포 내의 내인성 설치류 Tmprss 유전자좌에 동족 인간 TMPRSS 유전자를 포함하는 게놈 단편을 삽입하여 인간화 Tmprss 유전자를 형성하되, 상기 인간화 Tmprss 유전자는 내인성 설치류 Tmprss 유전자좌에서 상기 설치류 Tmprss 유전자의 프로모터에 의해 조절되는 것인, 단계;
(b) (a) 단계의 상기 인간화 Tmprss 유전자를 포함하는 설치류 배아 줄기 세포를 수득하는 단계; 및
(c) (b) 단계의 상기 설치류 배아 줄기 세포를 사용해 설치류를 생성하는 단계를 포함하는, 방법. - 제49항에 있어서, 상기 인간화 Tmprss 유전자는 상기 동족 인간 TMPRSS 유전자에 의해 암호화된 상기 인간 TMPRSS 단백질의 세포외 도메인과 실질적으로 동일한 세포외 도메인을 포함하는 인간화 Tmprss 단백질을 암호화하는, 방법.
- 제50항에 있어서, 상기 인간화 Tmprss 단백질은 상기 내인성 설치류 Tmprss 유전자좌에서 상기 설치류 Tmprss 유전자에 의해 암호화된 상기 설치류 Tmprss 단백질의 세포질 및 막관통 부분과 실질적으로 동일한 세포질 및 막관통 부분을 추가로 포함하는, 방법.
- 제49항에 있어서, 상기 인간화 Tmprss 유전자는 인간화 Tmprss2 유전자, 인간화 Tmprss4 유전자, 및 인간화 Tmprss11d 유전자로 이루어지는 군으로부터 선택된 것인, 방법.
- 제52항에 있어서, 상기 인간화 Tmprss2 유전자는 상기 내인성 설치류 Tmprss2 유전자의 코딩 엑손 1 내지 코딩 엑손 2 및 상기 인간 TMPRSS2 유전자의 코딩 엑손 4 내지 코딩 엑손 13을 포함하는, 방법.
- 제53항에 있어서, 상기 인간화 Tmprss2 유전자는 상기 내인성 설치류 Tmprss2 유전자의 코딩 엑손 3의 5' 부분 및 상기 인간 TMPRSS2 유전자의 코딩 엑손 3의 3' 부분을 포함하는 엑손 3을 포함하는, 방법.
- 제52항에 있어서, 상기 인간화 Tmprss4 유전자는 상기 내인성 설치류 Tmprss4 유전자의 코딩 엑손 1 내지 3 및 상기 인간 TMPRSS4 유전자의 코딩 엑손 4 내지 코딩 엑손 13 내의 정지 코돈을 포함하는, 방법.
- 제52항에 있어서, 상기 인간화 Tmprss11d 유전자는 상기 내인성 설치류 Tmprss11d 유전자의 코딩 엑손 1 내지 코딩 엑손 2 및 상기 인간 TMPRSS11D 유전자의 코딩 엑손 3 내지 코딩 엑손 10을 포함하는, 방법.
- 제52항에 있어서, 상기 인간화 Tmprss 유전자는 인간 TMPRSS2 단백질, 인간 TMPRSS4 단백질, 및 인간 TMPRSS11D 단백질로 이루어지는 군으로부터 선택된 인간 TMPRSS 단백질의 세포외 도메인을 포함하는 인간화 Tmprss 단백질을 암호화하는, 방법.
- 제57항에 있어서, 상기 인간화 Tmprss 단백질은 인간 TMPRSS2 단백질의 W106 내지 G492 또는 C 말단 387 아미노산을 포함하는 인간화 Tmprss2 단백질인, 방법.
- 제57항에 있어서, 상기 인간화 Tmprss 단백질은 인간 TMPRSS4 단백질의 K54 내지 L437 또는 C 말단 384 아미노산을 포함하는 인간화 Tmprss4 단백질인, 방법.
- 제57항에 있어서, 상기 인간화 Tmprss 단백질은 인간 TMPRSS11D 단백질의 A42 내지 I418 또는 C 말단 377 아미노산을 포함하는 인간화 Tmprss11d 단백질인, 방법.
- 제49항에 있어서, 상기 설치류는 마우스 또는 랫트인, 방법.
- 인플루엔자 바이러스 감염의 치료에 있어서 화합물의 치료 효능을 평가하는 방법으로서,
제1항 내지 제41항 중 어느 한 항의 설치류를 제공하는 단계;
상기 설치류에 인플루엔자 바이러스와 후보 화합물을 투여하는 단계; 및
상기 후보 화합물의 치료 효능을 결정하기 위해 상기 설치류에서 인플루엔자 바이러스 감염의 존재 및 중증도를 모니터링하는 단계를 포함하는, 방법. - 제62항에 있어서, 상기 인플루엔자 바이러스는 상기 후보 화합물 이전에 상기 설치류에 투여되는, 방법.
- 제62항에 있어서, 상기 인플루엔자 바이러스는 상기 후보 화합물 이후에 상기 설치류에 투여되는, 방법.
- 제62항에 있어서, 상기 후보 화합물은 인간 TMPRSS 단백질에 특이적인 항체 또는 이의 항원 결합 단편인, 방법.
- 제65항에 있어서, 상기 인간 TMPRSS 단백질은 인간 TMPRSS2 단백질, 인간 TMPRSS4 단백질, 및 인간 TMPRSS11D 단백질로 이루어지는 군으로부터 선택되는, 방법.
- 제62항에 있어서, 상기 설치류는 마우스 또는 랫트인, 방법.
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DK3841877T3 (da) | 2014-05-19 | 2023-11-27 | Regeneron Pharma | Genetisk modificeret mus, der eksprimerer human EPO |
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PT3230320T (pt) | 2014-12-09 | 2021-01-08 | Regeneron Pharma | Animais não humanos tendo um gene do cluster humanizado de diferenciação 274 |
HRP20231039T1 (hr) | 2015-04-06 | 2023-12-22 | Regeneron Pharmaceuticals, Inc. | Imunosni odgovori posredovani humaniziranim t stanicama kod ne-humanih životinja |
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