JP3045581B2 - 麻疹ワクチンウイルス株同定方法 - Google Patents

麻疹ワクチンウイルス株同定方法

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JP3045581B2
JP3045581B2 JP3293625A JP29362591A JP3045581B2 JP 3045581 B2 JP3045581 B2 JP 3045581B2 JP 3293625 A JP3293625 A JP 3293625A JP 29362591 A JP29362591 A JP 29362591A JP 3045581 B2 JP3045581 B2 JP 3045581B2
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JPH05103665A (ja
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綮子 佐々木
孝之 森
慧 牧野
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Kitasato Institute
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Kitasato Institute
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Priority to JP3293625A priority Critical patent/JP3045581B2/ja
Priority to KR1019920003759A priority patent/KR950012759B1/ko
Priority to DE69231143T priority patent/DE69231143T2/de
Priority to ES92302004T priority patent/ES2148164T3/es
Priority to AT92302004T priority patent/ATE193726T1/de
Priority to EP92302004A priority patent/EP0540135B1/en
Priority to PT92302004T priority patent/PT540135E/pt
Priority to DK92302004T priority patent/DK0540135T3/da
Publication of JPH05103665A publication Critical patent/JPH05103665A/ja
Priority to US08/348,891 priority patent/US5654136A/en
Priority to US08/905,817 priority patent/US5824777A/en
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Description

【発明の詳細な説明】
【０００１】
【産業上の利用分野】本発明は、特定塩基配列を含む麻
疹生ワクチンウイルス株およびそれの絶対的同定法に関
する。
【０００２】
【従来の技術】麻疹ウイルスは、麻疹の病因ウイルスで
あり、パラミクソウイルス科（Ｐａｒａｍｙｘｏｖｉｒ
ｉｄａｅ）に属するＲＮＡウイルスである。１９５４年
にＪ．Ｆ．Ｅｎｄｅｒｓ等により麻疹ウイルスが患者か
らヒト腎初代培養細胞を用いて、初めて分離された（Ｅ
ｎｄｅｒｓ，Ｊ．Ｆ．ｅｔ．ａｌ：Ｐｒｏｃ．Ｓｏｃ．
Ｅｘｐ．Ｂｉｏｌ．Ｍｅｄ．８６，２２７−２８６，１
９５４）。
【０００３】また、彼らは、この時分離した麻疹ウイル
スＥｄｍｏｎｏｓｔｏｎ株を弱毒化して、麻疹ワクチン
を開発した（Ｅｎｄｅｒｓ．Ｊ．Ｆ．ｅｔ．ａｌ：Ｎｅ
ｗＥｎｇ１．Ｊ．Ｍｅｄ．，２６３，１５３−１５９，
１９６０）。
【０００４】この麻疹ワクチンは、発熱と発疹の副反応
を高頻度に誘発する生ワクチンであった。その後、多く
の研究者により弱毒Ｅｄｍｏｎｏｓｔｏｎ株を更に弱毒
化したいくつかの高度弱毒生ワクチン株が樹立された。
これらの中で、Ａ．Ｊ．Ｆ．Ｓｃｈｗａｒｚにより樹立
されたＳｃｈｗａｒｚ株生ワクチンが世界で一般に広く
用いられて来た。
【０００５】一方、本発明者らはＥｎｄｅｒｓ博士より
分与をうけた強毒Ｅｄｍｏｎｓｔｏｎ株から羊腎臓細胞
培養を用いて４つの低温変異株の分離に成功した。（Ｍ
ａｋｉｎｏ，Ｓ．ｅｔ．ａｌ：Ｊａｐａｎ Ｊ．Ｍｉｃ
ｒｏｂｉｏｌ．，１４，５０１−５０４，１９７０）。
【０００６】麻疹ウイルスは、弱毒化の程度が進むにつ
れて、平行して免疫原性すなわち有効性が低下すること
が一般に知られている。本発明者らが分離した低温変異
株の中、３３℃で増殖する適応株は、先の麻疹ウイルス
一般にみられる性質と異なり、高度に弱毒化しているに
も拘わらず、高い免疫原生を示す特徴ある変異株であっ
た。（Ｍａｋｉｎｏ，Ｓ．ｅｔ．ａｌ：Ｊａｐａｎ
Ｊ．Ｍｉｃｒｏｂｉｏｌ．，１７，７５−７９，１９７
３）。
【０００７】本発明者の一人は、この低温変異株を実用
的生ワクチンの種ウイルスにするために、この株から病
原微生物感染フリー（ＳＰＦ；ｓｐｅｃｉｆｉｃｐａｔ
ｈｏｇｅｎ ｆｒｅｅ）の鶏卵より得られたニワトリ胚
細胞に適応させ、かつ親株と同じ温度マーカーを担った
クローンウイルスを分離樹立し、これをＡＩＫ−Ｃ株と
命名した。（Ｓａｓａｋｉ，Ｋ．：Ｋｉｔｓａｔｏ Ａ
ｒｃｈ．Ｅｘｐ．Ｍｅｄ．，４７，１３−２１，１９７
４）。
【０００８】ＡＩＫ−Ｃ株を種として製造したＡＩＫ−
Ｃ株生ワクチンの麻疹感受性児に対する発熱率（≦３
７．５℃）は、Ｓｃｈｗａｒｚ株ワクチンの約１／３−
１／４である。このように、ＡＩＫ−Ｃ株は、Ｓｃｈｗ
ａｒｚ株より更に弱毒化されているにも拘わらず、その
抗体産生応答は、十分に高く、免疫原生の低下が見られ
ない特質を示す麻疹ワクチンウイルス株である。（Ｍａ
ｋｉｎｏ，Ｓ．ｅｔ．ａｌ：Ｋｉｔａｓａｔｏ Ａｒ
ｃ．Ｅｘｐ．Ｍｅｄ．，４７，１３−２１，１９７
４）。
【０００９】これまで使用されてきた他の麻疹生ワクチ
ン株ワクチンは、被接種者１００万人あたり、１−３人
の割合でワクチンに起因したと考えられる脳炎の発生が
知られているが、ＡＩＫ−Ｃ株生ワクチンはこれまで、
日本で１，０００万人以上使用されてきたが、このよう
な発生の報告をみない。（Ｈｉｒａｙａｍａ，Ｍ．：Ｉ
ｎｆ，Ｄｉｓ．，５，４９５−５０３，１９８３；Ｍａ
ｋｉｎｏ，Ｓ．：同雑誌，５，５０４−５０５，１９８
３）。
【００１０】
【発明が解決しようとする課題】以上のように、ＡＩＫ
−Ｃ株の生物学的性状は他の株のそれと異なった特性を
示すことが明らかになってきた。しかしながら、ウイル
スは極めて変異を起こしやすく、前記ＡＩＫ−Ｃ株のよ
うな弱毒性麻疹ウイルス株であっても、その増殖時に極
くわずかな比率で変異株の産生がみられる。麻疹生ワク
チンの製造にとつて、種ウイルス株とその製造されたワ
クチンウイルスが同じ性状を示すことの検査が、最も大
事である。
【００１１】
【課題を解決するための手段】この品質管理上の試験に
は、これまでＡＩＫ−Ｃ株特有の温度マーカー試験（Ｓ
ａｓａｋｉ，Ｋ．：Ｋｉｔａｓａｔｏ Ａｒｃｈ．Ｅｘ
ｐ．Ｍｅｄ．，４７，１−１２，１９７４）が用いられ
てきた。しかし、この生物反応試験は、必ずしもＡＩＫ
−Ｃ株に対する絶対的同定法とはいえなかつた。
【００１２】ウイルスの基本的生物学的性状は、そのウ
イルス粒子の核酸からなる遺伝子によって規定される。
麻疹ウイルスの核酸は１本鎖のネガテイブＲＮＡからな
つており、各ウイルス株はそれぞれ特有の塩基配列から
なる核酸をもっている。
【００１３】それ故、各ウイルス株間の確実な鑑別法
は、その株のウイルス核酸の塩基配列を検べることであ
る。本発明者らは、この点に着目し、前記麻疹ウイルス
ＡＩＫ−Ｃ株の、麻疹ウイルス感染に関与する核酸の塩
基配列を解明することにより、麻疹ウイルスＡＩＫ−Ｃ
株の安定した管理を可能ならしめ、本発明を完成した。
【００１４】これまで、各種の麻疹ウイルス株の同定方
法には、そのウイルス株特有の生物反応試験が応用され
てきたが、それは絶対的な同定法ではなかつた。ＡＩＫ
−Ｃ株ワクチンの品質管理には、前記した温度マーカー
試験が利用されてきたが、本発明者らはこの同定試験を
絶対的証明法とするため、ＡＩＫ−Ｃ株ウイルスゲノム
の全塩基配列を初めて解明した。
【００１５】本発明は、ＡＩＫ−Ｃ株の特定塩基配列１
５８９４の全塩基配列の解明を実現したことにより、被
検査ウイルスが遺伝子レベルで検査可能となり、したが
つて、その同定試験が絶対的証明法となるが故に、ＡＩ
Ｋ−Ｃ株ワクチンの安定した品質管理が極めて正確とな
る特定塩基配列を含む麻疹生ワクチンウイルス株および
それの絶対的同定法を提供し得るものである。
【００１６】上記の如き目的は本発明によれば、麻疹生
ワクチン製造に使用する種ウイルス株とそのワクチン最
終製品に含む主たるワクチンウイルスのゲノムが、１５
８９４塩基配列からなることを特徴とする特定塩基配列
を含む麻疹生ワクチンウイルス株により達成される。
【配列番号：１】
【００１７】また、本発明によれば、麻疹生ワクチン種
ウイルス株とそのワクチン最終製品に含まれるウイルス
中の一部に請求項１記載の塩基配列を基本にした一部変
異挿入または一部欠損配列のあるウイルスを含むことか
らなる麻疹ワクチンウイルスにより達成される。
【００１８】更に本発明によれば、麻疹生ウイルス株に
おいて、該ワクチンウイルスのゲノムが前記１５８９４
塩基配列からなる特定塩基配列を含むことを検出するこ
とからなる麻疹生ワクチンウイルス株の絶対的同定法に
より達成される。
【００１９】更に又本発明によれば、検出方法がノーザ
ンブロツト法およびＰＣＲ法によるウイルスゲノムの一
部の塩基配列の決定であることからなる麻疹生ワクチン
ウイルス株の絶対的同定法により達成される。
【００２０】本発明においては、先ず麻疹ＡＩＫ−Ｃ株
生ワクチンの種ウイルスが使用される。この種ウイルス
をＳＰＦニワトリの胚細胞中で培養して得られる、いわ
ゆるワクチンバルクから精製前のウイルス浮遊液を調製
する。このワクチンバルクは市販用ワクチンの原料とな
る市販用ワクチンバルクであってもよい。
【００２１】このワクチンの浮遊液を、シヨ糖密度勾配
超遠心法によりウイルスを濃縮精製し、ＳＤＳ−フエノ
ール抽出法でウイルスＲＮＡゲノムを調整する。使用す
る合成プライマーは、２５ｍｅｒ前後の合成プライマー
をアミダイト法で合成したものを用いればよい。
【００２２】このものは例えば、Ｃｙｃｌｏｎｅ ＤＮ
Ａ Ｓｙｎｔｈｅｓｉｚｅｒ（Ｂｉｏｓｅｒｃｈ，Ｉｎ
ｃ．）を使用して、簡便に合成し得る。上記の合成ＤＮ
ＡをプライマーとしてＡＩＫ−Ｃ株ウイルスＲＮＡを逆
転写酵素処理により、ｃＤＮＡをＲＮａｓｅＨ法で２本
鎖とし、適切な制限酵素で切断した後、ｐＵＣ１８ある
いはｐＵＣ１９にクローニングする。以上を模式化すれ
ば図１に示す通りである。
【００２３】得られたｃＤＮＡクローンの同定は、数種
の制限酵素切断様式たとえば合成プライマー、ＭＰ−１
により得られたｃＤＮＡ中にはＢａｍＨＩ、ＥｃｏＲＶ
およびＸｂａＩの制限酵素サイトがある。アンピシリン
耐性菌より抽出されたプラスミド中に、このｃＤＮＡが
含まれていればＢａｍＨＩとＸｂａＩによる切断によ
り、約１５０４ベースの断片がアガロースゲルの電気泳
動により確認され、しかもこの断片をＥｃｏＲＶで処理
すると、そこから６５０ベースと８５４ベースの２種の
断片が検出されてくる。このようにして挿入した断片の
プラスミドからの切断およびサイズの確認、あるいは、
その断片中に含まれる麻疹特有の制限サイトの同定によ
り行った。
【００２４】更に塩基の決定は、そのクローニング部位
を適切な制限酵素で切断したＭ１３フアージベクター
に、得られたｃＤＮＡクローンを同様の付着末端を作る
制限酵素あるいは平滑末端を作る制限酵素で切断して挿
入した。この組み換え体フアージを大腸菌に感染させフ
アージプラークより一本鎖組み換えＤＮＡを抽出し、ダ
イデオキシシークエンス法により行つた。
【００２５】プライマー、例えばＭＰ−１により得られ
たｃＤＮＡ ｐＭＮ２をＢａｍＨＩとＸｂａＩで切断
し、ｐＵＣプラスミツドでクローニングした。ｃＤＮＡ
の同定を行つた後、同種の制限酵素を用いてＡＩＫ−Ｃ
由来のＤＮＡ断片を切り出し、更にこの断片をＥｃｏＲ
Ｖで切断し、６５０ｂｐと８５４ｂｐから成る２種の断
片を作成した。
【００２６】これらの断片を、予めＢａｍＨＩ、Ｘｂａ
Ｉで切断しておいたＭ１３複製型二本鎖ＤＮＡに連結
し、大腸菌にトランスフエクシヨンして、組み換え体フ
アージを選別後、大腸菌に感染増殖し、フアージ上清液
より一本鎖組み換えＤＮＡを抽出してダイデオキシシー
クエンス法を用いて塩基配列を決定した。
【００２７】上記方法で検索した結果、ＡＩＫ−Ｃ株ウ
イルスゲノムは１５８９４塩基からなり、その全塩基配
列は配列表に示す通りであった。このようにして検出さ
れたＲＮＡゲノムを含む麻疹ウイルスは、その性質にお
いて、ＡＩＫ−Ｃ株ウイルスの有する優れた特徴を示す
ものであつた。
【００２８】＜上記で得た本麻疹生ワクチンウイルス株
の管理方法＞他の麻疹ウイルス株とは異なる塩基配列を
含むＡＩＫ−Ｃ株の領域を獲得し得るようにＰＣＲ法に
より、そのゲノムの塩基配列を決定し、ワクチン用に使
用され得る、あるいは製造されたＡＩＫ−Ｃ株が常に同
一のウイルスであるかどうかを同定し、あるいはワクチ
ン接種後の小児より得られたリンパ球中に、もしこの小
児が発疹したのならば、その原因ウイルスがワクチンに
よるものなのか、否かの同定のために、この塩基配列を
基に判断し得るものである。
【００２９】本明細書中に記載の略記号は次の意味を有
する。 Ｍｅｔ；メチオニン Ａｌａ；アラニン Ｔｈｒ；スレオニン Ｌｅｕ；ロイシン Ａｒｇ；アルギニン Ｓｅｒ；セリン Ｐｈｅ；フエニルアラニン Ｌｙｓ；リジン Ａｓｎ；アスパラギン Ａｓｐ；アスパラギン酸
【００３０】Ｐｒｏ；プロリン ＩＩｅ；イソロイシン Ｇｌｙ；グリシン Ｈｉｓ；ヒスチジン Ｖａｌ；バリン Ｇｌｕ；グルタミン酸 Ｇｌｎ；グルタミン
【００３１】次に実施例を挙げて具体的に説明する。 実施例 １ ＡＩＫ−Ｃ株ワクチン製造に仕込んだワク
チン原液から採取したウイルスの塩基配列決定
【００３２】ステツプ−ａ：大型Ｒｏｕｘ（ルー）瓶容
積約１l 、細胞培養表面積（２３０cm2 ）に培養した。
ＳＰＦニワトリ胚細胞層にＡＩＫ−Ｃ株種ウイルス（Ｓ
ｅｅｄ Ｌｏｔ Ｎｏ．０−２）を１細胞宛感染価０．
０５になるように接種した後、組織培養用イーグル（Ｅ
ａｇｌｅ’ｓ）ＭＥＭに、１％仔牛血清を含む培養液１
５０mlを加え、３３℃でウイルスを培養した。
【００３３】ステツプ−ｂ：ウイルス接種後、３日目に
培養液を除去し、新たに上記の培養液を１５０ml加え
て、さらに培養を続けた。
【００３４】ステツプｃ：ウイルス接種後、６日目に培
養液を除去し、感染ニワトリ胚細胞層をハンクス（Ｈａ
ｎｋｓ）液１００mlを用いて、３回十分に洗浄した後、
０．１％のグルタミン酸ナトリウムを含む組織培養用イ
ーグル（Ｅａｇｌｅ’ｓ）ＭＥＭ２００mlを加え、３３
℃で培養を続けた。
【００３５】ステツプ：ｄ 麻疹ウイルスに特徴ある細胞変性効果が、感染細胞層の
全域に出現したウイルス接種１０日目に、その培養液を
採取してワクチン原液（容量：約２００ml、感染価：１
０7.2 ＴＣＩＤ50／ml）とした。
【００３６】ステツプ：ｅ 採取したワクチン原液を３０００ｒｐｍ、３０分間遠心
後、その遠心上清をさらに、２５０００ｒｐｍ、９０分
間超遠心〔遠心機：ベツクマン（Ｂｅｃｋｍａｎ）Ｌ８
−５５Ｍ型、ローター：ＳＷ２８型〕した。
【００３７】ステツプ：ｆ 遠心上清を除去後、各遠心管中の沈渣にテン（ＴＥＮ）
緩衝液（１０ｍＭ−トリス、１ｍＭ−ＥＤＴＡ、１００
ｍＭ−ＮａＣl 、ｐＨ７．４）を１ml加え、充分に懸濁
し、これを濃縮ウイルス材料とした。得られた濃縮ウイ
ルス材料の最終容量が１０mlになるようにテン緩衝液を
さらに加え、出発ウイルス検体とした。
【００３８】ステツプ：ｇ ベツクマン（Ｂｅｃｋｍａｎ）ＳＷ４１ローター用の遠
心チューブ２本に１本当り６．８mlの６０％（ｗ／ｖ）
ショ糖液（ＴＥＮ緩衝液）と６．８mlの３０％（ｗ／
ｖ）ショ糖液（ＴＥＮ緩衝液）を用いた３０〜６０％の
連続シヨ糖密度勾配層上に、上記ウイルス検体５mlを重
層し、２０７，０００ｇ、９０分間の超遠心を４℃で行
つた。遠心後、それぞれの遠心チューブよりフラクシヨ
ンコレクターを用いて分画し、感染価の最も高い画分
（１０8.3ＴＣＩＤ50／ml）を集め、これをさらに同一
条件の超遠心操作にかけて感染価を基にウイルスを回収
し、精製ウイルス粒子とした。
【００３９】ステツプ：ｈ 上記精製したウイルス粒子材料をテン（ＴＥＮ）緩衝液
で５倍希釈し、１．５mlマイクロテストチューブに２０
０μl づつ分注後、２０％ＳＤＳ、５μl 、フエノール
１００μl 、クロロホルム１００μl をそれぞれ加え、
ボルテツクス（Ｖｏｒｔｅｘ）ミキサーを用いて、充分
に攪拌する。
【００４０】更に、微量遠心機で１２０００ｒｐｍ、５
分間遠心して有機溶媒層と水層とに分離する。この水層
を別の１．５mlのマイクロテストチューブにとり、上記
フエノール抽出を２回繰り返す。
【００４１】この抽出操作後、回収した水層に５Ｍ−Ｎ
ａＣl １／２５容、エタノール２．５容を混ぜて、−２
０℃で２時間放置した後、微量遠心機で１２０００ｒｐ
ｍ、１０分間遠心してＲＮＡの沈澱を集め、７０％エタ
ノールでその沈澱を洗浄後、風乾する。これをオートク
レーブにかけた再蒸留水５０μlで溶解し、ＲＮＡ懸濁
液とする。
【００４２】ステツプ：ｉ サイクロンＤＮＡシンセサ
イザー（ＣｙｃｌｏｎｅＤＮＡｓｙｎｔｈｅｓｉｚｅ
ｒ） バイオサーチ社製（Ｂｉｏｓｅｒｃｈ Ｉｎｃ．）を用
いて、図３に示す如く２５ｍｅｒ前後のＭＰ−１ないし
ＭＰ−１１およびＢＥＰ（ｄＴ7 ）の合成プライマーを
１２種合成した。
【００４３】ステツプ：ｊ 上記合成ＤＮＡそれぞれ２μl を合成プライマー（ＭＰ
−１ないしＭＰ−１１）として前記のステツプ：ｈにお
けるＲＮＡ懸濁液１０μl に対して逆転写酵素処理によ
りｃＤＮＡ合成を行った。このｃＤＮＡをＲＮａｓｅＨ
−ＤＮＡポリメラーゼＩを用いた反応により、２本鎖ｃ
ＤＮＡとした（ＧｕｂｌｅｒａｎｄＨｏｆｆｍａｎ，Ｇ
ＥＮＥ ２５，ｐ２６３−２６９，１９８３）。
【００４４】ステツプ：ｋ 得られたｃＤＮＡ中に存在する制限酵素サイトを利用し
てそれぞれＢａｍＨＩ−ＸｂａＩ、ＸｂａＩ−ＢａｍＨ
Ｉ、ＢａｍＨＩ−ＥｃｏＲＩ、ＥｃｏＲＩ−ＢａｍＨ
Ｉ、ＢａｍＨＩ−ＥｃｏＲＩ、ＥｃｏＲＩ−ＢｇｌII、
ＢｇｌII−ＳａｃＩ、ＳａｃＩ−ＮｃｏＩ−ＸｂａＩで
切断し、各フラグメントをｐＵＣプラスミツド（ｐＵＣ
１８およびｐＵＣ１９）のそれぞれ対応するクローニン
グサイトへ挿入した。
【００４５】ステツプ：ｌ 上記組み換えプラスミツドで大腸菌ＨＢ１０１をトラン
スフオームさせ、アンピシリン耐性のコロニーを獲得し
た。得られたコロニーよりプラスミツドＤＮＡを抽出
し、各フラグメントに相当する長さの塩基を保有するコ
ロニーを０．８％のアガロースゲルを用いた電気泳動に
よりスクリーニングした。
【００４６】ステツプ：ｍ ゲノム３’末端のクローニングに際しては、前記ステツ
プ：ｈのＲＮＡ懸濁液にポリ（Ａ）ポリメラーゼを用い
て、アデノシン３リン酸（ＡＴＰ）をテイルさせ、得ら
れた３’Ａ付加ＲＮＡ懸濁液に対して、前記ステツプ：
ｊに従い、ｃＤＮＡを合成し、以後、同様にクローニン
グを行つた。なお、使用した合成プライマーはＢＥＰ
（ｄＴ7 ）プライマーと名づけ、該プライマーは、５’
−ＣＴＧＴＧＡＡＴＴＣＴＧＣＡＧＧＡＴＣＣＴＴＴＴ
ＴＴＴ−３’の配列である。
【００４７】ステツプ：ｎ ゲノム５’末端に関しては麻疹ゲノムの１５５９２−１
５６１５領域に相補的なＤＮＡを含むプライマーを合成
した。この合成プライマーは５’−ＴＧＧＡＡＧＣＴＴ
ＡＴＣＣＡＧＡＡＴＣＴＣＡＡＧＴＣＣＧＧＣＴ−３’
である。この合成したＤＮＡをプライマーとして逆転写
酵素を用いてＤＮＡ−ＲＮＡハイブリツドを作成し、ア
ルカリ変性処理後、ターミナル デオキシヌクレオチジ
ルトランスフエラーゼによりｃＤＮＡの３’末端にｄＡ
ＴＰをテイルさせた。
【００４８】このｃＤＮＡを鋳型にして上記のステツ
プ：ｍにおけるＢＥＰ（ｄＴ7 ）をプライマーにしてク
レノーフラグメント（Ｋｌｅｎｏｗ Ｆｒａｇｍｅｎ
ｔ）により２本鎖のＤＮＡを作成し、同様にクローニン
グを行った。
【００４９】ステツプ：ｏ 上記で得られたｃＤＮＡを更に、バクテリオフアージＭ
１３系ベクター（ｍｐ１８およびｍｐ１９）によりサブ
クローニングして、得られた１本鎖ＤＮＡを７−ＤＥＡ
ＺＥ−ｄＧＴＰシークエンシングキツト（宝社製）によ
るダイデオキシ法を用いて、それらｃＤＮＡの塩基配列
を決定した。
【００５０】ステツプ：ｐ 塩基配列および推定されるアミノ酸配列の解析にはジエ
ネンテイツクス（ＧＥＮＥＴＹＸ）のソフトウエアーを
使用した。
【００５１】実施例 ２ ＡＩＫ−Ｃ株製造用種ウイル
スをＶｅｒｏ細胞（アフリカミドリザル腎臓株化細胞）
中で増殖させたウイルスの塩基配列決定
【００５２】ステツプ：ａ 前記の実施例１と同様の接種方法で、ＡＩＫ−Ｃ株種ウ
イルス（Ｓｅｅｄ Ｌｏｔ Ｎｏ．０−２）を、前もつ
て培養せしめた大型Ｒｏｕｏｘ（ルー）瓶中のＶｅｒｏ
細胞層に接種し、３３℃で同様にウイルス培養した。
【００５３】ステツプ：ｂ 培養５日目に、感染細胞層を、ハンクス（Ｈａｎｋｓ）
液で充分洗浄後、仔牛牛血清を含まないイーグル（Ｅａ
ｇｌｅ’ｓ）ＭＥＭ２００mlを加えて、更に２日間培養
を続けて、ウイルス培養液を採取し、ウイルス原液（容
量：約２００ml、感染価：１０6.5 ＴＣＩＤ50／ml）と
した。
【００５４】ステツプ：ｃ 採取したワクチン原液を３０００ｒｐｍ、３０分間遠心
後、その遠心上清をさらに、２５０００ｒｐｍ、９０分
間超遠心〔遠心機：ベツクマン（Ｂｅｃｋｍａｎ）Ｌ８
−５５Ｍ型、ローター：ＳＷ２８型〕した。
【００５５】ステツプ：ｄ 遠心上清を除去後、各遠心管中の沈渣にテン（ＴＥＮ）
緩衝液（１０ｍＭ−トリス、１ｍＭ−ＥＤＴＡ、１００
ｍＭ−ＮａＣl 、ｐＨ７．４）を１ml加え、充分に懸濁
し、これを濃縮ウイルス材料とした。得られた濃縮ウイ
ルス材料の最終容量が１０mlになるようにテン緩衝液を
更に加え、出発ウイルス検体とした。
【００５６】ステツプ：ｅ ベツクマン（Ｂｅｃｋｍａｎ）ＳＷ４１ローター用の遠
心チューブ２本に１本当り６．８mlの６０％（ｗ／ｖ）
シヨ糖液（ＴＥＮ緩衝液）と６．８mlの３０％（ｗ／
ｖ）シヨ糖液（ＴＥＮ緩衝液）を用いた３０〜６０％の
連続シヨ糖密度勾配層上に、上記ウイルス検体５mlを重
層し、２０７，０００ｇ、９０分間の超遠心を４℃で行
つた。遠心後、それぞれの遠心チユーブよりフラクシヨ
ンコレクターを用いて分画し、感染価の最も高い画分
（１０8.3ＴＣＩＤ50／ml）を集め、これをさらに同一
条件の超遠心操作にかけて感染価を基にウイルスを回収
し、精製ウイルス粒子とした。
【００５７】ステツプ：ｆ 上記精製したウイルス粒子材料をテン（ＴＥＮ）緩衝液
で５倍希釈し、１．５mlマイクロテストチユーブに２０
０μl づつ分注後、２０％ＳＤＳ、５μl 、フエノール
１００μl 、クロロホルム１００μl をそれぞれ加え、
ボルテツクス（Ｖｏｒｔｅｘ）ミキサーを用いて、充分
に攪拌する。
【００５８】更に、微量遠心機で１２０００ｒｐｍ、５
分間遠心して有機溶媒層と水層とに分離する。この水層
を別の１．５mlのマイクロテストチユーブにとり、上記
フエノール抽出を２回繰り返す。
【００５９】この抽出操作後、回収した水層に５Ｍ−Ｎ
ａＣl １／２５容、エタノール２．５容を混ぜて、−２
０℃で２時間放置した後、微量遠心機で１２０００ｒｐ
ｍ、１０分間遠心してＲＮＡの沈澱を集め、７０％エタ
ノールでその沈澱を洗浄後、風乾する。これを滅菌し、
再蒸留水５０μl で溶解し、ＲＮＡ懸濁液とする。
【００６０】ステツプ：ｇ サイクロンＤＮＡシンセサ
イザー（ＣｙｃｌｏｎｅＤＮＡｓｙｎｔｈｅｓｉｚｅ
ｒ） バイオサーチ社製（Ｂｉｏｓｅｒｃｈ Ｉｎｃ．）を用
いて、図３に示すごとく２５ｍｅｒ前後のＭＰ−１ない
しＭＰ−１１およびＢＥＰ（ｄＴ7 ）の合成プライマー
を１２種合成した。
【００６１】ステツプ：ｈ 上記の合成ＤＮＡそれぞれ２μl を合成プライマー（Ｍ
Ｐ−１ないしＭＰ−１１）として前記のステツプ：ｈに
おけるＲＮＡ懸濁液１０μl に対して逆転写酵素処理に
よりｃＤＮＡ合成を行つた。このｃＤＮＡをＲＮａｓｅ
Ｈ−ＤＮＡポリメラーゼＩを用いた反応により、２本鎖
ｃＤＮＡとした（Ｇｕｂｌｅｒ ａｎｄＨｏｆｆｍａ
ｎ，ＧＥＮＥ ２５，ｐ２６３−２６９，１９８３）。
【００６２】ステツプ：ｉ 得られたｃＤＮＡ中に存在する制限酵素サイトを利用し
てそれぞれＢａｍＨＩ−ＸｂａＩ、ＸｂａＩ−ＢａｍＨ
Ｉ、ＢａｍＨＩ−ＥｃｏＲＩ、ＥｃｏＲＩ−ＢａｍＨ
Ｉ、ＢａｍＨＩ−ＥｃｏＲＩ、ＥｃｏＲＩ−ＢｇｌII、
ＢｇｌII−ＳａｃＩ、ＳａｃＩ−ＮｃｏＩ−ＸｂａＩで
切断し、各フラグメントをｐＵＣプラスミツド（ｐＵＣ
１８およびｐＵＣ１９）のそれぞれ対応するクローニン
グサイトへ挿入した。
【００６３】ステツプ：ｊ 上記組み換えプラスミツドで大腸菌ＨＢ１０１をトラン
スフオームさせ、アンピシリン耐性のコロニーを獲得し
た。得られたコロニーよりプラスミツドＤＮＡを抽出
し、各フラグメントに相当する長さの塩基を保有するコ
ロニーを０．８％のアガロースゲルを用いた電気泳動に
よりスクリーニングした。
【００６４】ステツプ：ｋ ゲノム３’末端のクローニングに際しては、前記ステツ
プ：ｈのＲＮＡ懸濁液にポリ（Ａ）ポリメラーゼを用い
て、アデノシン３リン酸（ＡＴＰ）をテイルさせ、得ら
れた３’Ａ付加ＲＮＡ懸濁液に対して、前記ステツプ：
ｊに従い、ｃＤＮＡを合成し、以後、同様にクローニン
グを行った。なお、使用した合成プライマーはＢＥＰ
（ｄＴ7 ）プライマーと名づけた５’−ＣＴＧＴＧＡＡ
ＴＴＣＴＧＣＡＧＧＡＴＣＣＴＴＴＴＴＴＴ−３’であ
る。
【００６５】ステツプ：ｌ ゲノム５’末端に関してはハシカゲノムの１５５９２−
１５６１５領域に相補的なＤＮＡを含むプライマーを合
成した。この合成プライマーは５’−ＴＧＧＡＡＧＣＴ
ＴＡＴＣＣＡＧＡＡＴＣＴＣＡＡＧＴＣＣＧＧＣＴ−
３’である。この合成したＤＮＡをプライマーとして逆
転写酵素を用いてＤＮＡ−ＲＮＡハイブリツドを作成
し、アルカリ変性処理後、ターミナル デオキシヌクレ
オチジルトランスフエラーゼによりｃＤＮＡの３’末端
にｄＡＴＰをテイルさせた。
【００６６】このｃＤＮＡを鋳型にして上記のステツ
プ：ｍにおけるＢＥＰ（ｄＴ7 ）をプライマーにしてク
レノーフラグメント（Ｋｌｅｎｏｗ Ｆｒａｇｍｅｎ
ｔ）により２本鎖のＤＮＡを作成し、同様にクローニン
グを行った。
【００６７】ステツプ：ｍ 上記で得られたｃＤＮＡを更に、バクテリオフアージＭ
１３系ベクター（ｍｐ１８およびｍｐ１９）によりサブ
クローニングして、得られた１本鎖ＤＮＡを７−ＤＥＡ
ＺＥ−ｄＧＴＰシークエンシングキツト（宝社製）によ
るダイデオキシ法を用いて、それらｃＤＮＡの塩基配列
を決定した。
【００６８】ステツプ：ｎ 塩基配列および推定されるアミノ酸配列の解析にはジエ
ネンテイツクス（ＧＥＮＥＴＹＸ）のソフトウエアーを
使用した。
【００６９】実施例 ３ 麻疹出現１日目の患者より検
出した麻疹ウイルスのＰＣＲ法による同定
【００７０】ステツプ：ａ 麻疹患者よりその麻疹出現の１日目に約５ml採血し、リ
ンパ球をフイコール分離する。
【００７１】ステツプ：ｂ ＰＢＳで２回洗浄後、このリンパ球に変性溶液Ｄ（４Ｍ
グアニジウム チオシアネート、２５ｍＭ クエン酸ナ
トリウム、ｐＨ７．５；０．５％ザルコシル、０．１Ｍ
２−メルカプトエタノール）を２００μl 加えて、静
かに攪拌後、２０μl の２Ｍ酢酸ナトリウム、ｐＨ４、
２００μl のフエノールおよび１００μl のクロロホル
ムを順次加えて行く。
【００７２】この混合液を１０秒間ボルテツクス（Ｖｏ
ｒｔｅｘ）ミキサーにかけた後、氷中に１５分間置く。
次に１００００ｇ×２０分間の遠心にかけ、水層を回収
し、等量のイソプロパノールを加えて−２０℃で１時
間、静置後、１００００ｇ×２０分間の遠心でＲＮＡを
沈澱させる（Ｃｈｏｍｃｚｙｎｓｋｉ ａｎｄ Ｓａｃ
ｃｈｉ：Ａｎａｌ Ｂｉｏｃｈｅｍ．１６２、１５−１
５９（１９８７）。
【００７３】ステツプ：ｃ 得られたＲＮＡを逆転写反応およびＰＣＲ法にかける。
【００７４】ステツプ：ｄ 塩基配列の決定およびワクチン株、野生株の同定を行
う。
【配列表】
【００７５】配列番号：１ 配列の長さ：１５８９４ 配列の型：核酸 鎖の数：一本鎖 トポロジー：直鎖状 配列の種類：アンチゲノム ＤＮＡ 起源 生物名：麻疹弱毒生ワクチン 株名：ＡＩＫ−Ｃ 配列 ACCAAACAAA GTTGGGTAAG GATAGTTCAA TCAATGATCA TCTTCTAGTG CACTTAGGAT 60 TCAAGATCCT ATTATCAGGG ACAAGAGCAG GATTAGGGAT ATCCGAG ATG GCC ACA 116 Met Ala Thr CTT TTA AGG AGC TTA GCA TTG TTC AAA AGA AAC AAG GAC AAA CCA CCC 164 Leu Leu Arg Ser Leu Ala Leu Phe Lys Arg Asn Lys Asp Lys Pro Pro 5 10 15 ATT ACA TCA GGA TCC GGT GGA GCC ATC AGA GGA ATC AAA CAC ATT ATT 212 Ile Thr Ser Gly Ser Gly Gly Ala Ile Arg Gly Ile Lys His Ile Ile 20 25 30 35 ATA GTA CCA ATC CCT GGA GAT TCC TCA ATT ACC ACT CGA TCC AGA CTT 260 Ile Val Pro Ile Pro Gly Asp Ser Ser Ile Thr Thr Arg Ser Arg Leu 40 45 50 CTG GAC CGG TTG GTC AGG TTA ATT GGA AAC CCG GAT GTG AGC GGG CCC 308 Leu Asp Arg Leu Val Arg Leu Ile Gly Asn Pro Asp Val Ser Gly Pro 55 60 65 AAA CTA ACA GGG GCA CTA ATA GGT ATA TTA TCC TTA TTT GTG GAG TCT 356 Lys Leu Thr Gly Ala Leu Ile Gly Ile Leu Ser Leu Phe Val Glu Ser 70 75 80 CCA GGT CAA TTG ATT CAG AGG ATC ACC GAT GAC CCT GAC GTT AGC ATA 404 Pro Gly Gln Leu Ile Gln Arg Ile Thr Asp Asp Pro Asp Val Ser Ile 85 90 95 AGG CTG TTA GAG GTT GTC CAG AGT GAC CAG TCA CAA TCT GGC CTT ACC 452 Arg Leu Leu Glu Val Val Gln Ser Asp Gln Ser Gln Ser Gly Leu Thr 100 105 110 115 TTC GCA TCA AGA GGT ACC AAC ATG GAG GAT GAG GCG GAC AAA TAC TTT 500 Phe Ala Ser Arg Gly Thr Asn Met Glu Asp Glu Ala Asp Lys Tyr Phe 120 125 130 TCA CAT GAT GAT CCA ATT AGT AGT GAT CAA TCC AGG TTC GGA TGG TTC 548 Ser His Asp Asp Pro Ile Ser Ser Asp Gln Ser Arg Phe Gly Trp Phe 135 140 145 GAG AAC AAG GAA ATC TCA GAT ATT GAA GTG CAA GAC CCT GAG GGA TTC 596 Glu Asn Lys Glu Ile Ser Asp Ile Glu Val Gln Asp Pro Glu Gly Phe 150 155 160 AAC ATG ATT CTG GGT ACC ATC CTA GCC CAA ATT TGG GTC TTG CTC GCA 644 Asn Met Ile Leu Gly Thr Ile Leu Ala Gln Ile Trp Val Leu Leu Ala 165 170 175 AAG GCG GTT ACG GCC CCA GAC ACG GCA GCT GAT TCG GAG CTA AGA AGG 692 Lys Ala Val Thr Ala Pro Asp Thr Ala Ala Asp Ser Glu Leu Arg Arg 180 185 190 195 TGG ATA AAG TAC ACC CAA CAA AGA AGG GTA GTT GGT GAA TTT AGA TTG 740 Trp Ile Lys Tyr Thr Gln Gln Arg Arg Val Val Gly Glu Phe Arg Leu 200 205 210 GAG AGA AAA TGG TTG GAT GTG GTG AGG AAC AGG ATT GCC GAG GAC CTC 788 Glu Arg Lys Trp Leu Asp Val Val Arg Asn Arg Ile Ala Glu Asp Leu 215 220 225 TCC TTA CGC CGA TTC ATG GTC GCT CTA ATC CTG GAT ATC AAG AGA ACA 836 Ser Leu Arg Arg Phe Met Val Ala Leu Ile Leu Asp Ile Lys Arg Thr 230 235 240 CCC GGA AAC AAA CCC AGG ATT GCT GAA ATG ATA TGT GAC ATT GAT ACA 884 Pro Gly Asn Lys Pro Arg Ile Ala Glu Met Ile Cys Asp Ile Asp Thr 245 250 255 TAT ATC GTA GAG GCA GGA TTA GCC AGT TTT ATC CTG ACT ATT AAG TTT 932 Tyr Ile Val Glu Ala Gly Leu Ala Ser Phe Ile Leu Thr Ile Lys Phe 260 265 270 275 GGG ATA GAA ACT ATG TAT CCT GCT CTT GGA CTG CAT GAA TTT GCT GGT 980 Gly Ile Glu Thr Met Tyr Pro Ala Leu Gly Leu His Glu Phe Ala Gly 280 285 290 GAG TTA TCC ACA CTT GAG TCC TTG ATG AAC CTT TAC CAG CAA ATG GGG 1028 Glu Leu Ser Thr Leu Glu Ser Leu Met Asn Leu Tyr Gln Gln Met Gly 295 300 305 GAA ACT GCA CCC TAC ATG GTA AAC CTG GAG AAC TCA ATT CAG AAC AAG 1076 Glu Thr Ala Pro Tyr Met Val Asn Leu Glu Asn Ser Ile Gln Asn Lys 310 315 320 TTC AGT GCA GGA TCA TAC CCT CTG CTC TGG AGC TAT GCC ATG GGA GTA 1124 Phe Ser Ala Gly Ser Tyr Pro Leu Leu Trp Ser Tyr Ala Met Gly Val 325 330 335 GGA GTG GAA CTT GAA AAC TCC ATG GGA GGT TTG AAC TTT GGC CGA TCT 1172 Gly Val Glu Leu Glu Asn Ser Met Gly Gly Leu Asn Phe Gly Arg Ser 340 345 350 355 TAC TTT GAT CCA GCA TAT TTT AGA TTA GGG CAA GAG ATG GTA AGG AGG 1220 Tyr Phe Asp Pro Ala Tyr Phe Arg Leu Gly Gln Glu Met Val Arg Arg 360 365 370 TCA GCT GGA AAG GTC AGT TCC ACA TTG GCA TCT GAA CTC GGT ATC ACT 1268 Ser Ala Gly Lys Val Ser Ser Thr Leu Ala Ser Glu Leu Gly Ile Thr 375 380 385 GCC GAG GAT GCA AGG CTT GTT TCA GAG ATT GCA ATG CAT ACT ACT GAG 1316 Ala Glu Asp Ala Arg Leu Val Ser Glu Ile Ala Met His Thr Thr Glu 390 395 400 GAC AAG ATC AGT AGA GCG GTT GGA CCC AGA CAA GCC CAA GTA TCA TTT 1364 Asp Lys Ile Ser Arg Ala Val Gly Pro Arg Gln Ala Gln Val Ser Phe 405 410 415 CTA CAC GGT GAT CAA AGT GAG AAT GAG CTA CCG AGA TTG GGG GGC AAG 1412 Leu His Gly Asp Gln Ser Glu Asn Glu Leu Pro Arg Leu Gly Gly Lys 420 425 430 435 GAA GAT AGG AGG GTC AAA CAG AGT CGA GGA GAA GCC AGG GAG AGC TAC 1460 Glu Asp Arg Arg Val Lys Gln Ser Arg Gly Glu Ala Arg Glu Ser Tyr 440 445 450 AGA GAA ACC GGG CCC AGC AGA GCA AGT GAT GCG AGA GCT GCC CAT CTT 1508 Arg Glu Thr Gly Pro Ser Arg Ala Ser Asp Ala Arg Ala Ala His Leu 455 460 465 CCA ACC GGC ACA CCC CTA GAC ATT GAC ACT GCA TCG GAG TCC AGC CAA 1556 Pro Thr Gly Thr Pro Leu Asp Ile Asp Thr Ala Ser Glu Ser Ser Gln 470 475 480 GAT CCG CAG GAC AGT CGA AGG TCA GCT GAC GCC CTG CTT AGG CTG CAA 1604 Asp Pro Gln Asp Ser Arg Arg Ser Ala Asp Ala Leu Leu Arg Leu Gln 485 490 495 GCC ATG GCA GGA ATC TCG GAA GAA CAA GGC TCA GAC ACG GAC ACC CCT 1652 Ala Met Ala Gly Ile Ser Glu Glu Gln Gly Ser Asp Thr Asp Thr Pro 500 505 510 515 ATA GTG TAC AAT GAC AGA AAT CTT CTA GAC TAGGTGCGAG AGGCCGAGGA 1702 Ile Val Tyr Asn Asp Arg Asn Leu Leu Asp 520 525 CCAGAACAAC ATCCGCCTAC CCTCCATCAT TGTTATAAAA AACTTAGGAA CCAGGTCCAC 1762 ACAGCCGCCA GCCCATCAAC CATCCACTCC CACGATTGGA GCCG ATG GCA GAA GAG 1818 Met Ala Glu Glu CAG GCA CGC CAT GTC AAA AAC GGA CTG GAA TGC ATC CGG GCT CTC AAG 1866 Gln Ala Arg His Val Lys Asn Gly Leu Glu Cys Ile Arg Ala Leu Lys 5 10 15 20 GCC GAG CCC ATC GGC TCA CTG GCC ATC GAG GAA GCT ATG GCA GCA TGG 1914 Ala Glu Pro Ile Gly Ser Leu Ala Ile Glu Glu Ala Met Ala Ala Trp 25 30 35 TCA GAA ATA TCA GAC AAC CCA GGA CAG GAG CGA GCC ACC TGC AGG GAA 1962 Ser Glu Ile Ser Asp Asn Pro Gly Gln Glu Arg Ala Thr Cys Arg Glu 40 45 50 GAG AAG GCA GGC AGT TCG GGT CTC AGC AAA CCA TGC CTC TCA GCA ATT 2010 Glu Lys Ala Gly Ser Ser Gly Leu Ser Lys Pro Cys Leu Ser Ala Ile 55 60 65 GGA TCA ACT GAA GGC GGT GCA CCT CGC ATC CGC GGT CAG GGA CCT GGA 2058 Gly Ser Thr Glu Gly Gly Ala Pro Arg Ile Arg Gly Gln Gly Pro Gly 70 75 80 GAG AGC GAT GAC GAC GCT GAA ACT TTG GGA ATC CCC CCA AGA AAT CTC 2106 Glu Ser Asp Asp Asp Ala Glu Thr Leu Gly Ile Pro Pro Arg Asn Leu 85 90 95 100 CAG GCA TCA AGC ACT GGG TTA CAG TGT TAT TAT GTT TAT GAT CAC AGC 2154 Gln Ala Ser Ser Thr Gly Leu Gln Cys Tyr Tyr Val Tyr Asp His Ser 105 110 115 GGT GAA GCG GTT AAG GGA ATC CAA GAT GCT GAC TCT ATC ATG GTT CAA 2202 Gly Glu Ala Val Lys Gly Ile Gln Asp Ala Asp Ser Ile Met Val Gln 120 125 130 TCA GGC CTT GAT GGT GAT AGC ACC CTA TCA GGA GGA GAC AAT GAA TCT 2250 Ser Gly Leu Asp Gly Asp Ser Thr Leu Ser Gly Gly Asp Asn Glu Ser 135 140 145 GAA AAC AGC GAT GTG GAT ATT GGC GAA CCT GAT ACC GAG GGA TAT GCT 2298 Glu Asn Ser Asp Val Asp Ile Gly Glu Pro Asp Thr Glu Gly Tyr Ala 150 155 160 ATC ACT GAC CGG GGA TCT GCT CCC ATC TCT ATG GGG TTC AGG GCT TCT 2346 Ile Thr Asp Arg Gly Ser Ala Pro Ile Ser Met Gly Phe Arg Ala Ser 165 170 175 180 GAT GTT GAA ACT GCA GAA GGA GGG GAG ATC CAC GAG CTC CTG AGA CTC 2394 Asp Val Glu Thr Ala Glu Gly Gly Glu Ile His Glu Leu Leu Arg Leu 185 190 195 CAA TCC AGA GGC AAC AAC TTT CCG AAG CTT GGG AAA ACT CTC AAT GTT 2442 Gln Ser Arg Gly Asn Asn Phe Pro Lys Leu Gly Lys Thr Leu Asn Val 200 205 210 CCT CCG CCC CCG GAC CCC GGT AGG GCC AGC ACT TCC GGG ACA CCC ATT 2490 Pro Pro Pro Pro Asp Pro Gly Arg Ala Ser Thr Ser Gly Thr Pro Ile 215 220 225 AAA AAG GGC ACA GAG CGC AGA TTA GCC TCA TTT GGA ACG GAG ATC GCG 2538 Lys Lys Gly Thr Glu Arg Arg Leu Ala Ser Phe Gly Thr Glu Ile Ala 230 235 240 TCT TTA TTG ACA GGT GGT GCA ACC CAA TGT GCT CGA AAG TCA CCC TCG 2586 Ser Leu Leu Thr Gly Gly Ala Thr Gln Cys Ala Arg Lys Ser Pro Ser 245 250 255 260 GAA CCA TCA GGG CCA GGT GCA CCT GCG GGG AAT GTC CCC GAG TAT GTG 2634 Glu Pro Ser Gly Pro Gly Ala Pro Ala Gly Asn Val Pro Glu Tyr Val 265 270 275 AGC AAT GCC GCA CTG ATA CAG GAG TGG ACA CCC GAA TCT GGT ACC ACA 2682 Ser Asn Ala Ala Leu Ile Gln Glu Trp Thr Pro Glu Ser Gly Thr Thr 280 285 290 ATC TCC CCG AGA TCC CAG AAT AAT GAA GAA GGG GGA GAC TAT TAT GAT 2730 Ile Ser Pro Arg Ser Gln Asn Asn Glu Glu Gly Gly Asp Tyr Tyr Asp 295 300 305 GAT GAG CTG TTC TCT GAT GTC CAA GAT ATT AAA ACA GCC TTG GCC AAA 2778 Asp Glu Leu Phe Ser Asp Val Gln Asp Ile Lys Thr Ala Leu Ala Lys 310 315 320 ATA CAC GAG GAT AAT CAG AAG ATA ATC TCC AAG CTA GAA TCA CTG CTG 2826 Ile His Glu Asp Asn Gln Lys Ile Ile Ser Lys Leu Glu Ser Leu Leu 325 330 335 340 TTA TTG AAG GGA GAA GTT GAG TCA ATT AAG AAG CAG ATC AAC AGG CAA 2874 Leu Leu Lys Gly Glu Val Glu Ser Ile Lys Lys Gln Ile Asn Arg Gln 345 350 355 AAT ATC AGC ATA TCC ACC CTG GAA GGA CAC CTC TCA AGC ATC ATG ATC 2922 Asn Ile Ser Ile Ser Thr Leu Glu Gly His Leu Ser Ser Ile Met Ile 360 365 370 GCC ATT CCT GGA CTT GGG AAG GAT CCC AAC GAC CCC ACT GCA GAT GTC 2970 Ala Ile Pro Gly Leu Gly Lys Asp Pro Asn Asp Pro Thr Ala Asp Val 375 380 385 GAA ATC AAT CCC GAC TTG AAA CCC ATC ATA GGC AGA GAT TCA GGC CGA 3018 Glu Ile Asn Pro Asp Leu Lys Pro Ile Ile Gly Arg Asp Ser Gly Arg 390 395 400 GCA CTG GCC GAA GTT CTC AAG AAA CCC GTT GCC AGC CGA CAA CTC CAA 3066 Ala Leu Ala Glu Val Leu Lys Lys Pro Val Ala Ser Arg Gln Leu Gln 405 410 415 420 GGA ATG ACA AAT GGA CGG ACC AGT TCC AGA GGA CAG CTG CTG AAG GAA 3114 Gly Met Thr Asn Gly Arg Thr Ser Ser Arg Gly Gln Leu Leu Lys Glu 425 430 435 TTT CAG CCA AAG CCG ATC GGG AAA AAG ATG AGC TCA GCC GTC GGG TTT 3162 Phe Gln Pro Lys Pro Ile Gly Lys Lys Met Ser Ser Ala Val Gly Phe 440 445 450 GTT CCT GAC ACC GGC CCT GCA TCA CGC AGT GTA ATC CGC TCC ATT ATA 3210 Val Pro Asp Thr Gly Pro Ala Ser Arg Ser Val Ile Arg Ser Ile Ile 455 460 465 AAA TCC AGC CGG CTA GAG GAG GAT CGG AAG CGT TAC CTG ATG ACT CTC 3258 Lys Ser Ser Arg Leu Glu Glu Asp Arg Lys Arg Tyr Leu Met Thr Leu 470 475 480 CTT GAT GAT ATC AAA GGA GCC AAT GAT CTT GCC AAG TTC CAC CAG ATG 3306 Leu Asp Asp Ile Lys Gly Ala Asn Asp Leu Ala Lys Phe His Gln Met 485 490 495 500 CTG ATG AAG ATA ATA ATG AAG TAGCTACAGC TCAACTTACC TGCCAACCCC 3357 Leu Met Lys Ile Ile Met Lys 505 ATGCCAGTCG ACCCAACTAG TACAACCTAA ATCCATTATA AAAAACTTAG GAGCAAAGTG 3417 ATTGCCTCCC AAGTTCCACA ATG ACA GAG ATC TAC GAC TTC GAC AAG TCG GCA 3470 Met Thr Glu Ile Tyr Asp Phe Asp Lys Ser Ala 5 10 TGG GAC ATC AAA GGG TCG ATC GCT CCG ATA CAA CCC ACC ACC TAC AGT 3518 Trp Asp Ile Lys Gly Ser Ile Ala Pro Ile Gln Pro Thr Thr Tyr Ser 15 20 25 GAT GGC AGG CTG GTG CCC CAG GTC AGA GTC ATA GAT CCT GGT CTA GGC 3566 Asp Gly Arg Leu Val Pro Gln Val Arg Val Ile Asp Pro Gly Leu Gly 30 35 40 GAC AGG AAG GAT GAA TGC TTT ATG TAC ATG TCT CTG CTG GGG GTT GTT 3614 Asp Arg Lys Asp Glu Cys Phe Met Tyr Met Ser Leu Leu Gly Val Val 45 50 55 GAG GAC AGC GAT CCC CTA GGG CCT CCA ATC GGG CGA GCA TTT GGG TCC 3662 Glu Asp Ser Asp Pro Leu Gly Pro Pro Ile Gly Arg Ala Phe Gly Ser 60 65 70 75 CTG CCC TTA GGT GTT GGC AGA TCC ACA GCA AAG CCC GAA AAA CTC CTC 3710 Leu Pro Leu Gly Val Gly Arg Ser Thr Ala Lys Pro Glu Lys Leu Leu 80 85 90 AAA GAG GCC ACT GAG CTT GAC ATA GTT GTT AGA CGT ACA GCA GGG CTC 3758 Lys Glu Ala Thr Glu Leu Asp Ile Val Val Arg Arg Thr Ala Gly Leu 95 100 105 AAT GAA AAA CTG GTG TTC TAC AAC AAC ACC CCA CTA ACT CTC CTC ACA 3806 Asn Glu Lys Leu Val Phe Tyr Asn Asn Thr Pro Leu Thr Leu Leu Thr 110 115 120 CCT TGG AGA AAG GTC CTA ACA ACA GGG AGT GTC TTC AAC GCA AAC CAA 3854 Pro Trp Arg Lys Val Leu Thr Thr Gly Ser Val Phe Asn Ala Asn Gln 125 130 135 GTG TGC AAT GCG GTT AAT CTG ATA CCG CTC GAT ACC CCG CAG AGG TTC 3902 Val Cys Asn Ala Val Asn Leu Ile Pro Leu Asp Thr Pro Gln Arg Phe 140 145 150 155 CGT GTT GTT TAT ATG AGC ATC ACC CGT CTT TCG GAT AAC GGG TAT TAC 3950 Arg Val Val Tyr Met Ser Ile Thr Arg Leu Ser Asp Asn Gly Tyr Tyr 160 165 170 ACC GTT CCT AGA AGA ATG CTG GAA TTC AGA TCG GTC AAT GCA GTG GCC 3998 Thr Val Pro Arg Arg Met Leu Glu Phe Arg Ser Val Asn Ala Val Ala 175 180 185 TTC AAC CTG CTG GTG ACC CTT AGG ATT GAC AAG GCG ATA GGC CCT GGG 4046 Phe Asn Leu Leu Val Thr Leu Arg Ile Asp Lys Ala Ile Gly Pro Gly 190 195 200 AAG ATC ATC GAC AAT ACA GAG CAA CTT CCT GAG GCA ACA TTT ATG GTC 4094 Lys Ile Ile Asp Asn Thr Glu Gln Leu Pro Glu Ala Thr Phe Met Val 205 210 215 CAC ATC GGG AAC TTC AGG AGA AAG AAG AGT GAA GTC TAC TCT GCC GAT 4142 His Ile Gly Asn Phe Arg Arg Lys Lys Ser Glu Val Tyr Ser Ala Asp 220 225 230 235 TAT TGC AAA ATG AAA ATC GAA AAG ATG GGC CTG GTT TTT GCA CTT GGT 4190 Tyr Cys Lys Met Lys Ile Glu Lys Met Gly Leu Val Phe Ala Leu Gly 240 245 250 GGG ATA GGG GGC ACC AGT CTT CAC ATT AGA AGC ACA GGC AAA ATG AGC 4238 Gly Ile Gly Gly Thr Ser Leu His Ile Arg Ser Thr Gly Lys Met Ser 255 260 265 AAG ACT CTC CAT GCA CAA CTC GGG TTC AAG AAG ACC TTA TGT TAC CCG 4286 Lys Thr Leu His Ala Gln Leu Gly Phe Lys Lys Thr Leu Cys Tyr Pro 270 275 280 CTG ATG GAT ATC AAT GAA GAC CTT AAT CGA TTA CTC TGG AGG AGC AGA 4334 Leu Met Asp Ile Asn Glu Asp Leu Asn Arg Leu Leu Trp Arg Ser Arg 285 290 295 TGC AAG ATA GTA AGA ATC CAG GCA GTT TTG CAG CCA TCA GTT CCT CAA 4382 Cys Lys Ile Val Arg Ile Gln Ala Val Leu Gln Pro Ser Val Pro Gln 300 305 310 315 GAA TTC CGC ATT TAC GAC GAC GTG ATC ATA AAT GAT GAC CAA GGA CTA 4430 Glu Phe Arg Ile Tyr Asp Asp Val Ile Ile Asn Asp Asp Gln Gly Leu 320 325 330 TTC AAA GTT CTG TAGACCGTAG TGCCCAGCAA TGCCCGAAAA CGACCCCCCT 4482 Phe Lys Val Leu 335 CACAATGACA GCCAGAAGGC CCGGACAAAA AAGCCCCCTC CGAAAGACTC CACTGACCAA 4542 GCGAGAGGCC AGCCAGCAGC CGACGGCAAG CACGAACACC AGGCGGCCCC AGCACAGAAC 4602 AGCCCTGATA CAAGGCCACC ACCAGCCACC CCAATCTGCA TCCTCCTCGT GGGACCCCCG 4662 AGGACCAACC CCCAAGGCTG CCCCCGATCC AAACCACCAA CCGCATCCCC ACCACCCCCG 4722 GGAAAGAAAC CCCCAGCAAT TGGAAGGCCC CTCCCCCTCT TCCTCAACAC AAGAACTCCA 4782 CAACCGAACC GCACAAGCGA CCGAGGTGAC CCAACCGCGC GGCATCCGAC TCCCTAGACA 4842 GATCCTCTCT CCCCGGCAAA CTAAACAAAA CTTAGGGCCA AGGAACATAC ACACCCAACA 4902 GAACCCAGAC CCCGGCCCAC GGCGCCGCGC CCCCAACCCC CGACAACCAG AGGGAGCCCC 4962 CAACCAATCC CGCCGGCTCC CCCGGTGCCC ACAGGCAGGG ACACCAACCC CCGAACAGAC 5022 CCAGCACCCA ACCATCGACA ATCCAAGACG GGGGGGCCCC CCCAAAAAAA GGCCCCCAGG 5082 GGCCGACAGC CAGCACCGCG AGGAAGCCCA CCCACCCCAC ACACGACCAC GGCAACCAAA 5142 CCAGAACCCA GACCACCCTG GCCACCAGCT CCCAGACTCG GCCATCACCC CGCAGAAAGG 5202 AAAGGCCACA ACCCGCGCAC CCCAGCCCCG ATCCGGCGGG GAGCCACCCA ACCCGAACCA 5262 GCACCCAAGA GCGATCCCCG AAGGACCCCC GAACCGCAAA GGACATCAGT ATCCCACAGC 5322 CTCTCCAAGT CCCCCGGTCT CCTCCTCTTC TCGAAGGGAC CAAAAGATCA ATCCACCACA 5382 CCCGACGACA CTCAACTCCC CACCCCTAAA GGAGACACCG GGAATCCCAG AATCAAGACT 5442 CATCCAATGT CCATC ATG GGT CTC AAG GTG AAC GTC TCT GCC ATA TTC ATG 5493 Met Gly Leu Lys Val Asn Val Ser Ala Ile Phe Met 5 10 GCA GTA CTG TTA ACT CTC CAA ACA CCC ACC GGT CAA ATC CAT TGG GGC 5541 Ala Val Leu Leu Thr Leu Gln Thr Pro Thr Gly Gln Ile His Trp Gly 15 20 25 AAT CTC TCT AAG ATA GGG GTG GTA GGA ATA GGA AGT GCA AGC TAC AAA 5589 Asn Leu Ser Lys Ile Gly Val Val Gly Ile Gly Ser Ala Ser Tyr Lys 30 35 40 GTT ATG ACT CGT TCC AGC CAT CAA TCA TTA GTC ATA AAA TTA ATG CCC 5637 Val Met Thr Arg Ser Ser His Gln Ser Leu Val Ile Lys Leu Met Pro 45 50 55 60 AAT ATA ACT CTC CTC AAT AAC TGC ACG AGG GTA GAG ATT GCA GAA TAC 5685 Asn Ile Thr Leu Leu Asn Asn Cys Thr Arg Val Glu Ile Ala Glu Tyr 65 70 75 AGG AGA CTA CTG AGA ACA GTT TTG GAA CCA ATT AGA GAT GCA CTT AAT 5733 Arg Arg Leu Leu Arg Thr Val Leu Glu Pro Ile Arg Asp Ala Leu Asn 80 85 90 GCA ATG ACC CAG AAT ATA AGA CCG GTT CAG AGT GTA GCT TCA AGT AGG 5781 Ala Met Thr Gln Asn Ile Arg Pro Val Gln Ser Val Ala Ser Ser Arg 95 100 105 AGA CAC AAG AGA TTT GCG GGA GTA GTC CTG GCA GGT GCG GCC CTA GGC 5829 Arg His Lys Arg Phe Ala Gly Val Val Leu Ala Gly Ala Ala Leu Gly 110 115 120 GTT GCC ACA GCT GCT CAG ATA ACA GCC GGC ATT GCA CTT CAC CAG TCC 5877 Val Ala Thr Ala Ala Gln Ile Thr Ala Gly Ile Ala Leu His Gln Ser 125 130 135 140 ATG CTG AAC TCT CAA GCC ATC GAC AAT CTG AGA GCG AGC CTG GAA ACT 5925 Met Leu Asn Ser Gln Ala Ile Asp Asn Leu Arg Ala Ser Leu Glu Thr 145 150 155 ACT AAT CAG GCA ATT GAG GCA ATC AGA CAA GCA GGG CAG GAG ATG ATA 5973 Thr Asn Gln Ala Ile Glu Ala Ile Arg Gln Ala Gly Gln Glu Met Ile 160 165 170 TTG GCT GTT CAG GGT GTC CAA GAC TAC ATC AAT AAT GAG CTG ATA CCG 6021 Leu Ala Val Gln Gly Val Gln Asp Tyr Ile Asn Asn Glu Leu Ile Pro 175 180 185 TCT ATG AAC CAA CTA TCT TGT GAT TTA ATC GGC CAG AAG CTC GGG CTC 6069 Ser Met Asn Gln Leu Ser Cys Asp Leu Ile Gly Gln Lys Leu Gly Leu 190 195 200 AAA TTG CTC AGA TAC TAT ACA GAA ATC CTG TCA TTA TTT GGC CCC AGC 6117 Lys Leu Leu Arg Tyr Tyr Thr Glu Ile Leu Ser Leu Phe Gly Pro Ser 205 210 215 220 TTA CGG GAC CCC ATA TCT GCG GAG ATA TCT ATC CAG GCT TTG AGC TAT 6165 Leu Arg Asp Pro Ile Ser Ala Glu Ile Ser Ile Gln Ala Leu Ser Tyr 225 230 235 GCG CTT GGA GGA GAC ATC AAT AAG GTG TTA GAA AAG CTC GGA TAC AGT 6213 Ala Leu Gly Gly Asp Ile Asn Lys Val Leu Glu Lys Leu Gly Tyr Ser 240 245 250 GGA GGT GAT TTA CTG GGC ATC TTA GAG AGC AGA GGA ATA AAG GCC CGG 6261 Gly Gly Asp Leu Leu Gly Ile Leu Glu Ser Arg Gly Ile Lys Ala Arg 255 260 265 ATA ACT CAC GTC GAC ACA GAG TCC TAC TTA ATT GTC CTC AGT ATA GCC 6309 Ile Thr His Val Asp Thr Glu Ser Tyr Leu Ile Val Leu Ser Ile Ala 270 275 280 TAT CCG ACG CTG TCC GAG ATT AAG GGG GTG ATT GTC CAC CGG CTA GAG 6357 Tyr Pro Thr Leu Ser Glu Ile Lys Gly Val Ile Val His Arg Leu Glu 285 290 295 300 GGG GTC TCG TAC AAC ATA GGC TCT CAA GAG TGG TAT ACC ACT GTG CCC 6405 Gly Val Ser Tyr Asn Ile Gly Ser Gln Glu Trp Tyr Thr Thr Val Pro 305 310 315 AAG TAT GTT GCA ACC CAA GGG TAC CTT ATC TCG AAT TTT GAT GAG TCA 6453 Lys Tyr Val Ala Thr Gln Gly Tyr Leu Ile Ser Asn Phe Asp Glu Ser 320 325 330 TCG TGT ACT TTC ATG CCA GAG GGG ACT GTG TGC AGC CAA AAT GCC TTG 6501 Ser Cys Thr Phe Met Pro Glu Gly Thr Val Cys Ser Gln Asn Ala Leu 335 340 345 TAC CCG ATG AGT CCT CTG CTC CAA GAA TGC CTC CGG GGG TCC ACC AAG 6549 Tyr Pro Met Ser Pro Leu Leu Gln Glu Cys Leu Arg Gly Ser Thr Lys 350 355 360 TCC TGT GCT CGT ACA CTC GTA TCC GGG TCT TTT GGG AAC CGG TTC ATT 6597 Ser Cys Ala Arg Thr Leu Val Ser Gly Ser Phe Gly Asn Arg Phe Ile 365 370 375 380 TTA TCA CAA GGG AAC CTA ATA GCC AAT TGT GCA TCA ATC CTT TGC AAG 6645 Leu Ser Gln Gly Asn Leu Ile Ala Asn Cys Ala Ser Ile Leu Cys Lys 385 390 395 TGT TAC ACA ACA GGA ACG ATC ATT AAT CAA GAC CCT GAC AAG ATC CTA 6693 Cys Tyr Thr Thr Gly Thr Ile Ile Asn Gln Asp Pro Asp Lys Ile Leu 400 405 410 ACA TAC ATT GCT GCC GAT CAC TGC CCG GTA GTC GAG GTG AAC GGC GTG 6741 Thr Tyr Ile Ala Ala Asp His Cys Pro Val Val Glu Val Asn Gly Val 415 420 425 ACC ATC CAA GTC GGG AGC AGG AGG TAT CCA GAC GCT GTG TAC TTG CAC 6789 Thr Ile Gln Val Gly Ser Arg Arg Tyr Pro Asp Ala Val Tyr Leu His 430 435 440 AGA ATT GAC CTC GGT CCT CCC ATA TTA TTG GAG AGG TTG GAC GTA GGG 6837 Arg Ile Asp Leu Gly Pro Pro Ile Leu Leu Glu Arg Leu Asp Val Gly 445 450 455 460 ACA AAT CTG GGG AAT GCA ATT GCT AAG TTG GAG GAT GCC AAG GAA TTG 6885 Thr Asn Leu Gly Asn Ala Ile Ala Lys Leu Glu Asp Ala Lys Glu Leu 465 470 475 TTG GAG TCA TCG GAC CAG ATA TTG AGG AGT ATG AAA GGT TTA TCG AGC 6933 Leu Glu Ser Ser Asp Gln Ile Leu Arg Ser Met Lys Gly Leu Ser Ser 480 485 490 ACT TGC ATA GTC TAC ATC CTG ATT GCA GTG TGT CTT GGA GGG TTG ATA 6981 Thr Cys Ile Val Tyr Ile Leu Ile Ala Val Cys Leu Gly Gly Leu Ile 495 500 505 GGG ATC CCC GCT TTA ATA TGT TGC TGC AGG GGG CGT TGT AAC AAA AAG 7029 Gly Ile Pro Ala Leu Ile Cys Cys Cys Arg Gly Arg Cys Asn Lys Lys 510 515 520 GGA GAA CAA GTT GGT ATG TCA AGA CCA GGC CTA AAG CCT GAT CTT ACG 7077 Gly Glu Gln Val Gly Met Ser Arg Pro Gly Leu Lys Pro Asp Leu Thr 525 530 535 540 GGA ACA TCA AAA TCC TAT GTA AGG TCG CTC TGATCCTCTA CAACTCTTGA 7127 Gly Thr Ser Lys Ser Tyr Val Arg Ser Leu 545 550 AACACAAATG TCCCACAAGT CTCCTCTTCG TCATCAAGCA ACCACCGCAC CCAGCATCAA 7187 GCCCACCTGA AATTATCTCC GGCTTCCCTC TGGCCGAACA ATATCGGTAG TTAATTAAAA 7247 CTTAGGGTGC AAGATCATCC ACA ATG TCA CCA CAA CGA GAC CGG ATA AAT GCC 7300 Met Ser Pro Gln Arg Asp Arg Ile Asn Ala 5 10 TTC TAC AAA GAT AAC CCC CAT CCC AAG GGA AGT AGG ATA GTC ATT AAC 7348 Phe Tyr Lys Asp Asn Pro His Pro Lys Gly Ser Arg Ile Val Ile Asn 15 20 25 AGA GAA CAT CTT ATG ATT GAT AGA CCT TAT GTT TTG CTG GCT GTT CTG 7396 Arg Glu His Leu Met Ile Asp Arg Pro Tyr Val Leu Leu Ala Val Leu 30 35 40 TTT GTC ATG TTT CTG AGC TTG ATC GGG TTG CTA GCC ATT GCA GGC ATT 7444 Phe Val Met Phe Leu Ser Leu Ile Gly Leu Leu Ala Ile Ala Gly Ile 45 50 55 AGA CTT CAT CGG GCA GCC ATC TAC ACC GCA GAG ATC CAT AAA AGC CTC 7492 Arg Leu His Arg Ala Ala Ile Tyr Thr Ala Glu Ile His Lys Ser Leu 60 65 70 AGC ACC AAT CTA GAT GTA ACT AAC TCA ATC GAG CAT CAG GTC AAG GAC 7540 Ser Thr Asn Leu Asp Val Thr Asn Ser Ile Glu His Gln Val Lys Asp 75 80 85 90 GTG CTG ACA CCA CTC TTC AAA ATC ATC GGT GAT GAA GTG GGC CTG AGG 7588 Val Leu Thr Pro Leu Phe Lys Ile Ile Gly Asp Glu Val Gly Leu Arg 95 100 105 ACA CCT CAG AGA TTC ACT GAC CTA GTG AAA TTC ATC TCT GAC AAG ATT 7636 Thr Pro Gln Arg Phe Thr Asp Leu Val Lys Phe Ile Ser Asp Lys Ile 110 115 120 AAA TTC CTT AAT CCG GAT AGG GAG TAC GAC TTC AGA GAT CTC ACT TGG 7684 Lys Phe Leu Asn Pro Asp Arg Glu Tyr Asp Phe Arg Asp Leu Thr Trp 125 130 135 TGT ATC AAC CCG CCA GAG AGA ATC AAA TTG GAT TAT GAT CAA TAC TGT 7732 Cys Ile Asn Pro Pro Glu Arg Ile Lys Leu Asp Tyr Asp Gln Tyr Cys 140 145 150 GCA GAT GTG GCT GCT GAA GAG CTC ATG AAT GCA TTG GTG AAC TCA ACT 7780 Ala Asp Val Ala Ala Glu Glu Leu Met Asn Ala Leu Val Asn Ser Thr 155 160 165 170 CTA CTG GAG ACC AGA ACA ACC AAT CAG TTC CTA GCT GTC TCA AAG GGA 7828 Leu Leu Glu Thr Arg Thr Thr Asn Gln Phe Leu Ala Val Ser Lys Gly 175 180 185 AAC TGC TCA GGG CCC ACT ACA ATC AGA GGT CAA TTC TCA AAC ATG TCG 7876 Asn Cys Ser Gly Pro Thr Thr Ile Arg Gly Gln Phe Ser Asn Met Ser 190 195 200 CTG TCC CTG TTA GAC TTG TAT TTA GGT CGA GGT TAC AAT GTG TCA TCT 7924 Leu Ser Leu Leu Asp Leu Tyr Leu Gly Arg Gly Tyr Asn Val Ser Ser 205 210 215 ATA GTC ACT ATG ACA TCC CAG GGA ATG TAT GGG GGA ACT TAC CTA GTG 7972 Ile Val Thr Met Thr Ser Gln Gly Met Tyr Gly Gly Thr Tyr Leu Val 220 225 230 GAA AAG CCT AAT CTG AGC AGC AAA AGG TCA GAG TTG TCA CAA CTG AGC 8020 Glu Lys Pro Asn Leu Ser Ser Lys Arg Ser Glu Leu Ser Gln Leu Ser 235 240 245 250 ATG TAC CGA GTG TTT GAA GTA GGT GTT ATC AGA AAT CCG GGT TTG GGG 8068 Met Tyr Arg Val Phe Glu Val Gly Val Ile Arg Asn Pro Gly Leu Gly 255 260 265 GCT CCG GTG TTC CAT ATG ACA AAC TAT CTT GAG CAA CCA GTC AGT AAT 8116 Ala Pro Val Phe His Met Thr Asn Tyr Leu Glu Gln Pro Val Ser Asn 270 275 280 GAT CTC AGC AAC TGT ATG GTG GCT TTG GGG GAG CTC AAA CTC GCA GCC 8164 Asp Leu Ser Asn Cys Met Val Ala Leu Gly Glu Leu Lys Leu Ala Ala 285 290 295 CTT TGT CAC CGG GAA GAT TCT ATC ACA ATT CCC TAT CAG GGA TCA GGG 8212 Leu Cys His Arg Glu Asp Ser Ile Thr Ile Pro Tyr Gln Gly Ser Gly 300 305 310 AAA GGT GTC AGC TTC CAG CTC GTC AAG CTA GGT GTC TGG AAA TCC CCA 8260 Lys Gly Val Ser Phe Gln Leu Val Lys Leu Gly Val Trp Lys Ser Pro 315 320 325 330 ACC GAC ATG CAA TCC TGG GTC ACC TTA TCA ACG GAT GAT CCA GTG ATA 8308 Thr Asp Met Gln Ser Trp Val Thr Leu Ser Thr Asp Asp Pro Val Ile 335 340 345 GAC AGG CTT TAC CTC TCA TCT CAC AGA GGT GTT ATC GCT GAC AAT CAA 8356 Asp Arg Leu Tyr Leu Ser Ser His Arg Gly Val Ile Ala Asp Asn Gln 350 355 360 GCA AAA TGG GCT GTC CCG ACA ACA CGA ACA GAT GAC AAG TTG CGA ATG 8404 Ala Lys Trp Ala Val Pro Thr Thr Arg Thr Asp Asp Lys Leu Arg Met 365 370 375 GAG ACA TGC TTC CAA CAG GCG TGT AAG GGT AAA ATC CAA GCA CTC TGC 8452 Glu Thr Cys Phe Gln Gln Ala Cys Lys Gly Lys Ile Gln Ala Leu Cys 380 385 390 GAG AAT CCC GAG TGG GCA CCA TTG AAG GAT AAC AGG ATT CCT TCA TAC 8500 Glu Asn Pro Glu Trp Ala Pro Leu Lys Asp Asn Arg Ile Pro Ser Tyr 395 400 405 410 GGG GTC TTG TCT GTT GAT CTG AGT CTG ACA GTT GAG CTT AAA ATC AAA 8548 Gly Val Leu Ser Val Asp Leu Ser Leu Thr Val Glu Leu Lys Ile Lys 415 420 425 ATT GCT TCG GGA TTC GGG CCA TTG ATC ACA CAC GGT TCA GGG ATG GAC 8596 Ile Ala Ser Gly Phe Gly Pro Leu Ile Thr His Gly Ser Gly Met Asp 430 435 440 CTA TAC AAA TCC AAC CAC AAC AAT GTG TAT TGG CTG ACT ATC CCA CCA 8644 Leu Tyr Lys Ser Asn His Asn Asn Val Tyr Trp Leu Thr Ile Pro Pro 445 450 455 ATG AAG AAC CTA GCC TTA GGT GTA ATC AAC ACA TTG GAG TGG ATA CCG 8692 Met Lys Asn Leu Ala Leu Gly Val Ile Asn Thr Leu Glu Trp Ile Pro 460 465 470 AGA TTC AAG GTT AGT CCC TAC CTC TTC AAT GTC CCA ATT AAG GAA GCA 8740 Arg Phe Lys Val Ser Pro Tyr Leu Phe Asn Val Pro Ile Lys Glu Ala 475 480 485 490 GGC GAA GAC TGC CAT GCC CCA ACA TAC CTA CCT GCG GAG GTG GAT GGT 8788 Gly Glu Asp Cys His Ala Pro Thr Tyr Leu Pro Ala Glu Val Asp Gly 495 500 505 GAT GTC AAA CTC AGT TCC AAT CTG GTG ATT CTA CCT GGT CAA GAT CTC 8836 Asp Val Lys Leu Ser Ser Asn Leu Val Ile Leu Pro Gly Gln Asp Leu 510 515 520 CAA TAT GTT TTG GCA ACC TAC GAT ACT TCC AGG GTT GAA CAT GCT GTG 8884 Gln Tyr Val Leu Ala Thr Tyr Asp Thr Ser Arg Val Glu His Ala Val 525 530 535 GTT TAT TAC GTT TAC AGC CCA AGC CGC TCA TTT TCT TAC TTT TAT CCT 8932 Val Tyr Tyr Val Tyr Ser Pro Ser Arg Ser Phe Ser Tyr Phe Tyr Pro 540 545 550 TTT AGG TTG CCT ATA AAG GGG GTC CCC ATC GAA TTA CAA GTG GAA TGC 8980 Phe Arg Leu Pro Ile Lys Gly Val Pro Ile Glu Leu Gln Val Glu Cys 555 560 565 570 TTC ACA TGG GAC CAA AAA CTC TGG TGC CGT CAC TTC TGT GTG CTT GCG 9028 Phe Thr Trp Asp Gln Lys Leu Trp Cys Arg His Phe Cys Val Leu Ala 575 580 585 GAC TCA GAA TCT GGT GGA CAT ATC ACT CAC TCT GGG ATG GTG GGC ATG 9076 Asp Ser Glu Ser Gly Gly His Ile Thr His Ser Gly Met Val Gly Met 590 595 600 GGA GTC AGC TGC ACA GTC ACC CGG GAA GAT GGA ACC AAT CGC AGA 9121 Gly Val Ser Cys Thr Val Thr Arg Glu Asp Gly Thr Asn Arg Arg 605 610 615 TAGGGCTGCT AGTGAACTAA TCTCATGATG TCACCCAGAC ATCAGGCATA CCCACTAGTG 9181 TGAAATAGAC ATCAGAATTA AGAAAAACGT AGGGTCCAAG TGGTTCCCCG TT ATG GAC 9239 Met Asp TCG CTA TCT GTC AAC CAG ATC TTA TAC CCT GAA GTT CAC CTA GAT AGC 9287 Ser Leu Ser Val Asn Gln Ile Leu Tyr Pro Glu Val His Leu Asp Ser 5 10 15 CCG ATA GTT ACC AAT AAG ATA GTA GCC ATC CTG GAG TAT GCT CGA GTT 9335 Pro Ile Val Thr Asn Lys Ile Val Ala Ile Leu Glu Tyr Ala Arg Val 20 25 30 CCT CAC GCT TAC AGC CTG GAG GAC CCT ACA CTG TGT CAG AAC ATC AAG 9383 Pro His Ala Tyr Ser Leu Glu Asp Pro Thr Leu Cys Gln Asn Ile Lys 35 40 45 50 CAC CGC CTA AAA AAC GGA TTT TCC AAC CAA ATG ATT ATA AAC AAT GTG 9431 His Arg Leu Lys Asn Gly Phe Ser Asn Gln Met Ile Ile Asn Asn Val 55 60 65 GAA GTT GGG AAT GTC ATC AAG TCC AAG CTT AGG AGT TAT CCG GCC CAC 9479 Glu Val Gly Asn Val Ile Lys Ser Lys Leu Arg Ser Tyr Pro Ala His 70 75 80 TCT CAT ATT CCA TAT CCA AAT TGT AAT CAG GAT TTA TTT AAC ATA GAA 9527 Ser His Ile Pro Tyr Pro Asn Cys Asn Gln Asp Leu Phe Asn Ile Glu 85 90 95 GAC AAA GAG TCA ACG AGG AAG ATC CGT GAA CTC CTC AAA AAG GGG AAT 9575 Asp Lys Glu Ser Thr Arg Lys Ile Arg Glu Leu Leu Lys Lys Gly Asn 100 105 110 TCG CTG TAC TCC AAA GTC AGT GAT AAG GTT TTC CAA TGC TTA AGG GAC 9623 Ser Leu Tyr Ser Lys Val Ser Asp Lys Val Phe Gln Cys Leu Arg Asp 115 120 125 130 ACT AAC TCA CGG CTT GGC CTA GGC TCC GAA TTG AGG GAG GAC ATC AAG 9671 Thr Asn Ser Arg Leu Gly Leu Gly Ser Glu Leu Arg Glu Asp Ile Lys 135 140 145 GAG AAA GTT ATT AAC TTG GGA GTT TAC ATG CAC AGC TCC CAG TGG TTT 9719 Glu Lys Val Ile Asn Leu Gly Val Tyr Met His Ser Ser Gln Trp Phe 150 155 160 GAG CCA TTT CTG TTT TGG TTT ACA GTC AAG ACT GAG ATG AGG TCA GTG 9767 Glu Pro Phe Leu Phe Trp Phe Thr Val Lys Thr Glu Met Arg Ser Val 165 170 175 ATT AAA TCA CAA ACC CAT ACT TGC CAT AGG AGG AGA CAC ACA CCT GTA 9815 Ile Lys Ser Gln Thr His Thr Cys His Arg Arg Arg His Thr Pro Val 180 185 190 TTC TTC ACT GGT AGT TCA GTT GAG TTG CTA ATC TCT CGT GAC CTT GTT 9863 Phe Phe Thr Gly Ser Ser Val Glu Leu Leu Ile Ser Arg Asp Leu Val 195 200 205 210 GCT ATA ATC AGT AAA GAG TCT CAA CAT GTA TAT TAC CTG ACA TTT GAA 9911 Ala Ile Ile Ser Lys Glu Ser Gln His Val Tyr Tyr Leu Thr Phe Glu 215 220 225 CTG GTT TTG ATG TAT TGT GAT GTC ATA GAG GGG AGG TTA ATG ACA GAG 9959 Leu Val Leu Met Tyr Cys Asp Val Ile Glu Gly Arg Leu Met Thr Glu 230 235 240 ACC GCT ATG ACT ATT GAT GCT AGG TAT ACA GAG CTT CTA GGA AGA GTC 10007 Thr Ala Met Thr Ile Asp Ala Arg Tyr Thr Glu Leu Leu Gly Arg Val 245 250 255 AGA TAC ATG TGG AAA CTG ATA GAT GGT TTC TTC CCT GCA CTC GGG AAT 10055 Arg Tyr Met Trp Lys Leu Ile Asp Gly Phe Phe Pro Ala Leu Gly Asn 260 265 270 CCA ACT TAT CAA ATT GTA GCC ATG CTG GAG CCT CTT TCA CTT GCT TAC 10103 Pro Thr Tyr Gln Ile Val Ala Met Leu Glu Pro Leu Ser Leu Ala Tyr 275 280 285 290 CTG CAG CTG AGG GAT ATA ACA GTA GAA CTC AGA GGT GCT TTC CTT AAC 10151 Leu Gln Leu Arg Asp Ile Thr Val Glu Leu Arg Gly Ala Phe Leu Asn 295 300 305 CAC TGC TTT ACT GAA ATA CAT GAT GTT CTT GAC CAA AAC GGG TTT TCT 10199 His Cys Phe Thr Glu Ile His Asp Val Leu Asp Gln Asn Gly Phe Ser 310 315 320 GAT GAA GGT ACT TAT CAT GAG TTA ATT GAA GCT CTA GAT TAC ATT TTC 10247 Asp Glu Gly Thr Tyr His Glu Leu Ile Glu Ala Leu Asp Tyr Ile Phe 325 330 335 ATA ACT GAT GAC ATA CAT CTG ACA GGG GAG ATT TTC TCA TTT TTC AGA 10296 Ile Thr Asp Asp Ile His Leu Thr Gly Glu Ile Phe Ser Phe Phe Arg 340 345 350 AGT TTC GGC CAC CCC AGA CTT GAA GCA GTA ACG GCT GCT GAA AAT GTT 10343 Ser Phe Gly His Pro Arg Leu Glu Ala Val Thr Ala Ala Glu Asn Val 355 360 365 370 AGG AAA TAC ATG AAT CAG CCT AAA GTC ATT GTG TAT GAG ACT CTG ATG 10391 Arg Lys Tyr Met Asn Gln Pro Lys Val Ile Val Tyr Glu Thr Leu Met 375 380 385 AAA GGT CAT GCC ATA TTT TGT GGA ATC ATA ATC AAC GGC TAT CGT GAC 10439 Lys Gly His Ala Ile Phe Cys Gly Ile Ile Ile Asn Gly Tyr Arg Asp 390 395 400 AGG CAC GGA GGC AGT TGG CCA CCG CTG ACC CTC CCC CTG CAT GCT GCA 10487 Arg His Gly Gly Ser Trp Pro Pro Leu Thr Leu Pro Leu His Ala Ala 405 410 415 GAC ACA ATC CGG AAT GCT CAA GCT TCA GGT GAA GGG TTA ACA CAT GAG 10535 Asp Thr Ile Arg Asn Ala Gln Ala Ser Gly Glu Gly Leu Thr His Glu 420 425 430 CAG TGC GTT GAT AAC TGG AAA TCT TTT GCT GGA GTG AAA TTT GGC TGC 10583 Gln Cys Val Asp Asn Trp Lys Ser Phe Ala Gly Val Lys Phe Gly Cys 435 440 445 450 TTT ATG CCT CTT AGC CTG GAT AGT GAT CTG ACA ATG TAC CTA AAG GAC 10631 Phe Met Pro Leu Ser Leu Asp Ser Asp Leu Thr Met Tyr Leu Lys Asp 455 460 465 AAG GCA CTT GCT GCT CTC CAA AGG GAA TGG GAT TCA GTT TAC CCG AAA 10679 Lys Ala Leu Ala Ala Leu Gln Arg Glu Trp Asp Ser Val Tyr Pro Lys 470 475 480 GAG TTC CTG CGT TAC GAC CCT CCC AAG GGA ACC GGG TCA CGG AGG CTT 10727 Glu Phe Leu Arg Tyr Asp Pro Pro Lys Gly Thr Gly Ser Arg Arg Leu 485 490 495 GTA GAT GTT TTC CTT AAT GAT TCG AGC TTT GAC CCA TAT GAT GTG ATA 10775 Val Asp Val Phe Leu Asn Asp Ser Ser Phe Asp Pro Tyr Asp Val Ile 500 505 510 ATG TAT GTT GTA AGT GGA GCT TAC CTC CAT GAC CCT GAG TTC AAC CTG 10823 Met Tyr Val Val Ser Gly Ala Tyr Leu His Asp Pro Glu Phe Asn Leu 515 520 525 530 TCT TAC AGC CTG AAA GAA AAG GAG ATC AAG GAA ACA GGT AGA CTT TTT 10871 Ser Tyr Ser Leu Lys Glu Lys Glu Ile Lys Glu Thr Gly Arg Leu Phe 535 540 545 GCT AAA ATG ACT TAC AAA ATG AGG GCA TGC CAA GTG ATT GCT GAA AAT 10919 Ala Lys Met Thr Tyr Lys Met Arg Ala Cys Gln Val Ile Ala Glu Asn 550 555 560 CTA ATC TCA AAC GGG ATT GGC AAA TAT TTT AAG GAC AAT GGG ATG GCC 10967 Leu Ile Ser Asn Gly Ile Gly Lys Tyr Phe Lys Asp Asn Gly Met Ala 565 570 575 AAG GAT GAG CAC GAT TTG ACT AAG GCA CTC CAC ACT CTA GCT GTC TCA 11015 Lys Asp Glu His Asp Leu Thr Lys Ala Leu His Thr Leu Ala Val Ser 580 585 590 GGA GTC CCC AAA GAT CTC AAA GAA AGT CAC AGG GGG GGG CCA GTC TTA 11063 Gly Val Pro Lys Asp Leu Lys Glu Ser His Arg Gly Gly Pro Val Leu 595 600 605 610 AAA ACC TAC TCC CGA AGC CCA GTC CAC ACA AGT ACC AGG AAC GTG AGA 11111 Lys Thr Tyr Ser Arg Ser Pro Val His Thr Ser Thr Arg Asn Val Arg 615 620 625 GCA GCA AAA GGG TTT ATA GGG TTC CCT CAA GTA ATT CGG CAG GAC CAA 11159 Ala Ala Lys Gly Phe Ile Gly Phe Pro Gln Val Ile Arg Gln Asp Gln 630 635 640 GAC ACT GAT CAT CCG GAG AAT ATG GAA GCT TAC GAG ACA GTC AGT GCA 11207 Asp Thr Asp His Pro Glu Asn Met Glu Ala Tyr Glu Thr Val Ser Ala 645 650 655 TTT ATC ACG ACT GAT CTC AAG AAG TAC TGC CTT AAT TGG AGA TAT GAG 11255 Phe Ile Thr Thr Asp Leu Lys Lys Tyr Cys Leu Asn Trp Arg Tyr Glu 660 665 670 ACC ATC AGC TTG TTT GCA CAG AGG CTA AAT GAG ATT TAC GGA TTG CCC 11303 Thr Ile Ser Leu Phe Ala Gln Arg Leu Asn Glu Ile Tyr Gly Leu Pro 675 680 685 690 TCA TTT TTC CAG TGG CTG CAT AAG AGG CTT GAG ACC TCT GTC CTG TAT 11351 Ser Phe Phe Gln Trp Leu His Lys Arg Leu Glu Thr Ser Val Leu Tyr 695 700 705 GTA AGT GAC CCT CAT TGC CCC CCC GAC CTT GAC GCC CAT ATC CCG TTA 11399 Val Ser Asp Pro His Cys Pro Pro Asp Leu Asp Ala His Ile Pro Leu 710 715 720 TAT AAA GTC CCC AAT GAT CAA ATC TTC ATT AAG TAC CCT ATG GGA GGT 11447 Tyr Lys Val Pro Asn Asp Gln Ile Phe Ile Lys Tyr Pro Met Gly Gly 725 730 735 ATA GAA GGG TAT TGT CAG AAG CTG TGG ACC ATC AGC ACC ATT CCC TAT 11495 Ile Glu Gly Tyr Cys Gln Lys Leu Trp Thr Ile Ser Thr Ile Pro Tyr 740 745 750 CTA TAC CTG GCT GCT TAT GAG AGC GGA GTA AGG ATT GCT TCG TTA GTG 11543 Leu Tyr Leu Ala Ala Tyr Glu Ser Gly Val Arg Ile Ala Ser Leu Val 755 760 765 770 CAA GGG GAC AAT CAG ACC ATA GCC GTA ACA AAA AGG GTA CCC AGC ACA 11591 Gln Gly Asp Asn Gln Thr Ile Ala Val Thr Lys Arg Val Pro Ser Thr 775 780 785 TGG CCC TAC AAC CTT AAG AAA CGG GAA GCT GCT AGA GTA ACT AGA GAT 11639 Trp Pro Tyr Asn Leu Lys Lys Arg Glu Ala Ala Arg Val Thr Arg Asp 790 795 800 TAC TTT GTA ATT CTT AGG CAA AGG CTA CAT GAT ATT GGC CAT CAC CTC 11687 Tyr Phe Val Ile Leu Arg Gln Arg Leu His Asp Ile Gly His His Leu 805 810 815 AAG GCA AAT GAG ACA ATT GTT TCA TCA CAT TTT TTT GTC TAT TCA AAA 11735 Lys Ala Asn Glu Thr Ile Val Ser Ser His Phe Phe Val Tyr Ser Lys 820 825 830 GGA ATA TAT TAT GAT GGG CTA CTT GTG TCC CAA TCA CTC AAG AGC ATC 11783 Gly Ile Tyr Tyr Asp Gly Leu Leu Val Ser Gln Ser Leu Lys Ser Ile 835 840 845 850 GCA AGA TGT GTA TTC TGG TCA GAG ACT ATA GTT GAT GAA ACA AGG GCA 11831 Ala Arg Cys Val Phe Trp Ser Glu Thr Ile Val Asp Glu Thr Arg Ala 855 860 865 GCA TGC AGT AAT ATT GCT ACA ACA ATG GCT AAA AGC ATC GAG AGA GGT 11879 Ala Cys Ser Asn Ile Ala Thr Thr Met Ala Lys Ser Ile Glu Arg Gly 870 875 880 TAT GAC CGT TAC CTT GCA TAT TCC CTG AAC GTC CTA AAA GTG ATA CAG 11927 Tyr Asp Arg Tyr Leu Ala Tyr Ser Leu Asn Val Leu Lys Val Ile Gln 885 890 895 CAA ATT CTG ATC TCT CTT GGC TTC ACA ATC AAT TCA ACC ATG ACC CGG 11975 Gln Ile Leu Ile Ser Leu Gly Phe Thr Ile Asn Ser Thr Met Thr Arg 900 905 910 GAT GTA GTC ATA CCC CTC CTC ACA AAC AAC GAC CTC TTA ATA AGG ATG 12023 Asp Val Val Ile Pro Leu Leu Thr Asn Asn Asp Leu Leu Ile Arg Met 915 920 925 930 GCA CTG TTG CCC GCT CCT ATT GGG GGG ATG AAT TAT CTG AAT ATG AGC 12071 Ala Leu Leu Pro Ala Pro Ile Gly Gly Met Asn Tyr Leu Asn Met Ser 935 940 945 AGG CTG TTT GTC AGA AAC ATC GGT GAT CCA GTA ACA TCA TCA ATT GCT 12119 Arg Leu Phe Val Arg Asn Ile Gly Asp Pro Val Thr Ser Ser Ile Ala 950 955 960 GAT CTC AAG AGA ATG ATT CTC GCC TCA CTA ATG CCT GAA GAG ACC CTC 12167 Asp Leu Lys Arg Met Ile Leu Ala Ser Leu Met Pro Glu Glu Thr Leu 965 970 975 CAT CAA GTA ATG ACA CAA CAA CCG GGG GAC TCT TCA TTC CTA GAC TGG 12215 His Gln Val Met Thr Gln Gln Pro Gly Asp Ser Ser Phe Leu Asp Trp 980 985 990 GCT AGC GAC CCT TAC TCA GCA AAT CTT GTA TGT GTC CAG AGC ATC ACT 12263 Ala Ser Asp Pro Tyr Ser Ala Asn Leu Val Cys Val Gln Ser Ile Thr 995 1000 1005 1010 AGA CTC CTC AAG AAC ATA ACT GCA AGG TTT GTC CTG ATC CAT AGT CCA 12311 Arg Leu Leu Lys Asn Ile Thr Ala Arg Phe Val Leu Ile His Ser Pro 1015 1020 1025 AAC CCA ATG TTA AAA GGA TTA TTC CAT GAT GAC AGT AAA GAA GAG GAC 12359 Asn Pro Met Leu Lys Gly Leu Phe His Asp Asp Ser Lys Glu Glu Asp 1030 1035 1040 GAG GGA CTG GCG GCA TTC CTC ATG GAC AGG CAT ATT ATA GTA CCT AGG 12407 Glu Gly Leu Ala Ala Phe Leu Met Asp Arg His Ile Ile Val Pro Arg 1045 1050 1055 GCA GCT CAT GAA ATC CTG GAT CAT AGT GTC ACA GGG GCA AGA GAG TCT 12455 Ala Ala His Glu Ile Leu Asp His Ser Val Thr Gly Ala Arg Glu Ser 1060 1065 1070 ATT GCA GGC ATG CTG GAT ACC ACA AAA GGC CTG ATT CGA GCC AGC ATG 12503 Ile Ala Gly Met Leu Asp Thr Thr Lys Gly Leu Ile Arg Ala Ser Met 1075 1080 1085 1090 AGG AAG GGG GGG TTA ACC TCT CGA GTG ATA ACC AGA TTG TCC AAT TAT 12551 Arg Lys Gly Gly Leu Thr Ser Arg Val Ile Thr Arg Leu Ser Asn Tyr 1095 1100 1105 GAC TAT GAA CAA TTC AGA GCA GGG ATG GTG CTA TTG ACG GGA AGA AAG 12599 Asp Tyr Glu Gln Phe Arg Ala Gly Met Val Leu Leu Thr Gly Arg Lys 1110 1115 1120 AGA AAT GTC CTC ATT GAC AAA GAG TCA TGT TCA GTG CAG CTG GCG AGA 12647 Arg Asn Val Leu Ile Asp Lys Glu Ser Cys Ser Val Gln Leu Ala Arg 1125 1130 1135 GCT CTA AGA AGC CAT ATG TGG GCG AGG CTA GCT CGA GGA CGG CCT ATT 12695 Ala Leu Arg Ser His Met Trp Ala Arg Leu Ala Arg Gly Arg Pro Ile 1140 1145 1150 TAC GGC CTT GAG GTC CCT GAT GTA CTA GAA TCT ATG CGA GGC CAC CTT 12743 Tyr Gly Leu Glu Val Pro Asp Val Leu Glu Ser Met Arg Gly His Leu 1155 1160 1165 1170 ATT CGG CGT CAT GAG ACA TGT GTC ATC TGC GAG TGT GGA TCA GTC AAC 12791 Ile Arg Arg His Glu Thr Cys Val Ile Cys Glu Cys Gly Ser Val Asn 1175 1180 1185 TAC GGA TGG TTT TTT GTC CCC TCG GGT TGC CAA CTG GAT GAT ATT GAC 12839 Tyr Gly Trp Phe Phe Val Pro Ser Gly Cys Gln Leu Asp Asp Ile Asp 1190 1195 1200 AAG GAA ACA TCA TCC TTG AGA GTC CCA TAT ATT GGT TCT ACC ACT GAT 12887 Lys Glu Thr Ser Ser Leu Arg Val Pro Tyr Ile Gly Ser Thr Thr Asp 1205 1210 1215 GAG AGA ACA GAC ATG AAG CTT GCC TTC GTA AGA GCC CCA AGT CGA TCC 12935 Glu Arg Thr Asp Met Lys Leu Ala Phe Val Arg Ala Pro Ser Arg Ser 1220 1225 1230 TTG CGA TCT GCT GTT AGA ATA GCA ACA GTG TAC TCA TGG GCT TAC GGT 12983 Leu Arg Ser Ala Val Arg Ile Ala Thr Val Tyr Ser Trp Ala Tyr Gly 1235 1240 1245 1250 GAT GAT GAT AGC TCT TGG AAC GAA GCC TGG TTG TTG GCT AGG CAA AGG 13031 Asp Asp Asp Ser Ser Trp Asn Glu Ala Trp Leu Leu Ala Arg Gln Arg 1255 1260 1265 GCC AAT GTG AGC CTG GAG GAG CTA AGG GTG ATC ACT CCC ATC TCA ACT 13079 Ala Asn Val Ser Leu Glu Glu Leu Arg Val Ile Thr Pro Ile Ser Thr 1270 1275 1280 TCG ACT AAT TTA GCG CAT AGG TTG AGG GAT CGT AGC ACT CAA GTG AAA 13127 Ser Thr Asn Leu Ala His Arg Leu Arg Asp Arg Ser Thr Gln Val Lys 1285 1290 1295 TAC TCA GGT ACA TCC CTT GTC CGA GTG GCG AGG TAT ACC ACA ATC TCC 13175 Tyr Ser Gly Thr Ser Leu Val Arg Val Ala Arg Tyr Thr Thr Ile Ser 1300 1305 1310 AAC GAC AAT CTC TCA TTT GTC ATA TCA GAT AAG AAG GTT GAT ACT AAC 13223 Asn Asp Asn Leu Ser Phe Val Ile Ser Asp Lys Lys Val Asp Thr Asn 1315 1320 1325 1330 TTT ATA TAC CAA CAA GGA ATG CTT CTA GGG TTG GGT GTT TTA GAA ACA 13271 Phe Ile Tyr Gln Gln Gly Met Leu Leu Gly Leu Gly Val Leu Glu Thr 1335 1340 1345 TTG TTT CGA CTC GAG AAA GAT ACC GGA TCA TCT AAC ACG GTA TTA CAT 13319 Leu Phe Arg Leu Glu Lys Asp Thr Gly Ser Ser Asn Thr Val Leu His 1350 1355 1360 CTT CAC GTC GAA ACA GAT TGT TGC GTG ATC CCG ATG ATA GAT CAT CCC 13367 Leu His Val Glu Thr Asp Cys Cys Val Ile Pro Met Ile Asp His Pro 1365 1370 1375 AGG ATA CCC AGC TCC CGC AAG CTA GAG CTG AGG GCA GAG CTA TGT ACC 13415 Arg Ile Pro Ser Ser Arg Lys Leu Glu Leu Arg Ala Glu Leu Cys Thr 1380 1385 1390 AAC CCA TTG ATA TAT GAT AAT GCA CCT TTA ATT GAC AGA GAT ACA ACA 13463 Asn Pro Leu Ile Tyr Asp Asn Ala Pro Leu Ile Asp Arg Asp Thr Thr 1395 1400 1405 1410 AGG CTA TAC ACC CAG AGC CAT AGG AGG CAC CTT GTG GAA TTT GTT ACA 13511 Arg Leu Tyr Thr Gln Ser His Arg Arg His Leu Val Glu Phe Val Thr 1415 1420 1425 TGG TCC ACA CCC CAA CTA TAT CAC ATT TTA GCT AAG TCC ACA GCA CTA 13559 Trp Ser Thr Pro Gln Leu Tyr His Ile Leu Ala Lys Ser Thr Ala Leu 1430 1435 1440 TCT ATG ATT GAC CTG GTA ACA AAA TTT GAG AAG GAC CAT ATG AAT GAA 13607 Ser Met Ile Asp Leu Val Thr Lys Phe Glu Lys Asp His Met Asn Glu 1445 1450 1455 ATT TCA GCT CTC ATA GGG GAT GAC GAT ATC AAT AGT TTC ATA ACT GAG 13655 Ile Ser Ala Leu Ile Gly Asp Asp Asp Ile Asn Ser Phe Ile Thr Glu 1460 1465 1470 TTT CTC GTC ATA GAG CCA AGA TTA TTC ACT ATC TAC TTG GGC CAG TGT 13703 Phe Leu Val Ile Glu Pro Arg Leu Phe Thr Ile Tyr Leu Gly Gln Cys 1475 1480 1485 1490 GCG GCC ATC AAT TGG GCA TTT GAT GTA CAT TAT CAT AGA CCA TCA GGG 13751 Ala Ala Ile Asn Trp Ala Phe Asp Val His Tyr His Arg Pro Ser Gly 1495 1500 1505 AAA TAT CAG ATG GGT GAG CTG TTG TCA TCG TTC CTT TCT AGA ATG AGC 13799 Lys Tyr Gln Met Gly Glu Leu Leu Ser Ser Phe Leu Ser Arg Met Ser 1510 1515 1520 AAA GGA GTG TTT AAG GTG CTT GTC AAT GCT CTA AGC CAC CCA AAG ATC 13847 Lys Gly Val Phe Lys Val Leu Val Asn Ala Leu Ser His Pro Lys Ile 1525 1530 1535 TAC AAG AAA TTC TGG CAT TGT GGT ATT ATA GAG CCT ATC CAT GGT CCT 13895 Tyr Lys Lys Phe Trp His Cys Gly Ile Ile Glu Pro Ile His Gly Pro 1540 1545 1550 TCA CTT GAT GCT CAA AAC TTG CAC ACA ACT GTG TGC AAC ATG GTT TAC 13943 Ser Leu Asp Ala Gln Asn Leu His Thr Thr Val Cys Asn Met Val Tyr 1555 1560 1565 1570 ACA TGC TAT ATG ACC TAC CTC GAC CTG TTG TTG AAT GAA GAG TTA GAA 13991 Thr Cys Tyr Met Thr Tyr Leu Asp Leu Leu Leu Asn Glu Glu Leu Glu 1575 1580 1585 GAG TTC ACA TTT CTC TTG TGT GAA AGC GAC GAG GAT GTA GTA CCG GAC 14039 Glu Phe Thr Phe Leu Leu Cys Glu Ser Asp Glu Asp Val Val Pro Asp 1590 1595 1600 AGA TTC GAC AAC ATC CAG GCA AAA CAC TTA TGT GTT CTG GCA GAT TTG 14087 Arg Phe Asp Asn Ile Gln Ala Lys His Leu Cys Val Leu Ala Asp Leu 1605 1610 1615 TAC TGT CAA CCA GGG GCC TGC CCA CCA ATT CGA GGT CTA AGA CCG GTA 14135 Tyr Cys Gln Pro Gly Ala Cys Pro Pro Ile Arg Gly Leu Arg Pro Val 1620 1625 1630 GAG AAA TGT GCA GTT CTA ACC GAC CAT ATC AAG GCA GAG GCT AGG TTA 14183 Glu Lys Cys Ala Val Leu Thr Asp His Ile Lys Ala Glu Ala Arg Leu 1635 1640 1645 1650 TCT CCA GCA GGA TCT TCG TGG AAC ATA AAT CCA ATT ATT GTA GAC CAT 14231 Ser Pro Ala Gly Ser Ser Trp Asn Ile Asn Pro Ile Ile Val Asp His 1655 1660 1665 TAC TCA TGC TCT CTG ACT TAT CTC CGG CGA GGA TCG ATC AAA CAG ATA 14279 Tyr Ser Cys Ser Leu Thr Tyr Leu Arg Arg Gly Ser Ile Lys Gln Ile 1670 1675 1680 AGA TTG AGA GTT GAT CCA GGA TTC ATT TTC GAC GCC CTC GCT GAG GTA 14327 Arg Leu Arg Val Asp Pro Gly Phe Ile Phe Asp Ala Leu Ala Glu Val 1685 1690 1695 AAT GTC AGT CAG CCA AAG ATC GGC AGC AAC AAC ATC TCA AAT ATG AGC 14375 Asn Val Ser Gln Pro Lys Ile Gly Ser Asn Asn Ile Ser Asn Met Ser 1700 1705 1710 ATC AAG GCT TTC AGA CCC CCA CAC GAT GAT GTT GCA AAA TTG CTC AAA 14423 Ile Lys Ala Phe Arg Pro Pro His Asp Asp Val Ala Lys Leu Leu Lys 1715 1720 1725 1730 GAT ATC AAC ACA AGC AAG CAC AAT CTT CCC ATT TCA GGG GGC AAT CTC 14471 Asp Ile Asn Thr Ser Lys His Asn Leu Pro Ile Ser Gly Gly Asn Leu 1735 1740 1745 GCC AAT TAT GAA ATC CAT GCT TTC CGC AGA ATC GGG TTG AAC TCA TCT 14519 Ala Asn Tyr Glu Ile His Ala Phe Arg Arg Ile Gly Leu Asn Ser Ser 1750 1755 1760 GCT TGC TAC AAA GCT GTT GAG ATA TCA ACA TTA ATT AGG AGA TGC CTT 14567 Ala Cys Tyr Lys Ala Val Glu Ile Ser Thr Leu Ile Arg Arg Cys Leu 1765 1770 1775 GAG CCA GGG GAG GAC GGC TTG TTC TTG GGT GAG GGA TCG GGT TCT ATG 14615 Glu Pro Gly Glu Asp Gly Leu Phe Leu Gly Glu Gly Ser Gly Ser Met 1780 1785 1790 TTG ATC ACT TAT AAG GAG ATA CTT AAA CTA AAC AAG TGC TTC TAT AAT 14663 Leu Ile Thr Tyr Lys Glu Ile Leu Lys Leu Asn Lys Cys Phe Tyr Asn 1795 1800 1805 1810 AGT GGG GTT TCC GCC AAT TCT AGA TCT GGT CAA AGG GAA TTA GCA CCC 14711 Ser Gly Val Ser Ala Asn Ser Arg Ser Gly Gln Arg Glu Leu Ala Pro 1815 1820 1825 TAT CCC TCC GAA GTT GGC CTT GTC GAA CAC AGA ATG GGA GTA GGT AAT 14759 Tyr Pro Ser Glu Val Gly Leu Val Glu His Arg Met Gly Val Gly Asn 1830 1835 1840 ATT GTC AAA GTG CTC TTT AAC GGG AGG CCC GAA GTC ACG TGG GTA GGC 14807 Ile Val Lys Val Leu Phe Asn Gly Arg Pro Glu Val Thr Trp Val Gly 1845 1850 1855 AGT GTA GAT TGC TTC AAT TTC ATA GTT AGT AAT ATC CCT ACC TCT AGT 14855 Ser Val Asp Cys Phe Asn Phe Ile Val Ser Asn Ile Pro Thr Ser Ser 1860 1865 1870 GTG GGG TTT ATC CAT TCA GAT ATA GAG ACC TTG CCT AAC AAA GAT ACT 14903 Val Gly Phe Ile His Ser Asp Ile Glu Thr Leu Pro Asn Lys Asp Thr 1875 1880 1885 1890 ATA GAG AAG CTA GAG GAA TTG GCA GCC ATC TTA TCG ATG GCT CTG CTC 14951 Ile Glu Lys Leu Glu Glu Leu Ala Ala Ile Leu Ser Met Ala Leu Leu 1895 1900 1905 CTG GGC AAA ATA GGA TCA ATA CTG GTG ATT AAG CTT ATG CCT TTC AGC 14999 Leu Gly Lys Ile Gly Ser Ile Leu Val Ile Lys Leu Met Pro Phe Ser 1910 1915 1920 GGG GAT TTT GTT CAG GGA TTT ATA AGT TAT GTA GGG TCT TAT TAT AGA 15047 Gly Asp Phe Val Gln Gly Phe Ile Ser Tyr Val Gly Ser Tyr Tyr Arg 1925 1930 1935 GAA GTG AAC CTT GTA TAC CCT AGA TAC AGC AAC TTC ATA TCT ACT GAA 15095 Glu Val Asn Leu Val Tyr Pro Arg Tyr Ser Asn Phe Ile Ser Thr Glu 1940 1945 1950 TCT TAT TTG GTT ATG ACA GAT CTC AAG GCT AAC CGG CTA ATG AAT CCT 15143 Ser Tyr Leu Val Met Thr Asp Leu Lys Ala Asn Arg Leu Met Asn Pro 1955 1960 1965 1970 GAA AAG ATT AAG CAG CAG ATA ATT GAA TCA TCT GTG AGG ACT TCA CCT 15191 Glu Lys Ile Lys Gln Gln Ile Ile Glu Ser Ser Val Arg Thr Ser Pro 1975 1980 1985 GGA CTT ATA GGT CAC ATC CTA TCC ATT AAG CAA CTA AGC TGC ATA CAA 15239 Gly Leu Ile Gly His Ile Leu Ser Ile Lys Gln Leu Ser Cys Ile Gln 1990 1995 2000 GCA ATT GTG GGA GAC GTA GTT AGT AGA GGT GAT ATC AAT CCT ACT CTG 15287 Ala Ile Val Gly Asp Val Val Ser Arg Gly Asp Ile Asn Pro Thr Leu 2005 2010 2015 AAA AAA CTT ACA CCT ATA GAG CAG GTG CTG ATC AAT TGC GGG TTG GCA 15335 Lys Lys Leu Thr Pro Ile Glu Gln Val Leu Ile Asn Cys Gly Leu Ala 2020 2025 2030 ATT AAC GGA CCT AAG CTG TGC AAA GAA TTG ATC CAC CAT GAT GTT GCC 15383 Ile Asn Gly Pro Lys Leu Cys Lys Glu Leu Ile His His Asp Val Ala 2035 2040 2045 2050 TCA GGG CAA GAT GGA TTG CTT AAT TCT ATC CTC ATC CTC TAC AGG GAG 15431 Ser Gly Gln Asp Gly Leu Leu Asn Ser Ile Leu Ile Leu Tyr Arg Glu 2055 2060 2065 TTG GCA AGA TTC AAA GAC AAC CGA AGA AGT CAA CAA GGG ATG TTC CAC 15479 Leu Ala Arg Phe Lys Asp Asn Arg Arg Ser Gln Gln Gly Met Phe His 2070 2075 2080 GCT TAC CCC GTA TTG GTA AGT AGC AGG CAA CGA GAA CTT ATA TCT AGG 15527 Ala Tyr Pro Val Leu Val Ser Ser Arg Gln Arg Glu Leu Ile Ser Arg 2085 2090 2095 ATC ACC CGC AAA TTT TGG GGG CAC ATT CTT CTT TAC TCC GGG AAC AGA 15575 Ile Thr Arg Lys Phe Trp Gly His Ile Leu Leu Tyr Ser Gly Asn Arg 2100 2105 2110 AAG TTG ATA AAT AAG TTT ATC CAG AAT CTC AAG TCC GGC TAT CTG ATA 15623 Lys Leu Ile Asn Lys Phe Ile Gln Asn Leu Lys Ser Gly Tyr Leu Ile 2115 2120 2125 2130 CTA GAC TTA CAC CAG AAT ATC TTC GTT AAG AAT CTA TCC AAG TCA GAG 15671 Leu Asp Leu His Gln Asn Ile Phe Val Lys Asn Leu Ser Lys Ser Glu 2135 2140 2145 AAA CAG ATT ATT ATG ACG GGG GGT TTG AAA CGT GAG TGG GTT TTT AAG 15719 Lys Gln Ile Ile Met Thr Gly Gly Leu Lys Arg Glu Trp Val Phe Lys 2150 2155 2160 GTA ACA GTC AAG GAG ACC AAA GAA TGG TAT AAG TTA GTC GGA TAC AGT 15767 Val Thr Val Lys Glu Thr Lys Glu Trp Tyr Lys Leu Val Gly Tyr Ser 2165 2170 2175 GCC CTG ATT AAG GAC TAATTGGTTG AACTCCGGAA CCCTAATCCT GCCCTAGGTG 15822 Ala Leu Ile Lys Asp 2180 GTTAGGCATT ATTTGCAATA TATTAAAGAA AACTTTGAAA ATACGAAGTT TCTATTCCCA 15882 GCTTTGTCTG GT 15894
【図面の簡単な説明】
【図１】ｃＤＮＡ作成の概略を示す模式図である。
【図２】ＡＩＫ−Ｃのフイジカルマツプ及び獲得ｃＤＮ
Ａの位置を示すものである。
【図３】合成プライマーの塩基配列を示すものである。
フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) C12N 15/00 - 15/90 A61P 31/12 C12N 7/00 - 7/08 C12Q 1/00 - 1/70 ＢＩＯＳＩＳ（ＤＩＡＬＯＧ) ＧｅｎＢａｎｋ／ＥＭＢＬ／ＤＤＢＪ（Ｇ ＥＮＥＴＹＸ) ＷＰＩ（ＤＩＡＬＯＧ)

Claims (5)

    (57)【特許請求の範囲】
  1. 【請求項１】 麻疹ワクチンウイルス株のゲノムＲＮＡ
    に相当するｃＤＮＡの配列を決定し、該決定配列を下記
    に記載のＤＮＡ配列と比較することを含む麻疹ワクチン
    ウイルス株同定方法。 ACCAAACAAA GTTGGGTAAG GATAGTTCAA TCAATGATCA TCTTCTAGTG CACTTAGGAT 60 TCAAGATCCT ATTATCAGGG ACAAGAGCAG GATTAGGGAT ATCCGAG ATG GCC ACA 116 Met Ala Thr CTT TTA AGG AGC TTA GCA TTG TTC AAA AGA AAC AAG GAC AAA CCA CCC 164 Leu Leu Arg Ser Leu Ala Leu Phe Lys Arg Asn Lys Asp Lys Pro Pro 5 10 15 ATT ACA TCA GGA TCC GGT GGA GCC ATC AGA GGA ATC AAA CAC ATT ATT 212 Ile Thr Ser Gly Ser Gly Gly Ala Ile Arg Gly Ile Lys His Ile Ile 20 25 30 35 ATA GTA CCA ATC CCT GGA GAT TCC TCA ATT ACC ACT CGA TCC AGA CTT 260 Ile Val Pro Ile Pro Gly Asp Ser Ser Ile Thr Thr Arg Ser Arg Leu 40 45 50 CTG GAC CGG TTG GTC AGG TTA ATT GGA AAC CCG GAT GTG AGC GGG CCC 308 Leu Asp Arg Leu Val Arg Leu Ile Gly Asn Pro Asp Val Ser Gly Pro 55 60 65 AAA CTA ACA GGG GCA CTA ATA GGT ATA TTA TCC TTA TTT GTG GAG TCT 356 Lys Leu Thr Gly Ala Leu Ile Gly Ile Leu Ser Leu Phe Val Glu Ser 70 75 80 CCA GGT CAA TTG ATT CAG AGG ATC ACC GAT GAC CCT GAC GTT AGC ATA 404 Pro Gly Gln Leu Ile Gln Arg Ile Thr Asp Asp Pro Asp Val Ser Ile 85 90 95 AGG CTG TTA GAG GTT GTC CAG AGT GAC CAG TCA CAA TCT GGC CTT ACC 452 Arg Leu Leu Glu Val Val Gln Ser Asp Gln Ser Gln Ser Gly Leu Thr 100 105 110 115 TTC GCA TCA AGA GGT ACC AAC ATG GAG GAT GAG GCG GAC AAA TAC TTT 500 Phe Ala Ser Arg Gly Thr Asn Met Glu Asp Glu Ala Asp Lys Tyr Phe 120 125 130 TCA CAT GAT GAT CCA ATT AGT AGT GAT CAA TCC AGG TTC GGA TGG TTC 548 Ser His Asp Asp Pro Ile Ser Ser Asp Gln Ser Arg Phe Gly Trp Phe 135 140 145 GAG AAC AAG GAA ATC TCA GAT ATT GAA GTG CAA GAC CCT GAG GGA TTC 596 Glu Asn Lys Glu Ile Ser Asp Ile Glu Val Gln Asp Pro Glu Gly Phe 150 155 160 AAC ATG ATT CTG GGT ACC ATC CTA GCC CAA ATT TGG GTC TTG CTC GCA 644 Asn Met Ile Leu Gly Thr Ile Leu Ala Gln Ile Trp Val Leu Leu Ala 165 170 175 AAG GCG GTT ACG GCC CCA GAC ACG GCA GCT GAT TCG GAG CTA AGA AGG 692 Lys Ala Val Thr Ala Pro Asp Thr Ala Ala Asp Ser Glu Leu Arg Arg 180 185 190 195 TGG ATA AAG TAC ACC CAA CAA AGA AGG GTA GTT GGT GAA TTT AGA TTG 740 Trp Ile Lys Tyr Thr Gln Gln Arg Arg Val Val Gly Glu Phe Arg Leu 200 205 210 GAG AGA AAA TGG TTG GAT GTG GTG AGG AAC AGG ATT GCC GAG GAC CTC 788 Glu Arg Lys Trp Leu Asp Val Val Arg Asn Arg Ile Ala Glu Asp Leu 215 220 225 TCC TTA CGC CGA TTC ATG GTC GCT CTA ATC CTG GAT ATC AAG AGA ACA 836 Ser Leu Arg Arg Phe Met Val Ala Leu Ile Leu Asp Ile Lys Arg Thr 230 235 240 CCC GGA AAC AAA CCC AGG ATT GCT GAA ATG ATA TGT GAC ATT GAT ACA 884 Pro Gly Asn Lys Pro Arg Ile Ala Glu Met Ile Cys Asp Ile Asp Thr 245 250 255 TAT ATC GTA GAG GCA GGA TTA GCC AGT TTT ATC CTG ACT ATT AAG TTT 932 Tyr Ile Val Glu Ala Gly Leu Ala Ser Phe Ile Leu Thr Ile Lys Phe 260 265 270 275 GGG ATA GAA ACT ATG TAT CCT GCT CTT GGA CTG CAT GAA TTT GCT GGT 980 Gly Ile Glu Thr Met Tyr Pro Ala Leu Gly Leu His Glu Phe Ala Gly 280 285 290 GAG TTA TCC ACA CTT GAG TCC TTG ATG AAC CTT TAC CAG CAA ATG GGG 1028 Glu Leu Ser Thr Leu Glu Ser Leu Met Asn Leu Tyr Gln Gln Met Gly 295 300 305 GAA ACT GCA CCC TAC ATG GTA AAC CTG GAG AAC TCA ATT CAG AAC AAG 1076 Glu Thr Ala Pro Tyr Met Val Asn Leu Glu Asn Ser Ile Gln Asn Lys 310 315 320 TTC AGT GCA GGA TCA TAC CCT CTG CTC TGG AGC TAT GCC ATG GGA GTA 1124 Phe Ser Ala Gly Ser Tyr Pro Leu Leu Trp Ser Tyr Ala Met Gly Val 325 330 335 GGA GTG GAA CTT GAA AAC TCC ATG GGA GGT TTG AAC TTT GGC CGA TCT 1172 Gly Val Glu Leu Glu Asn Ser Met Gly Gly Leu Asn Phe Gly Arg Ser 340 345 350 355 TAC TTT GAT CCA GCA TAT TTT AGA TTA GGG CAA GAG ATG GTA AGG AGG 1220 Tyr Phe Asp Pro Ala Tyr Phe Arg Leu Gly Gln Glu Met Val Arg Arg 360 365 370 TCA GCT GGA AAG GTC AGT TCC ACA TTG GCA TCT GAA CTC GGT ATC ACT 1268 Ser Ala Gly Lys Val Ser Ser Thr Leu Ala Ser Glu Leu Gly Ile Thr 375 380 385 GCC GAG GAT GCA AGG CTT GTT TCA GAG ATT GCA ATG CAT ACT ACT GAG 1316 Ala Glu Asp Ala Arg Leu Val Ser Glu Ile Ala Met His Thr Thr Glu 390 395 400 GAC AAG ATC AGT AGA GCG GTT GGA CCC AGA CAA GCC CAA GTA TCA TTT 1364 Asp Lys Ile Ser Arg Ala Val Gly Pro Arg Gln Ala Gln Val Ser Phe 405 410 415 CTA CAC GGT GAT CAA AGT GAG AAT GAG CTA CCG AGA TTG GGG GGC AAG 1412 Leu His Gly Asp Gln Ser Glu Asn Glu Leu Pro Arg Leu Gly Gly Lys 420 425 430 435 GAA GAT AGG AGG GTC AAA CAG AGT CGA GGA GAA GCC AGG GAG AGC TAC 1460 Glu Asp Arg Arg Val Lys Gln Ser Arg Gly Glu Ala Arg Glu Ser Tyr 440 445 450 AGA GAA ACC GGG CCC AGC AGA GCA AGT GAT GCG AGA GCT GCC CAT CTT 1508 Arg Glu Thr Gly Pro Ser Arg Ala Ser Asp Ala Arg Ala Ala His Leu 455 460 465 CCA ACC GGC ACA CCC CTA GAC ATT GAC ACT GCA TCG GAG TCC AGC CAA 1556 Pro Thr Gly Thr Pro Leu Asp Ile Asp Thr Ala Ser Glu Ser Ser Gln 470 475 480 GAT CCG CAG GAC AGT CGA AGG TCA GCT GAC GCC CTG CTT AGG CTG CAA 1604 Asp Pro Gln Asp Ser Arg Arg Ser Ala Asp Ala Leu Leu Arg Leu Gln 485 490 495 GCC ATG GCA GGA ATC TCG GAA GAA CAA GGC TCA GAC ACG GAC ACC CCT 1652 Ala Met Ala Gly Ile Ser Glu Glu Gln Gly Ser Asp Thr Asp Thr Pro 500 505 510 515 ATA GTG TAC AAT GAC AGA AAT CTT CTA GAC TAGGTGCGAG AGGCCGAGGA 1702 Ile Val Tyr Asn Asp Arg Asn Leu Leu Asp 520 525 CCAGAACAAC ATCCGCCTAC CCTCCATCAT TGTTATAAAA AACTTAGGAA CCAGGTCCAC 1762 ACAGCCGCCA GCCCATCAAC CATCCACTCC CACGATTGGA GCCG ATG GCA GAA GAG 1818 Met Ala Glu Glu CAG GCA CGC CAT GTC AAA AAC GGA CTG GAA TGC ATC CGG GCT CTC AAG 1866 Gln Ala Arg His Val Lys Asn Gly Leu Glu Cys Ile Arg Ala Leu Lys 5 10 15 20 GCC GAG CCC ATC GGC TCA CTG GCC ATC GAG GAA GCT ATG GCA GCA TGG 1914 Ala Glu Pro Ile Gly Ser Leu Ala Ile Glu Glu Ala Met Ala Ala Trp 25 30 35 TCA GAA ATA TCA GAC AAC CCA GGA CAG GAG CGA GCC ACC TGC AGG GAA 1962 Ser Glu Ile Ser Asp Asn Pro Gly Gln Glu Arg Ala Thr Cys Arg Glu 40 45 50 GAG AAG GCA GGC AGT TCG GGT CTC AGC AAA CCA TGC CTC TCA GCA ATT 2010 Glu Lys Ala Gly Ser Ser Gly Leu Ser Lys Pro Cys Leu Ser Ala Ile 55 60 65 GGA TCA ACT GAA GGC GGT GCA CCT CGC ATC CGC GGT CAG GGA CCT GGA 2058 Gly Ser Thr Glu Gly Gly Ala Pro Arg Ile Arg Gly Gln Gly Pro Gly 70 75 80 GAG AGC GAT GAC GAC GCT GAA ACT TTG GGA ATC CCC CCA AGA AAT CTC 2106 Glu Ser Asp Asp Asp Ala Glu Thr Leu Gly Ile Pro Pro Arg Asn Leu 85 90 95 100 CAG GCA TCA AGC ACT GGG TTA CAG TGT TAT TAT GTT TAT GAT CAC AGC 2154 Gln Ala Ser Ser Thr Gly Leu Gln Cys Tyr Tyr Val Tyr Asp His Ser 105 110 115 GGT GAA GCG GTT AAG GGA ATC CAA GAT GCT GAC TCT ATC ATG GTT CAA 2202 Gly Glu Ala Val Lys Gly Ile Gln Asp Ala Asp Ser Ile Met Val Gln 120 125 130 TCA GGC CTT GAT GGT GAT AGC ACC CTA TCA GGA GGA GAC AAT GAA TCT 2250 Ser Gly Leu Asp Gly Asp Ser Thr Leu Ser Gly Gly Asp Asn Glu Ser 135 140 145 GAA AAC AGC GAT GTG GAT ATT GGC GAA CCT GAT ACC GAG GGA TAT GCT 2298 Glu Asn Ser Asp Val Asp Ile Gly Glu Pro Asp Thr Glu Gly Tyr Ala 150 155 160 ATC ACT GAC CGG GGA TCT GCT CCC ATC TCT ATG GGG TTC AGG GCT TCT 2346 Ile Thr Asp Arg Gly Ser Ala Pro Ile Ser Met Gly Phe Arg Ala Ser 165 170 175 180 GAT GTT GAA ACT GCA GAA GGA GGG GAG ATC CAC GAG CTC CTG AGA CTC 2394 Asp Val Glu Thr Ala Glu Gly Gly Glu Ile His Glu Leu Leu Arg Leu 185 190 195 CAA TCC AGA GGC AAC AAC TTT CCG AAG CTT GGG AAA ACT CTC AAT GTT 2442 Gln Ser Arg Gly Asn Asn Phe Pro Lys Leu Gly Lys Thr Leu Asn Val 200 205 210 CCT CCG CCC CCG GAC CCC GGT AGG GCC AGC ACT TCC GGG ACA CCC ATT 2490 Pro Pro Pro Pro Asp Pro Gly Arg Ala Ser Thr Ser Gly Thr Pro Ile 215 220 225 AAA AAG GGC ACA GAG CGC AGA TTA GCC TCA TTT GGA ACG GAG ATC GCG 2538 Lys Lys Gly Thr Glu Arg Arg Leu Ala Ser Phe Gly Thr Glu Ile Ala 230 235 240 TCT TTA TTG ACA GGT GGT GCA ACC CAA TGT GCT CGA AAG TCA CCC TCG 2586 Ser Leu Leu Thr Gly Gly Ala Thr Gln Cys Ala Arg Lys Ser Pro Ser 245 250 255 260 GAA CCA TCA GGG CCA GGT GCA CCT GCG GGG AAT GTC CCC GAG TAT GTG 2634 Glu Pro Ser Gly Pro Gly Ala Pro Ala Gly Asn Val Pro Glu Tyr Val 265 270 275 AGC AAT GCC GCA CTG ATA CAG GAG TGG ACA CCC GAA TCT GGT ACC ACA 2682 Ser Asn Ala Ala Leu Ile Gln Glu Trp Thr Pro Glu Ser Gly Thr Thr 280 285 290 ATC TCC CCG AGA TCC CAG AAT AAT GAA GAA GGG GGA GAC TAT TAT GAT 2730 Ile Ser Pro Arg Ser Gln Asn Asn Glu Glu Gly Gly Asp Tyr Tyr Asp 295 300 305 GAT GAG CTG TTC TCT GAT GTC CAA GAT ATT AAA ACA GCC TTG GCC AAA 2778 Asp Glu Leu Phe Ser Asp Val Gln Asp Ile Lys Thr Ala Leu Ala Lys 310 315 320 ATA CAC GAG GAT AAT CAG AAG ATA ATC TCC AAG CTA GAA TCA CTG CTG 2826 Ile His Glu Asp Asn Gln Lys Ile Ile Ser Lys Leu Glu Ser Leu Leu 325 330 335 340 TTA TTG AAG GGA GAA GTT GAG TCA ATT AAG AAG CAG ATC AAC AGG CAA 2874 Leu Leu Lys Gly Glu Val Glu Ser Ile Lys Lys Gln Ile Asn Arg Gln 345 350 355 AAT ATC AGC ATA TCC ACC CTG GAA GGA CAC CTC TCA AGC ATC ATG ATC 2922 Asn Ile Ser Ile Ser Thr Leu Glu Gly His Leu Ser Ser Ile Met Ile 360 365 370 GCC ATT CCT GGA CTT GGG AAG GAT CCC AAC GAC CCC ACT GCA GAT GTC 2970 Ala Ile Pro Gly Leu Gly Lys Asp Pro Asn Asp Pro Thr Ala Asp Val 375 380 385 GAA ATC AAT CCC GAC TTG AAA CCC ATC ATA GGC AGA GAT TCA GGC CGA 3018 Glu Ile Asn Pro Asp Leu Lys Pro Ile Ile Gly Arg Asp Ser Gly Arg 390 395 400 GCA CTG GCC GAA GTT CTC AAG AAA CCC GTT GCC AGC CGA CAA CTC CAA 3066 Ala Leu Ala Glu Val Leu Lys Lys Pro Val Ala Ser Arg Gln Leu Gln 405 410 415 420 GGA ATG ACA AAT GGA CGG ACC AGT TCC AGA GGA CAG CTG CTG AAG GAA 3114 Gly Met Thr Asn Gly Arg Thr Ser Ser Arg Gly Gln Leu Leu Lys Glu 425 430 435 TTT CAG CCA AAG CCG ATC GGG AAA AAG ATG AGC TCA GCC GTC GGG TTT 3162 Phe Gln Pro Lys Pro Ile Gly Lys Lys Met Ser Ser Ala Val Gly Phe 440 445 450 GTT CCT GAC ACC GGC CCT GCA TCA CGC AGT GTA ATC CGC TCC ATT ATA 3210 Val Pro Asp Thr Gly Pro Ala Ser Arg Ser Val Ile Arg Ser Ile Ile 455 460 465 AAA TCC AGC CGG CTA GAG GAG GAT CGG AAG CGT TAC CTG ATG ACT CTC 3258 Lys Ser Ser Arg Leu Glu Glu Asp Arg Lys Arg Tyr Leu Met Thr Leu 470 475 480 CTT GAT GAT ATC AAA GGA GCC AAT GAT CTT GCC AAG TTC CAC CAG ATG 3306 Leu Asp Asp Ile Lys Gly Ala Asn Asp Leu Ala Lys Phe His Gln Met 485 490 495 500 CTG ATG AAG ATA ATA ATG AAG TAGCTACAGC TCAACTTACC TGCCAACCCC 3357 Leu Met Lys Ile Ile Met Lys 505 ATGCCAGTCG ACCCAACTAG TACAACCTAA ATCCATTATA AAAAACTTAG GAGCAAAGTG 3417 ATTGCCTCCC AAGTTCCACA ATG ACA GAG ATC TAC GAC TTC GAC AAG TCG GCA 3470 Met Thr Glu Ile Tyr Asp Phe Asp Lys Ser Ala 5 10 TGG GAC ATC AAA GGG TCG ATC GCT CCG ATA CAA CCC ACC ACC TAC AGT 3518 Trp Asp Ile Lys Gly Ser Ile Ala Pro Ile Gln Pro Thr Thr Tyr Ser 15 20 25 GAT GGC AGG CTG GTG CCC CAG GTC AGA GTC ATA GAT CCT GGT CTA GGC 3566 Asp Gly Arg Leu Val Pro Gln Val Arg Val Ile Asp Pro Gly Leu Gly 30 35 40 GAC AGG AAG GAT GAA TGC TTT ATG TAC ATG TCT CTG CTG GGG GTT GTT 3614 Asp Arg Lys Asp Glu Cys Phe Met Tyr Met Ser Leu Leu Gly Val Val 45 50 55 GAG GAC AGC GAT CCC CTA GGG CCT CCA ATC GGG CGA GCA TTT GGG TCC 3662 Glu Asp Ser Asp Pro Leu Gly Pro Pro Ile Gly Arg Ala Phe Gly Ser 60 65 70 75 CTG CCC TTA GGT GTT GGC AGA TCC ACA GCA AAG CCC GAA AAA CTC CTC 3710 Leu Pro Leu Gly Val Gly Arg Ser Thr Ala Lys Pro Glu Lys Leu Leu 80 85 90 AAA GAG GCC ACT GAG CTT GAC ATA GTT GTT AGA CGT ACA GCA GGG CTC 3758 Lys Glu Ala Thr Glu Leu Asp Ile Val Val Arg Arg Thr Ala Gly Leu 95 100 105 AAT GAA AAA CTG GTG TTC TAC AAC AAC ACC CCA CTA ACT CTC CTC ACA 3806 Asn Glu Lys Leu Val Phe Tyr Asn Asn Thr Pro Leu Thr Leu Leu Thr 110 115 120 CCT TGG AGA AAG GTC CTA ACA ACA GGG AGT GTC TTC AAC GCA AAC CAA 3854 Pro Trp Arg Lys Val Leu Thr Thr Gly Ser Val Phe Asn Ala Asn Gln 125 130 135 GTG TGC AAT GCG GTT AAT CTG ATA CCG CTC GAT ACC CCG CAG AGG TTC 3902 Val Cys Asn Ala Val Asn Leu Ile Pro Leu Asp Thr Pro Gln Arg Phe 140 145 150 155 CGT GTT GTT TAT ATG AGC ATC ACC CGT CTT TCG GAT AAC GGG TAT TAC 3950 Arg Val Val Tyr Met Ser Ile Thr Arg Leu Ser Asp Asn Gly Tyr Tyr 160 165 170 ACC GTT CCT AGA AGA ATG CTG GAA TTC AGA TCG GTC AAT GCA GTG GCC 3998 Thr Val Pro Arg Arg Met Leu Glu Phe Arg Ser Val Asn Ala Val Ala 175 180 185 TTC AAC CTG CTG GTG ACC CTT AGG ATT GAC AAG GCG ATA GGC CCT GGG 4046 Phe Asn Leu Leu Val Thr Leu Arg Ile Asp Lys Ala Ile Gly Pro Gly 190 195 200 AAG ATC ATC GAC AAT ACA GAG CAA CTT CCT GAG GCA ACA TTT ATG GTC 4094 Lys Ile Ile Asp Asn Thr Glu Gln Leu Pro Glu Ala Thr Phe Met Val 205 210 215 CAC ATC GGG AAC TTC AGG AGA AAG AAG AGT GAA GTC TAC TCT GCC GAT 4142 His Ile Gly Asn Phe Arg Arg Lys Lys Ser Glu Val Tyr Ser Ala Asp 220 225 230 235 TAT TGC AAA ATG AAA ATC GAA AAG ATG GGC CTG GTT TTT GCA CTT GGT 4190 Tyr Cys Lys Met Lys Ile Glu Lys Met Gly Leu Val Phe Ala Leu Gly 240 245 250 GGG ATA GGG GGC ACC AGT CTT CAC ATT AGA AGC ACA GGC AAA ATG AGC 4238 Gly Ile Gly Gly Thr Ser Leu His Ile Arg Ser Thr Gly Lys Met Ser 255 260 265 AAG ACT CTC CAT GCA CAA CTC GGG TTC AAG AAG ACC TTA TGT TAC CCG 4286 Lys Thr Leu His Ala Gln Leu Gly Phe Lys Lys Thr Leu Cys Tyr Pro 270 275 280 CTG ATG GAT ATC AAT GAA GAC CTT AAT CGA TTA CTC TGG AGG AGC AGA 4334 Leu Met Asp Ile Asn Glu Asp Leu Asn Arg Leu Leu Trp Arg Ser Arg 285 290 295 TGC AAG ATA GTA AGA ATC CAG GCA GTT TTG CAG CCA TCA GTT CCT CAA 4382 Cys Lys Ile Val Arg Ile Gln Ala Val Leu Gln Pro Ser Val Pro Gln 300 305 310 315 GAA TTC CGC ATT TAC GAC GAC GTG ATC ATA AAT GAT GAC CAA GGA CTA 4430 Glu Phe Arg Ile Tyr Asp Asp Val Ile Ile Asn Asp Asp Gln Gly Leu 320 325 330 TTC AAA GTT CTG TAGACCGTAG TGCCCAGCAA TGCCCGAAAA CGACCCCCCT 4482 Phe Lys Val Leu 335 CACAATGACA GCCAGAAGGC CCGGACAAAA AAGCCCCCTC CGAAAGACTC CACTGACCAA 4542 GCGAGAGGCC AGCCAGCAGC CGACGGCAAG CACGAACACC AGGCGGCCCC AGCACAGAAC 4602 AGCCCTGATA CAAGGCCACC ACCAGCCACC CCAATCTGCA TCCTCCTCGT GGGACCCCCG 4662 AGGACCAACC CCCAAGGCTG CCCCCGATCC AAACCACCAA CCGCATCCCC ACCACCCCCG 4722 GGAAAGAAAC CCCCAGCAAT TGGAAGGCCC CTCCCCCTCT TCCTCAACAC AAGAACTCCA 4782 CAACCGAACC GCACAAGCGA CCGAGGTGAC CCAACCGCGC GGCATCCGAC TCCCTAGACA 4842 GATCCTCTCT CCCCGGCAAA CTAAACAAAA CTTAGGGCCA AGGAACATAC ACACCCAACA 4902 GAACCCAGAC CCCGGCCCAC GGCGCCGCGC CCCCAACCCC CGACAACCAG AGGGAGCCCC 4962 CAACCAATCC CGCCGGCTCC CCCGGTGCCC ACAGGCAGGG ACACCAACCC CCGAACAGAC 5022 CCAGCACCCA ACCATCGACA ATCCAAGACG GGGGGGCCCC CCCAAAAAAA GGCCCCCAGG 5082 GGCCGACAGC CAGCACCGCG AGGAAGCCCA CCCACCCCAC ACACGACCAC GGCAACCAAA 5142 CCAGAACCCA GACCACCCTG GCCACCAGCT CCCAGACTCG GCCATCACCC CGCAGAAAGG 5202 AAAGGCCACA ACCCGCGCAC CCCAGCCCCG ATCCGGCGGG GAGCCACCCA ACCCGAACCA 5262 GCACCCAAGA GCGATCCCCG AAGGACCCCC GAACCGCAAA GGACATCAGT ATCCCACAGC 5322 CTCTCCAAGT CCCCCGGTCT CCTCCTCTTC TCGAAGGGAC CAAAAGATCA ATCCACCACA 5382 CCCGACGACA CTCAACTCCC CACCCCTAAA GGAGACACCG GGAATCCCAG AATCAAGACT 5442 CATCCAATGT CCATC ATG GGT CTC AAG GTG AAC GTC TCT GCC ATA TTC ATG 5493 Met Gly Leu Lys Val Asn Val Ser Ala Ile Phe Met 5 10 GCA GTA CTG TTA ACT CTC CAA ACA CCC ACC GGT CAA ATC CAT TGG GGC 5541 Ala Val Leu Leu Thr Leu Gln Thr Pro Thr Gly Gln Ile His Trp Gly 15 20 25 AAT CTC TCT AAG ATA GGG GTG GTA GGA ATA GGA AGT GCA AGC TAC AAA 5589 Asn Leu Ser Lys Ile Gly Val Val Gly Ile Gly Ser Ala Ser Tyr Lys 30 35 40 GTT ATG ACT CGT TCC AGC CAT CAA TCA TTA GTC ATA AAA TTA ATG CCC 5637 Val Met Thr Arg Ser Ser His Gln Ser Leu Val Ile Lys Leu Met Pro 45 50 55 60 AAT ATA ACT CTC CTC AAT AAC TGC ACG AGG GTA GAG ATT GCA GAA TAC 5685 Asn Ile Thr Leu Leu Asn Asn Cys Thr Arg Val Glu Ile Ala Glu Tyr 65 70 75 AGG AGA CTA CTG AGA ACA GTT TTG GAA CCA ATT AGA GAT GCA CTT AAT 5733 Arg Arg Leu Leu Arg Thr Val Leu Glu Pro Ile Arg Asp Ala Leu Asn 80 85 90 GCA ATG ACC CAG AAT ATA AGA CCG GTT CAG AGT GTA GCT TCA AGT AGG 5781 Ala Met Thr Gln Asn Ile Arg Pro Val Gln Ser Val Ala Ser Ser Arg 95 100 105 AGA CAC AAG AGA TTT GCG GGA GTA GTC CTG GCA GGT GCG GCC CTA GGC 5829 Arg His Lys Arg Phe Ala Gly Val Val Leu Ala Gly Ala Ala Leu Gly 110 115 120 GTT GCC ACA GCT GCT CAG ATA ACA GCC GGC ATT GCA CTT CAC CAG TCC 5877 Val Ala Thr Ala Ala Gln Ile Thr Ala Gly Ile Ala Leu His Gln Ser 125 130 135 140 ATG CTG AAC TCT CAA GCC ATC GAC AAT CTG AGA GCG AGC CTG GAA ACT 5925 Met Leu Asn Ser Gln Ala Ile Asp Asn Leu Arg Ala Ser Leu Glu Thr 145 150 155 ACT AAT CAG GCA ATT GAG GCA ATC AGA CAA GCA GGG CAG GAG ATG ATA 5973 Thr Asn Gln Ala Ile Glu Ala Ile Arg Gln Ala Gly Gln Glu Met Ile 160 165 170 TTG GCT GTT CAG GGT GTC CAA GAC TAC ATC AAT AAT GAG CTG ATA CCG 6021 Leu Ala Val Gln Gly Val Gln Asp Tyr Ile Asn Asn Glu Leu Ile Pro 175 180 185 TCT ATG AAC CAA CTA TCT TGT GAT TTA ATC GGC CAG AAG CTC GGG CTC 6069 Ser Met Asn Gln Leu Ser Cys Asp Leu Ile Gly Gln Lys Leu Gly Leu 190 195 200 AAA TTG CTC AGA TAC TAT ACA GAA ATC CTG TCA TTA TTT GGC CCC AGC 6117 Lys Leu Leu Arg Tyr Tyr Thr Glu Ile Leu Ser Leu Phe Gly Pro Ser 205 210 215 220 TTA CGG GAC CCC ATA TCT GCG GAG ATA TCT ATC CAG GCT TTG AGC TAT 6165 Leu Arg Asp Pro Ile Ser Ala Glu Ile Ser Ile Gln Ala Leu Ser Tyr 225 230 235 GCG CTT GGA GGA GAC ATC AAT AAG GTG TTA GAA AAG CTC GGA TAC AGT 6213 Ala Leu Gly Gly Asp Ile Asn Lys Val Leu Glu Lys Leu Gly Tyr Ser 240 245 250 GGA GGT GAT TTA CTG GGC ATC TTA GAG AGC AGA GGA ATA AAG GCC CGG 6261 Gly Gly Asp Leu Leu Gly Ile Leu Glu Ser Arg Gly Ile Lys Ala Arg 255 260 265 ATA ACT CAC GTC GAC ACA GAG TCC TAC TTA ATT GTC CTC AGT ATA GCC 6309 Ile Thr His Val Asp Thr Glu Ser Tyr Leu Ile Val Leu Ser Ile Ala 270 275 280 TAT CCG ACG CTG TCC GAG ATT AAG GGG GTG ATT GTC CAC CGG CTA GAG 6357 Tyr Pro Thr Leu Ser Glu Ile Lys Gly Val Ile Val His Arg Leu Glu 285 290 295 300 GGG GTC TCG TAC AAC ATA GGC TCT CAA GAG TGG TAT ACC ACT GTG CCC 6405 Gly Val Ser Tyr Asn Ile Gly Ser Gln Glu Trp Tyr Thr Thr Val Pro 305 310 315 AAG TAT GTT GCA ACC CAA GGG TAC CTT ATC TCG AAT TTT GAT GAG TCA 6453 Lys Tyr Val Ala Thr Gln Gly Tyr Leu Ile Ser Asn Phe Asp Glu Ser 320 325 330 TCG TGT ACT TTC ATG CCA GAG GGG ACT GTG TGC AGC CAA AAT GCC TTG 6501 Ser Cys Thr Phe Met Pro Glu Gly Thr Val Cys Ser Gln Asn Ala Leu 335 340 345 TAC CCG ATG AGT CCT CTG CTC CAA GAA TGC CTC CGG GGG TCC ACC AAG 6549 Tyr Pro Met Ser Pro Leu Leu Gln Glu Cys Leu Arg Gly Ser Thr Lys 350 355 360 TCC TGT GCT CGT ACA CTC GTA TCC GGG TCT TTT GGG AAC CGG TTC ATT 6597 Ser Cys Ala Arg Thr Leu Val Ser Gly Ser Phe Gly Asn Arg Phe Ile 365 370 375 380 TTA TCA CAA GGG AAC CTA ATA GCC AAT TGT GCA TCA ATC CTT TGC AAG 6645 Leu Ser Gln Gly Asn Leu Ile Ala Asn Cys Ala Ser Ile Leu Cys Lys 385 390 395 TGT TAC ACA ACA GGA ACG ATC ATT AAT CAA GAC CCT GAC AAG ATC CTA 6693 Cys Tyr Thr Thr Gly Thr Ile Ile Asn Gln Asp Pro Asp Lys Ile Leu 400 405 410 ACA TAC ATT GCT GCC GAT CAC TGC CCG GTA GTC GAG GTG AAC GGC GTG 6741 Thr Tyr Ile Ala Ala Asp His Cys Pro Val Val Glu Val Asn Gly Val 415 420 425 ACC ATC CAA GTC GGG AGC AGG AGG TAT CCA GAC GCT GTG TAC TTG CAC 6789 Thr Ile Gln Val Gly Ser Arg Arg Tyr Pro Asp Ala Val Tyr Leu His 430 435 440 AGA ATT GAC CTC GGT CCT CCC ATA TTA TTG GAG AGG TTG GAC GTA GGG 6837 Arg Ile Asp Leu Gly Pro Pro Ile Leu Leu Glu Arg Leu Asp Val Gly 445 450 455 460 ACA AAT CTG GGG AAT GCA ATT GCT AAG TTG GAG GAT GCC AAG GAA TTG 6885 Thr Asn Leu Gly Asn Ala Ile Ala Lys Leu Glu Asp Ala Lys Glu Leu 465 470 475 TTG GAG TCA TCG GAC CAG ATA TTG AGG AGT ATG AAA GGT TTA TCG AGC 6933 Leu Glu Ser Ser Asp Gln Ile Leu Arg Ser Met Lys Gly Leu Ser Ser 480 485 490 ACT TGC ATA GTC TAC ATC CTG ATT GCA GTG TGT CTT GGA GGG TTG ATA 6981 Thr Cys Ile Val Tyr Ile Leu Ile Ala Val Cys Leu Gly Gly Leu Ile 495 500 505 GGG ATC CCC GCT TTA ATA TGT TGC TGC AGG GGG CGT TGT AAC AAA AAG 7029 Gly Ile Pro Ala Leu Ile Cys Cys Cys Arg Gly Arg Cys Asn Lys Lys 510 515 520 GGA GAA CAA GTT GGT ATG TCA AGA CCA GGC CTA AAG CCT GAT CTT ACG 7077 Gly Glu Gln Val Gly Met Ser Arg Pro Gly Leu Lys Pro Asp Leu Thr 525 530 535 540 GGA ACA TCA AAA TCC TAT GTA AGG TCG CTC TGATCCTCTA CAACTCTTGA 7127 Gly Thr Ser Lys Ser Tyr Val Arg Ser Leu 545 550 AACACAAATG TCCCACAAGT CTCCTCTTCG TCATCAAGCA ACCACCGCAC CCAGCATCAA 7187 GCCCACCTGA AATTATCTCC GGCTTCCCTC TGGCCGAACA ATATCGGTAG TTAATTAAAA 7247 CTTAGGGTGC AAGATCATCC ACA ATG TCA CCA CAA CGA GAC CGG ATA AAT GCC 7300 Met Ser Pro Gln Arg Asp Arg Ile Asn Ala 5 10 TTC TAC AAA GAT AAC CCC CAT CCC AAG GGA AGT AGG ATA GTC ATT AAC 7348 Phe Tyr Lys Asp Asn Pro His Pro Lys Gly Ser Arg Ile Val Ile Asn 15 20 25 AGA GAA CAT CTT ATG ATT GAT AGA CCT TAT GTT TTG CTG GCT GTT CTG 7396 Arg Glu His Leu Met Ile Asp Arg Pro Tyr Val Leu Leu Ala Val Leu 30 35 40 TTT GTC ATG TTT CTG AGC TTG ATC GGG TTG CTA GCC ATT GCA GGC ATT 7444 Phe Val Met Phe Leu Ser Leu Ile Gly Leu Leu Ala Ile Ala Gly Ile 45 50 55 AGA CTT CAT CGG GCA GCC ATC TAC ACC GCA GAG ATC CAT AAA AGC CTC 7492 Arg Leu His Arg Ala Ala Ile Tyr Thr Ala Glu Ile His Lys Ser Leu 60 65 70 AGC ACC AAT CTA GAT GTA ACT AAC TCA ATC GAG CAT CAG GTC AAG GAC 7540 Ser Thr Asn Leu Asp Val Thr Asn Ser Ile Glu His Gln Val Lys Asp 75 80 85 90 GTG CTG ACA CCA CTC TTC AAA ATC ATC GGT GAT GAA GTG GGC CTG AGG 7588 Val Leu Thr Pro Leu Phe Lys Ile Ile Gly Asp Glu Val Gly Leu Arg 95 100 105 ACA CCT CAG AGA TTC ACT GAC CTA GTG AAA TTC ATC TCT GAC AAG ATT 7636 Thr Pro Gln Arg Phe Thr Asp Leu Val Lys Phe Ile Ser Asp Lys Ile 110 115 120 AAA TTC CTT AAT CCG GAT AGG GAG TAC GAC TTC AGA GAT CTC ACT TGG 7684 Lys Phe Leu Asn Pro Asp Arg Glu Tyr Asp Phe Arg Asp Leu Thr Trp 125 130 135 TGT ATC AAC CCG CCA GAG AGA ATC AAA TTG GAT TAT GAT CAA TAC TGT 7732 Cys Ile Asn Pro Pro Glu Arg Ile Lys Leu Asp Tyr Asp Gln Tyr Cys 140 145 150 GCA GAT GTG GCT GCT GAA GAG CTC ATG AAT GCA TTG GTG AAC TCA ACT 7780 Ala Asp Val Ala Ala Glu Glu Leu Met Asn Ala Leu Val Asn Ser Thr 155 160 165 170 CTA CTG GAG ACC AGA ACA ACC AAT CAG TTC CTA GCT GTC TCA AAG GGA 7828 Leu Leu Glu Thr Arg Thr Thr Asn Gln Phe Leu Ala Val Ser Lys Gly 175 180 185 AAC TGC TCA GGG CCC ACT ACA ATC AGA GGT CAA TTC TCA AAC ATG TCG 7876 Asn Cys Ser Gly Pro Thr Thr Ile Arg Gly Gln Phe Ser Asn Met Ser 190 195 200 CTG TCC CTG TTA GAC TTG TAT TTA GGT CGA GGT TAC AAT GTG TCA TCT 7924 Leu Ser Leu Leu Asp Leu Tyr Leu Gly Arg Gly Tyr Asn Val Ser Ser 205 210 215 ATA GTC ACT ATG ACA TCC CAG GGA ATG TAT GGG GGA ACT TAC CTA GTG 7972 Ile Val Thr Met Thr Ser Gln Gly Met Tyr Gly Gly Thr Tyr Leu Val 220 225 230 GAA AAG CCT AAT CTG AGC AGC AAA AGG TCA GAG TTG TCA CAA CTG AGC 8020 Glu Lys Pro Asn Leu Ser Ser Lys Arg Ser Glu Leu Ser Gln Leu Ser 235 240 245 250 ATG TAC CGA GTG TTT GAA GTA GGT GTT ATC AGA AAT CCG GGT TTG GGG 8068 Met Tyr Arg Val Phe Glu Val Gly Val Ile Arg Asn Pro Gly Leu Gly 255 260 265 GCT CCG GTG TTC CAT ATG ACA AAC TAT CTT GAG CAA CCA GTC AGT AAT 8116 Ala Pro Val Phe His Met Thr Asn Tyr Leu Glu Gln Pro Val Ser Asn 270 275 280 GAT CTC AGC AAC TGT ATG GTG GCT TTG GGG GAG CTC AAA CTC GCA GCC 8164 Asp Leu Ser Asn Cys Met Val Ala Leu Gly Glu Leu Lys Leu Ala Ala 285 290 295 CTT TGT CAC CGG GAA GAT TCT ATC ACA ATT CCC TAT CAG GGA TCA GGG 8212 Leu Cys His Arg Glu Asp Ser Ile Thr Ile Pro Tyr Gln Gly Ser Gly 300 305 310 AAA GGT GTC AGC TTC CAG CTC GTC AAG CTA GGT GTC TGG AAA TCC CCA 8260 Lys Gly Val Ser Phe Gln Leu Val Lys Leu Gly Val Trp Lys Ser Pro 315 320 325 330 ACC GAC ATG CAA TCC TGG GTC ACC TTA TCA ACG GAT GAT CCA GTG ATA 8308 Thr Asp Met Gln Ser Trp Val Thr Leu Ser Thr Asp Asp Pro Val Ile 335 340 345 GAC AGG CTT TAC CTC TCA TCT CAC AGA GGT GTT ATC GCT GAC AAT CAA 8356 Asp Arg Leu Tyr Leu Ser Ser His Arg Gly Val Ile Ala Asp Asn Gln 350 355 360 GCA AAA TGG GCT GTC CCG ACA ACA CGA ACA GAT GAC AAG TTG CGA ATG 8404 Ala Lys Trp Ala Val Pro Thr Thr Arg Thr Asp Asp Lys Leu Arg Met 365 370 375 GAG ACA TGC TTC CAA CAG GCG TGT AAG GGT AAA ATC CAA GCA CTC TGC 8452 Glu Thr Cys Phe Gln Gln Ala Cys Lys Gly Lys Ile Gln Ala Leu Cys 380 385 390 GAG AAT CCC GAG TGG GCA CCA TTG AAG GAT AAC AGG ATT CCT TCA TAC 8500 Glu Asn Pro Glu Trp Ala Pro Leu Lys Asp Asn Arg Ile Pro Ser Tyr 395 400 405 410 GGG GTC TTG TCT GTT GAT CTG AGT CTG ACA GTT GAG CTT AAA ATC AAA 8548 Gly Val Leu Ser Val Asp Leu Ser Leu Thr Val Glu Leu Lys Ile Lys 415 420 425 ATT GCT TCG GGA TTC GGG CCA TTG ATC ACA CAC GGT TCA GGG ATG GAC 8596 Ile Ala Ser Gly Phe Gly Pro Leu Ile Thr His Gly Ser Gly Met Asp 430 435 440 CTA TAC AAA TCC AAC CAC AAC AAT GTG TAT TGG CTG ACT ATC CCA CCA 8644 Leu Tyr Lys Ser Asn His Asn Asn Val Tyr Trp Leu Thr Ile Pro Pro 445 450 455 ATG AAG AAC CTA GCC TTA GGT GTA ATC AAC ACA TTG GAG TGG ATA CCG 8692 Met Lys Asn Leu Ala Leu Gly Val Ile Asn Thr Leu Glu Trp Ile Pro 460 465 470 AGA TTC AAG GTT AGT CCC TAC CTC TTC AAT GTC CCA ATT AAG GAA GCA 8740 Arg Phe Lys Val Ser Pro Tyr Leu Phe Asn Val Pro Ile Lys Glu Ala 475 480 485 490 GGC GAA GAC TGC CAT GCC CCA ACA TAC CTA CCT GCG GAG GTG GAT GGT 8788 Gly Glu Asp Cys His Ala Pro Thr Tyr Leu Pro Ala Glu Val Asp Gly 495 500 505 GAT GTC AAA CTC AGT TCC AAT CTG GTG ATT CTA CCT GGT CAA GAT CTC 8836 Asp Val Lys Leu Ser Ser Asn Leu Val Ile Leu Pro Gly Gln Asp Leu 510 515 520 CAA TAT GTT TTG GCA ACC TAC GAT ACT TCC AGG GTT GAA CAT GCT GTG 8884 Gln Tyr Val Leu Ala Thr Tyr Asp Thr Ser Arg Val Glu His Ala Val 525 530 535 GTT TAT TAC GTT TAC AGC CCA AGC CGC TCA TTT TCT TAC TTT TAT CCT 8932 Val Tyr Tyr Val Tyr Ser Pro Ser Arg Ser Phe Ser Tyr Phe Tyr Pro 540 545 550 TTT AGG TTG CCT ATA AAG GGG GTC CCC ATC GAA TTA CAA GTG GAA TGC 8980 Phe Arg Leu Pro Ile Lys Gly Val Pro Ile Glu Leu Gln Val Glu Cys 555 560 565 570 TTC ACA TGG GAC CAA AAA CTC TGG TGC CGT CAC TTC TGT GTG CTT GCG 9028 Phe Thr Trp Asp Gln Lys Leu Trp Cys Arg His Phe Cys Val Leu Ala 575 580 585 GAC TCA GAA TCT GGT GGA CAT ATC ACT CAC TCT GGG ATG GTG GGC ATG 9076 Asp Ser Glu Ser Gly Gly His Ile Thr His Ser Gly Met Val Gly Met 590 595 600 GGA GTC AGC TGC ACA GTC ACC CGG GAA GAT GGA ACC AAT CGC AGA 9121 Gly Val Ser Cys Thr Val Thr Arg Glu Asp Gly Thr Asn Arg Arg 605 610 615 TAGGGCTGCT AGTGAACTAA TCTCATGATG TCACCCAGAC ATCAGGCATA CCCACTAGTG 9181 TGAAATAGAC ATCAGAATTA AGAAAAACGT AGGGTCCAAG TGGTTCCCCG TT ATG GAC 9239 Met Asp TCG CTA TCT GTC AAC CAG ATC TTA TAC CCT GAA GTT CAC CTA GAT AGC 9287 Ser Leu Ser Val Asn Gln Ile Leu Tyr Pro Glu Val His Leu Asp Ser 5 10 15 CCG ATA GTT ACC AAT AAG ATA GTA GCC ATC CTG GAG TAT GCT CGA GTT 9335 Pro Ile Val Thr Asn Lys Ile Val Ala Ile Leu Glu Tyr Ala Arg Val 20 25 30 CCT CAC GCT TAC AGC CTG GAG GAC CCT ACA CTG TGT CAG AAC ATC AAG 9383 Pro His Ala Tyr Ser Leu Glu Asp Pro Thr Leu Cys Gln Asn Ile Lys 35 40 45 50 CAC CGC CTA AAA AAC GGA TTT TCC AAC CAA ATG ATT ATA AAC AAT GTG 9431 His Arg Leu Lys Asn Gly Phe Ser Asn Gln Met Ile Ile Asn Asn Val 55 60 65 GAA GTT GGG AAT GTC ATC AAG TCC AAG CTT AGG AGT TAT CCG GCC CAC 9479 Glu Val Gly Asn Val Ile Lys Ser Lys Leu Arg Ser Tyr Pro Ala His 70 75 80 TCT CAT ATT CCA TAT CCA AAT TGT AAT CAG GAT TTA TTT AAC ATA GAA 9527 Ser His Ile Pro Tyr Pro Asn Cys Asn Gln Asp Leu Phe Asn Ile Glu 85 90 95 GAC AAA GAG TCA ACG AGG AAG ATC CGT GAA CTC CTC AAA AAG GGG AAT 9575 Asp Lys Glu Ser Thr Arg Lys Ile Arg Glu Leu Leu Lys Lys Gly Asn 100 105 110 TCG CTG TAC TCC AAA GTC AGT GAT AAG GTT TTC CAA TGC TTA AGG GAC 9623 Ser Leu Tyr Ser Lys Val Ser Asp Lys Val Phe Gln Cys Leu Arg Asp 115 120 125 130 ACT AAC TCA CGG CTT GGC CTA GGC TCC GAA TTG AGG GAG GAC ATC AAG 9671 Thr Asn Ser Arg Leu Gly Leu Gly Ser Glu Leu Arg Glu Asp Ile Lys 135 140 145 GAG AAA GTT ATT AAC TTG GGA GTT TAC ATG CAC AGC TCC CAG TGG TTT 9719 Glu Lys Val Ile Asn Leu Gly Val Tyr Met His Ser Ser Gln Trp Phe 150 155 160 GAG CCA TTT CTG TTT TGG TTT ACA GTC AAG ACT GAG ATG AGG TCA GTG 9767 Glu Pro Phe Leu Phe Trp Phe Thr Val Lys Thr Glu Met Arg Ser Val 165 170 175 ATT AAA TCA CAA ACC CAT ACT TGC CAT AGG AGG AGA CAC ACA CCT GTA 9815 Ile Lys Ser Gln Thr His Thr Cys His Arg Arg Arg His Thr Pro Val 180 185 190 TTC TTC ACT GGT AGT TCA GTT GAG TTG CTA ATC TCT CGT GAC CTT GTT 9863 Phe Phe Thr Gly Ser Ser Val Glu Leu Leu Ile Ser Arg Asp Leu Val 195 200 205 210 GCT ATA ATC AGT AAA GAG TCT CAA CAT GTA TAT TAC CTG ACA TTT GAA 9911 Ala Ile Ile Ser Lys Glu Ser Gln His Val Tyr Tyr Leu Thr Phe Glu 215 220 225 CTG GTT TTG ATG TAT TGT GAT GTC ATA GAG GGG AGG TTA ATG ACA GAG 9959 Leu Val Leu Met Tyr Cys Asp Val Ile Glu Gly Arg Leu Met Thr Glu 230 235 240 ACC GCT ATG ACT ATT GAT GCT AGG TAT ACA GAG CTT CTA GGA AGA GTC 10007 Thr Ala Met Thr Ile Asp Ala Arg Tyr Thr Glu Leu Leu Gly Arg Val 245 250 255 AGA TAC ATG TGG AAA CTG ATA GAT GGT TTC TTC CCT GCA CTC GGG AAT 10055 Arg Tyr Met Trp Lys Leu Ile Asp Gly Phe Phe Pro Ala Leu Gly Asn 260 265 270 CCA ACT TAT CAA ATT GTA GCC ATG CTG GAG CCT CTT TCA CTT GCT TAC 10103 Pro Thr Tyr Gln Ile Val Ala Met Leu Glu Pro Leu Ser Leu Ala Tyr 275 280 285 290 CTG CAG CTG AGG GAT ATA ACA GTA GAA CTC AGA GGT GCT TTC CTT AAC 10151 Leu Gln Leu Arg Asp Ile Thr Val Glu Leu Arg Gly Ala Phe Leu Asn 295 300 305 CAC TGC TTT ACT GAA ATA CAT GAT GTT CTT GAC CAA AAC GGG TTT TCT 10199 His Cys Phe Thr Glu Ile His Asp Val Leu Asp Gln Asn Gly Phe Ser 310 315 320 GAT GAA GGT ACT TAT CAT GAG TTA ATT GAA GCT CTA GAT TAC ATT TTC 10247 Asp Glu Gly Thr Tyr His Glu Leu Ile Glu Ala Leu Asp Tyr Ile Phe 325 330 335 ATA ACT GAT GAC ATA CAT CTG ACA GGG GAG ATT TTC TCA TTT TTC AGA 10296 Ile Thr Asp Asp Ile His Leu Thr Gly Glu Ile Phe Ser Phe Phe Arg 340 345 350 AGT TTC GGC CAC CCC AGA CTT GAA GCA GTA ACG GCT GCT GAA AAT GTT 10343 Ser Phe Gly His Pro Arg Leu Glu Ala Val Thr Ala Ala Glu Asn Val 355 360 365 370 AGG AAA TAC ATG AAT CAG CCT AAA GTC ATT GTG TAT GAG ACT CTG ATG 10391 Arg Lys Tyr Met Asn Gln Pro Lys Val Ile Val Tyr Glu Thr Leu Met 375 380 385 AAA GGT CAT GCC ATA TTT TGT GGA ATC ATA ATC AAC GGC TAT CGT GAC 10439 Lys Gly His Ala Ile Phe Cys Gly Ile Ile Ile Asn Gly Tyr Arg Asp 390 395 400 AGG CAC GGA GGC AGT TGG CCA CCG CTG ACC CTC CCC CTG CAT GCT GCA 10487 Arg His Gly Gly Ser Trp Pro Pro Leu Thr Leu Pro Leu His Ala Ala 405 410 415 GAC ACA ATC CGG AAT GCT CAA GCT TCA GGT GAA GGG TTA ACA CAT GAG 10535 Asp Thr Ile Arg Asn Ala Gln Ala Ser Gly Glu Gly Leu Thr His Glu 420 425 430 CAG TGC GTT GAT AAC TGG AAA TCT TTT GCT GGA GTG AAA TTT GGC TGC 10583 Gln Cys Val Asp Asn Trp Lys Ser Phe Ala Gly Val Lys Phe Gly Cys 435 440 445 450 TTT ATG CCT CTT AGC CTG GAT AGT GAT CTG ACA ATG TAC CTA AAG GAC 10631 Phe Met Pro Leu Ser Leu Asp Ser Asp Leu Thr Met Tyr Leu Lys Asp 455 460 465 AAG GCA CTT GCT GCT CTC CAA AGG GAA TGG GAT TCA GTT TAC CCG AAA 10679 Lys Ala Leu Ala Ala Leu Gln Arg Glu Trp Asp Ser Val Tyr Pro Lys 470 475 480 GAG TTC CTG CGT TAC GAC CCT CCC AAG GGA ACC GGG TCA CGG AGG CTT 10727 Glu Phe Leu Arg Tyr Asp Pro Pro Lys Gly Thr Gly Ser Arg Arg Leu 485 490 495 GTA GAT GTT TTC CTT AAT GAT TCG AGC TTT GAC CCA TAT GAT GTG ATA 10775 Val Asp Val Phe Leu Asn Asp Ser Ser Phe Asp Pro Tyr Asp Val Ile 500 505 510 ATG TAT GTT GTA AGT GGA GCT TAC CTC CAT GAC CCT GAG TTC AAC CTG 10823 Met Tyr Val Val Ser Gly Ala Tyr Leu His Asp Pro Glu Phe Asn Leu 515 520 525 530 TCT TAC AGC CTG AAA GAA AAG GAG ATC AAG GAA ACA GGT AGA CTT TTT 10871 Ser Tyr Ser Leu Lys Glu Lys Glu Ile Lys Glu Thr Gly Arg Leu Phe 535 540 545 GCT AAA ATG ACT TAC AAA ATG AGG GCA TGC CAA GTG ATT GCT GAA AAT 10919 Ala Lys Met Thr Tyr Lys Met Arg Ala Cys Gln Val Ile Ala Glu Asn 550 555 560 CTA ATC TCA AAC GGG ATT GGC AAA TAT TTT AAG GAC AAT GGG ATG GCC 10967 Leu Ile Ser Asn Gly Ile Gly Lys Tyr Phe Lys Asp Asn Gly Met Ala 565 570 575 AAG GAT GAG CAC GAT TTG ACT AAG GCA CTC CAC ACT CTA GCT GTC TCA 11015 Lys Asp Glu His Asp Leu Thr Lys Ala Leu His Thr Leu Ala Val Ser 580 585 590 GGA GTC CCC AAA GAT CTC AAA GAA AGT CAC AGG GGG GGG CCA GTC TTA 11063 Gly Val Pro Lys Asp Leu Lys Glu Ser His Arg Gly Gly Pro Val Leu 595 600 605 610 AAA ACC TAC TCC CGA AGC CCA GTC CAC ACA AGT ACC AGG AAC GTG AGA 11111 Lys Thr Tyr Ser Arg Ser Pro Val His Thr Ser Thr Arg Asn Val Arg 615 620 625 GCA GCA AAA GGG TTT ATA GGG TTC CCT CAA GTA ATT CGG CAG GAC CAA 11159 Ala Ala Lys Gly Phe Ile Gly Phe Pro Gln Val Ile Arg Gln Asp Gln 630 635 640 GAC ACT GAT CAT CCG GAG AAT ATG GAA GCT TAC GAG ACA GTC AGT GCA 11207 Asp Thr Asp His Pro Glu Asn Met Glu Ala Tyr Glu Thr Val Ser Ala 645 650 655 TTT ATC ACG ACT GAT CTC AAG AAG TAC TGC CTT AAT TGG AGA TAT GAG 11255 Phe Ile Thr Thr Asp Leu Lys Lys Tyr Cys Leu Asn Trp Arg Tyr Glu 660 665 670 ACC ATC AGC TTG TTT GCA CAG AGG CTA AAT GAG ATT TAC GGA TTG CCC 11303 Thr Ile Ser Leu Phe Ala Gln Arg Leu Asn Glu Ile Tyr Gly Leu Pro 675 680 685 690 TCA TTT TTC CAG TGG CTG CAT AAG AGG CTT GAG ACC TCT GTC CTG TAT 11351 Ser Phe Phe Gln Trp Leu His Lys Arg Leu Glu Thr Ser Val Leu Tyr 695 700 705 GTA AGT GAC CCT CAT TGC CCC CCC GAC CTT GAC GCC CAT ATC CCG TTA 11399 Val Ser Asp Pro His Cys Pro Pro Asp Leu Asp Ala His Ile Pro Leu 710 715 720 TAT AAA GTC CCC AAT GAT CAA ATC TTC ATT AAG TAC CCT ATG GGA GGT 11447 Tyr Lys Val Pro Asn Asp Gln Ile Phe Ile Lys Tyr Pro Met Gly Gly 725 730 735 ATA GAA GGG TAT TGT CAG AAG CTG TGG ACC ATC AGC ACC ATT CCC TAT 11495 Ile Glu Gly Tyr Cys Gln Lys Leu Trp Thr Ile Ser Thr Ile Pro Tyr 740 745 750 CTA TAC CTG GCT GCT TAT GAG AGC GGA GTA AGG ATT GCT TCG TTA GTG 11543 Leu Tyr Leu Ala Ala Tyr Glu Ser Gly Val Arg Ile Ala Ser Leu Val 755 760 765 770 CAA GGG GAC AAT CAG ACC ATA GCC GTA ACA AAA AGG GTA CCC AGC ACA 11591 Gln Gly Asp Asn Gln Thr Ile Ala Val Thr Lys Arg Val Pro Ser Thr 775 780 785 TGG CCC TAC AAC CTT AAG AAA CGG GAA GCT GCT AGA GTA ACT AGA GAT 11639 Trp Pro Tyr Asn Leu Lys Lys Arg Glu Ala Ala Arg Val Thr Arg Asp 790 795 800 TAC TTT GTA ATT CTT AGG CAA AGG CTA CAT GAT ATT GGC CAT CAC CTC 11687 Tyr Phe Val Ile Leu Arg Gln Arg Leu His Asp Ile Gly His His Leu 805 810 815 AAG GCA AAT GAG ACA ATT GTT TCA TCA CAT TTT TTT GTC TAT TCA AAA 11735 Lys Ala Asn Glu Thr Ile Val Ser Ser His Phe Phe Val Tyr Ser Lys 820 825 830 GGA ATA TAT TAT GAT GGG CTA CTT GTG TCC CAA TCA CTC AAG AGC ATC 11783 Gly Ile Tyr Tyr Asp Gly Leu Leu Val Ser Gln Ser Leu Lys Ser Ile 835 840 845 850 GCA AGA TGT GTA TTC TGG TCA GAG ACT ATA GTT GAT GAA ACA AGG GCA 11831 Ala Arg Cys Val Phe Trp Ser Glu Thr Ile Val Asp Glu Thr Arg Ala 855 860 865 GCA TGC AGT AAT ATT GCT ACA ACA ATG GCT AAA AGC ATC GAG AGA GGT 11879 Ala Cys Ser Asn Ile Ala Thr Thr Met Ala Lys Ser Ile Glu Arg Gly 870 875 880 TAT GAC CGT TAC CTT GCA TAT TCC CTG AAC GTC CTA AAA GTG ATA CAG 11927 Tyr Asp Arg Tyr Leu Ala Tyr Ser Leu Asn Val Leu Lys Val Ile Gln 885 890 895 CAA ATT CTG ATC TCT CTT GGC TTC ACA ATC AAT TCA ACC ATG ACC CGG 11975 Gln Ile Leu Ile Ser Leu Gly Phe Thr Ile Asn Ser Thr Met Thr Arg 900 905 910 GAT GTA GTC ATA CCC CTC CTC ACA AAC AAC GAC CTC TTA ATA AGG ATG 12023 Asp Val Val Ile Pro Leu Leu Thr Asn Asn Asp Leu Leu Ile Arg Met 915 920 925 930 GCA CTG TTG CCC GCT CCT ATT GGG GGG ATG AAT TAT CTG AAT ATG AGC 12071 Ala Leu Leu Pro Ala Pro Ile Gly Gly Met Asn Tyr Leu Asn Met Ser 935 940 945 AGG CTG TTT GTC AGA AAC ATC GGT GAT CCA GTA ACA TCA TCA ATT GCT 12119 Arg Leu Phe Val Arg Asn Ile Gly Asp Pro Val Thr Ser Ser Ile Ala 950 955 960 GAT CTC AAG AGA ATG ATT CTC GCC TCA CTA ATG CCT GAA GAG ACC CTC 12167 Asp Leu Lys Arg Met Ile Leu Ala Ser Leu Met Pro Glu Glu Thr Leu 965 970 975 CAT CAA GTA ATG ACA CAA CAA CCG GGG GAC TCT TCA TTC CTA GAC TGG 12215 His Gln Val Met Thr Gln Gln Pro Gly Asp Ser Ser Phe Leu Asp Trp 980 985 990 GCT AGC GAC CCT TAC TCA GCA AAT CTT GTA TGT GTC CAG AGC ATC ACT 12263 Ala Ser Asp Pro Tyr Ser Ala Asn Leu Val Cys Val Gln Ser Ile Thr 995 1000 1005 1010 AGA CTC CTC AAG AAC ATA ACT GCA AGG TTT GTC CTG ATC CAT AGT CCA 12311 Arg Leu Leu Lys Asn Ile Thr Ala Arg Phe Val Leu Ile His Ser Pro 1015 1020 1025 AAC CCA ATG TTA AAA GGA TTA TTC CAT GAT GAC AGT AAA GAA GAG GAC 12359 Asn Pro Met Leu Lys Gly Leu Phe His Asp Asp Ser Lys Glu Glu Asp 1030 1035 1040 GAG GGA CTG GCG GCA TTC CTC ATG GAC AGG CAT ATT ATA GTA CCT AGG 12407 Glu Gly Leu Ala Ala Phe Leu Met Asp Arg His Ile Ile Val Pro Arg 1045 1050 1055 GCA GCT CAT GAA ATC CTG GAT CAT AGT GTC ACA GGG GCA AGA GAG TCT 12455 Ala Ala His Glu Ile Leu Asp His Ser Val Thr Gly Ala Arg Glu Ser 1060 1065 1070 ATT GCA GGC ATG CTG GAT ACC ACA AAA GGC CTG ATT CGA GCC AGC ATG 12503 Ile Ala Gly Met Leu Asp Thr Thr Lys Gly Leu Ile Arg Ala Ser Met 1075 1080 1085 1090 AGG AAG GGG GGG TTA ACC TCT CGA GTG ATA ACC AGA TTG TCC AAT TAT 12551 Arg Lys Gly Gly Leu Thr Ser Arg Val Ile Thr Arg Leu Ser Asn Tyr 1095 1100 1105 GAC TAT GAA CAA TTC AGA GCA GGG ATG GTG CTA TTG ACG GGA AGA AAG 12599 Asp Tyr Glu Gln Phe Arg Ala Gly Met Val Leu Leu Thr Gly Arg Lys 1110 1115 1120 AGA AAT GTC CTC ATT GAC AAA GAG TCA TGT TCA GTG CAG CTG GCG AGA 12647 Arg Asn Val Leu Ile Asp Lys Glu Ser Cys Ser Val Gln Leu Ala Arg 1125 1130 1135 GCT CTA AGA AGC CAT ATG TGG GCG AGG CTA GCT CGA GGA CGG CCT ATT 12695 Ala Leu Arg Ser His Met Trp Ala Arg Leu Ala Arg Gly Arg Pro Ile 1140 1145 1150 TAC GGC CTT GAG GTC CCT GAT GTA CTA GAA TCT ATG CGA GGC CAC CTT 12743 Tyr Gly Leu Glu Val Pro Asp Val Leu Glu Ser Met Arg Gly His Leu 1155 1160 1165 1170 ATT CGG CGT CAT GAG ACA TGT GTC ATC TGC GAG TGT GGA TCA GTC AAC 12791 Ile Arg Arg His Glu Thr Cys Val Ile Cys Glu Cys Gly Ser Val Asn 1175 1180 1185 TAC GGA TGG TTT TTT GTC CCC TCG GGT TGC CAA CTG GAT GAT ATT GAC 12839 Tyr Gly Trp Phe Phe Val Pro Ser Gly Cys Gln Leu Asp Asp Ile Asp 1190 1195 1200 AAG GAA ACA TCA TCC TTG AGA GTC CCA TAT ATT GGT TCT ACC ACT GAT 12887 Lys Glu Thr Ser Ser Leu Arg Val Pro Tyr Ile Gly Ser Thr Thr Asp 1205 1210 1215 GAG AGA ACA GAC ATG AAG CTT GCC TTC GTA AGA GCC CCA AGT CGA TCC 12935 Glu Arg Thr Asp Met Lys Leu Ala Phe Val Arg Ala Pro Ser Arg Ser 1220 1225 1230 TTG CGA TCT GCT GTT AGA ATA GCA ACA GTG TAC TCA TGG GCT TAC GGT 12983 Leu Arg Ser Ala Val Arg Ile Ala Thr Val Tyr Ser Trp Ala Tyr Gly 1235 1240 1245 1250 GAT GAT GAT AGC TCT TGG AAC GAA GCC TGG TTG TTG GCT AGG CAA AGG 13031 Asp Asp Asp Ser Ser Trp Asn Glu Ala Trp Leu Leu Ala Arg Gln Arg 1255 1260 1265 GCC AAT GTG AGC CTG GAG GAG CTA AGG GTG ATC ACT CCC ATC TCA ACT 13079 Ala Asn Val Ser Leu Glu Glu Leu Arg Val Ile Thr Pro Ile Ser Thr 1270 1275 1280 TCG ACT AAT TTA GCG CAT AGG TTG AGG GAT CGT AGC ACT CAA GTG AAA 13127 Ser Thr Asn Leu Ala His Arg Leu Arg Asp Arg Ser Thr Gln Val Lys 1285 1290 1295 TAC TCA GGT ACA TCC CTT GTC CGA GTG GCG AGG TAT ACC ACA ATC TCC 13175 Tyr Ser Gly Thr Ser Leu Val Arg Val Ala Arg Tyr Thr Thr Ile Ser 1300 1305 1310 AAC GAC AAT CTC TCA TTT GTC ATA TCA GAT AAG AAG GTT GAT ACT AAC 13223 Asn Asp Asn Leu Ser Phe Val Ile Ser Asp Lys Lys Val Asp Thr Asn 1315 1320 1325 1330 TTT ATA TAC CAA CAA GGA ATG CTT CTA GGG TTG GGT GTT TTA GAA ACA 13271 Phe Ile Tyr Gln Gln Gly Met Leu Leu Gly Leu Gly Val Leu Glu Thr 1335 1340 1345 TTG TTT CGA CTC GAG AAA GAT ACC GGA TCA TCT AAC ACG GTA TTA CAT 13319 Leu Phe Arg Leu Glu Lys Asp Thr Gly Ser Ser Asn Thr Val Leu His 1350 1355 1360 CTT CAC GTC GAA ACA GAT TGT TGC GTG ATC CCG ATG ATA GAT CAT CCC 13367 Leu His Val Glu Thr Asp Cys Cys Val Ile Pro Met Ile Asp His Pro 1365 1370 1375 AGG ATA CCC AGC TCC CGC AAG CTA GAG CTG AGG GCA GAG CTA TGT ACC 13415 Arg Ile Pro Ser Ser Arg Lys Leu Glu Leu Arg Ala Glu Leu Cys Thr 1380 1385 1390 AAC CCA TTG ATA TAT GAT AAT GCA CCT TTA ATT GAC AGA GAT ACA ACA 13463 Asn Pro Leu Ile Tyr Asp Asn Ala Pro Leu Ile Asp Arg Asp Thr Thr 1395 1400 1405 1410 AGG CTA TAC ACC CAG AGC CAT AGG AGG CAC CTT GTG GAA TTT GTT ACA 13511 Arg Leu Tyr Thr Gln Ser His Arg Arg His Leu Val Glu Phe Val Thr 1415 1420 1425 TGG TCC ACA CCC CAA CTA TAT CAC ATT TTA GCT AAG TCC ACA GCA CTA 13559 Trp Ser Thr Pro Gln Leu Tyr His Ile Leu Ala Lys Ser Thr Ala Leu 1430 1435 1440 TCT ATG ATT GAC CTG GTA ACA AAA TTT GAG AAG GAC CAT ATG AAT GAA 13607 Ser Met Ile Asp Leu Val Thr Lys Phe Glu Lys Asp His Met Asn Glu 1445 1450 1455 ATT TCA GCT CTC ATA GGG GAT GAC GAT ATC AAT AGT TTC ATA ACT GAG 13655 Ile Ser Ala Leu Ile Gly Asp Asp Asp Ile Asn Ser Phe Ile Thr Glu 1460 1465 1470 TTT CTC GTC ATA GAG CCA AGA TTA TTC ACT ATC TAC TTG GGC CAG TGT 13703 Phe Leu Val Ile Glu Pro Arg Leu Phe Thr Ile Tyr Leu Gly Gln Cys 1475 1480 1485 1490 GCG GCC ATC AAT TGG GCA TTT GAT GTA CAT TAT CAT AGA CCA TCA GGG 13751 Ala Ala Ile Asn Trp Ala Phe Asp Val His Tyr His Arg Pro Ser Gly 1495 1500 1505 AAA TAT CAG ATG GGT GAG CTG TTG TCA TCG TTC CTT TCT AGA ATG AGC 13799 Lys Tyr Gln Met Gly Glu Leu Leu Ser Ser Phe Leu Ser Arg Met Ser 1510 1515 1520 AAA GGA GTG TTT AAG GTG CTT GTC AAT GCT CTA AGC CAC CCA AAG ATC 13847 Lys Gly Val Phe Lys Val Leu Val Asn Ala Leu Ser His Pro Lys Ile 1525 1530 1535 TAC AAG AAA TTC TGG CAT TGT GGT ATT ATA GAG CCT ATC CAT GGT CCT 13895 Tyr Lys Lys Phe Trp His Cys Gly Ile Ile Glu Pro Ile His Gly Pro 1540 1545 1550 TCA CTT GAT GCT CAA AAC TTG CAC ACA ACT GTG TGC AAC ATG GTT TAC 13943 Ser Leu Asp Ala Gln Asn Leu His Thr Thr Val Cys Asn Met Val Tyr 1555 1560 1565 1570 ACA TGC TAT ATG ACC TAC CTC GAC CTG TTG TTG AAT GAA GAG TTA GAA 13991 Thr Cys Tyr Met Thr Tyr Leu Asp Leu Leu Leu Asn Glu Glu Leu Glu 1575 1580 1585 GAG TTC ACA TTT CTC TTG TGT GAA AGC GAC GAG GAT GTA GTA CCG GAC 14039 Glu Phe Thr Phe Leu Leu Cys Glu Ser Asp Glu Asp Val Val Pro Asp 1590 1595 1600 AGA TTC GAC AAC ATC CAG GCA AAA CAC TTA TGT GTT CTG GCA GAT TTG 14087 Arg Phe Asp Asn Ile Gln Ala Lys His Leu Cys Val Leu Ala Asp Leu 1605 1610 1615 TAC TGT CAA CCA GGG GCC TGC CCA CCA ATT CGA GGT CTA AGA CCG GTA 14135 Tyr Cys Gln Pro Gly Ala Cys Pro Pro Ile Arg Gly Leu Arg Pro Val 1620 1625 1630 GAG AAA TGT GCA GTT CTA ACC GAC CAT ATC AAG GCA GAG GCT AGG TTA 14183 Glu Lys Cys Ala Val Leu Thr Asp His Ile Lys Ala Glu Ala Arg Leu 1635 1640 1645 1650 TCT CCA GCA GGA TCT TCG TGG AAC ATA AAT CCA ATT ATT GTA GAC CAT 14231 Ser Pro Ala Gly Ser Ser Trp Asn Ile Asn Pro Ile Ile Val Asp His 1655 1660 1665 TAC TCA TGC TCT CTG ACT TAT CTC CGG CGA GGA TCG ATC AAA CAG ATA 14279 Tyr Ser Cys Ser Leu Thr Tyr Leu Arg Arg Gly Ser Ile Lys Gln Ile 1670 1675 1680 AGA TTG AGA GTT GAT CCA GGA TTC ATT TTC GAC GCC CTC GCT GAG GTA 14327 Arg Leu Arg Val Asp Pro Gly Phe Ile Phe Asp Ala Leu Ala Glu Val 1685 1690 1695 AAT GTC AGT CAG CCA AAG ATC GGC AGC AAC AAC ATC TCA AAT ATG AGC 14375 Asn Val Ser Gln Pro Lys Ile Gly Ser Asn Asn Ile Ser Asn Met Ser 1700 1705 1710 ATC AAG GCT TTC AGA CCC CCA CAC GAT GAT GTT GCA AAA TTG CTC AAA 14423 Ile Lys Ala Phe Arg Pro Pro His Asp Asp Val Ala Lys Leu Leu Lys 1715 1720 1725 1730 GAT ATC AAC ACA AGC AAG CAC AAT CTT CCC ATT TCA GGG GGC AAT CTC 14471 Asp Ile Asn Thr Ser Lys His Asn Leu Pro Ile Ser Gly Gly Asn Leu 1735 1740 1745 GCC AAT TAT GAA ATC CAT GCT TTC CGC AGA ATC GGG TTG AAC TCA TCT 14519 Ala Asn Tyr Glu Ile His Ala Phe Arg Arg Ile Gly Leu Asn Ser Ser 1750 1755 1760 GCT TGC TAC AAA GCT GTT GAG ATA TCA ACA TTA ATT AGG AGA TGC CTT 14567 Ala Cys Tyr Lys Ala Val Glu Ile Ser Thr Leu Ile Arg Arg Cys Leu 1765 1770 1775 GAG CCA GGG GAG GAC GGC TTG TTC TTG GGT GAG GGA TCG GGT TCT ATG 14615 Glu Pro Gly Glu Asp Gly Leu Phe Leu Gly Glu Gly Ser Gly Ser Met 1780 1785 1790 TTG ATC ACT TAT AAG GAG ATA CTT AAA CTA AAC AAG TGC TTC TAT AAT 14663 Leu Ile Thr Tyr Lys Glu Ile Leu Lys Leu Asn Lys Cys Phe Tyr Asn 1795 1800 1805 1810 AGT GGG GTT TCC GCC AAT TCT AGA TCT GGT CAA AGG GAA TTA GCA CCC 14711 Ser Gly Val Ser Ala Asn Ser Arg Ser Gly Gln Arg Glu Leu Ala Pro 1815 1820 1825 TAT CCC TCC GAA GTT GGC CTT GTC GAA CAC AGA ATG GGA GTA GGT AAT 14759 Tyr Pro Ser Glu Val Gly Leu Val Glu His Arg Met Gly Val Gly Asn 1830 1835 1840 ATT GTC AAA GTG CTC TTT AAC GGG AGG CCC GAA GTC ACG TGG GTA GGC 14807 Ile Val Lys Val Leu Phe Asn Gly Arg Pro Glu Val Thr Trp Val Gly 1845 1850 1855 AGT GTA GAT TGC TTC AAT TTC ATA GTT AGT AAT ATC CCT ACC TCT AGT 14855 Ser Val Asp Cys Phe Asn Phe Ile Val Ser Asn Ile Pro Thr Ser Ser 1860 1865 1870 GTG GGG TTT ATC CAT TCA GAT ATA GAG ACC TTG CCT AAC AAA GAT ACT 14903 Val Gly Phe Ile His Ser Asp Ile Glu Thr Leu Pro Asn Lys Asp Thr 1875 1880 1885 1890 ATA GAG AAG CTA GAG GAA TTG GCA GCC ATC TTA TCG ATG GCT CTG CTC 14951 Ile Glu Lys Leu Glu Glu Leu Ala Ala Ile Leu Ser Met Ala Leu Leu 1895 1900 1905 CTG GGC AAA ATA GGA TCA ATA CTG GTG ATT AAG CTT ATG CCT TTC AGC 14999 Leu Gly Lys Ile Gly Ser Ile Leu Val Ile Lys Leu Met Pro Phe Ser 1910 1915 1920 GGG GAT TTT GTT CAG GGA TTT ATA AGT TAT GTA GGG TCT TAT TAT AGA 15047 Gly Asp Phe Val Gln Gly Phe Ile Ser Tyr Val Gly Ser Tyr Tyr Arg 1925 1930 1935 GAA GTG AAC CTT GTA TAC CCT AGA TAC AGC AAC TTC ATA TCT ACT GAA 15095 Glu Val Asn Leu Val Tyr Pro Arg Tyr Ser Asn Phe Ile Ser Thr Glu 1940 1945 1950 TCT TAT TTG GTT ATG ACA GAT CTC AAG GCT AAC CGG CTA ATG AAT CCT 15143 Ser Tyr Leu Val Met Thr Asp Leu Lys Ala Asn Arg Leu Met Asn Pro 1955 1960 1965 1970 GAA AAG ATT AAG CAG CAG ATA ATT GAA TCA TCT GTG AGG ACT TCA CCT 15191 Glu Lys Ile Lys Gln Gln Ile Ile Glu Ser Ser Val Arg Thr Ser Pro 1975 1980 1985 GGA CTT ATA GGT CAC ATC CTA TCC ATT AAG CAA CTA AGC TGC ATA CAA 15239 Gly Leu Ile Gly His Ile Leu Ser Ile Lys Gln Leu Ser Cys Ile Gln 1990 1995 2000 GCA ATT GTG GGA GAC GTA GTT AGT AGA GGT GAT ATC AAT CCT ACT CTG 15287 Ala Ile Val Gly Asp Val Val Ser Arg Gly Asp Ile Asn Pro Thr Leu 2005 2010 2015 AAA AAA CTT ACA CCT ATA GAG CAG GTG CTG ATC AAT TGC GGG TTG GCA 15335 Lys Lys Leu Thr Pro Ile Glu Gln Val Leu Ile Asn Cys Gly Leu Ala 2020 2025 2030 ATT AAC GGA CCT AAG CTG TGC AAA GAA TTG ATC CAC CAT GAT GTT GCC 15383 Ile Asn Gly Pro Lys Leu Cys Lys Glu Leu Ile His His Asp Val Ala 2035 2040 2045 2050 TCA GGG CAA GAT GGA TTG CTT AAT TCT ATC CTC ATC CTC TAC AGG GAG 15431 Ser Gly Gln Asp Gly Leu Leu Asn Ser Ile Leu Ile Leu Tyr Arg Glu 2055 2060 2065 TTG GCA AGA TTC AAA GAC AAC CGA AGA AGT CAA CAA GGG ATG TTC CAC 15479 Leu Ala Arg Phe Lys Asp Asn Arg Arg Ser Gln Gln Gly Met Phe His 2070 2075 2080 GCT TAC CCC GTA TTG GTA AGT AGC AGG CAA CGA GAA CTT ATA TCT AGG 15527 Ala Tyr Pro Val Leu Val Ser Ser Arg Gln Arg Glu Leu Ile Ser Arg 2085 2090 2095 ATC ACC CGC AAA TTT TGG GGG CAC ATT CTT CTT TAC TCC GGG AAC AGA 15575 Ile Thr Arg Lys Phe Trp Gly His Ile Leu Leu Tyr Ser Gly Asn Arg 2100 2105 2110 AAG TTG ATA AAT AAG TTT ATC CAG AAT CTC AAG TCC GGC TAT CTG ATA 15623 Lys Leu Ile Asn Lys Phe Ile Gln Asn Leu Lys Ser Gly Tyr Leu Ile 2115 2120 2125 2130 CTA GAC TTA CAC CAG AAT ATC TTC GTT AAG AAT CTA TCC AAG TCA GAG 15671 Leu Asp Leu His Gln Asn Ile Phe Val Lys Asn Leu Ser Lys Ser Glu 2135 2140 2145 AAA CAG ATT ATT ATG ACG GGG GGT TTG AAA CGT GAG TGG GTT TTT AAG 15719 Lys Gln Ile Ile Met Thr Gly Gly Leu Lys Arg Glu Trp Val Phe Lys 2150 2155 2160 GTA ACA GTC AAG GAG ACC AAA GAA TGG TAT AAG TTA GTC GGA TAC AGT 15767 Val Thr Val Lys Glu Thr Lys Glu Trp Tyr Lys Leu Val Gly Tyr Ser 2165 2170 2175 GCC CTG ATT AAG GAC TAATTGGTTG AACTCCGGAA CCCTAATCCT GCCCTAGGTG 15822 Ala Leu Ile Lys Asp 2180 GTTAGGCATT ATTTGCAATA TATTAAAGAA AACTTTGAAA ATACGAAGTT TCTATTCCCA 15882 GCTTTGTCTG GT 15894
  2. 【請求項２】 ワクチン用麻疹ウイルスが種ＡＩＫ−Ｃ
    株麻疹ウイルスより生産され、該生産されたウイルスの
    品質がウイルスのゲノムＲＮＡに相当するｃＤＮＡのヌ
    クレオチド配列を決定し、該決定された配列を請求項１
    に記載のＤＮＡ配列と比較することにより検査する請求
    項１に記載の方法。
  3. 【請求項３】 請求項１に記載のヌクレオチド配列を有
    するｃＤＮＡ。
  4. 【請求項４】 請求項３に記載の単離されたｃＤＮＡ。
  5. 【請求項５】 請求項１に記載の配列に相当するヌクレ
    オチド配列を有するＲＮＡ。
JP3293625A 1991-10-14 1991-10-14 麻疹ワクチンウイルス株同定方法 Expired - Lifetime JP3045581B2 (ja)

Priority Applications (11)

Application Number Priority Date Filing Date Title
JP3293625A JP3045581B2 (ja) 1991-10-14 1991-10-14 麻疹ワクチンウイルス株同定方法
KR1019920003759A KR950012759B1 (ko) 1991-10-14 1992-03-07 특정 염기 배열을 포함하는 약독화(弱毒化)된 홍역 백신 바이러스주 및 그의 절대적 동정법
DK92302004T DK0540135T3 (da) 1991-10-14 1992-03-10 Attenueret mæslingevaccine-virusstamme indeholdende specifik nuklotidsekvens og en fremgangsmåde til dens absolutte identif
AT92302004T ATE193726T1 (de) 1991-10-14 1992-03-10 Spezifische nukleotidsequenz enthaltender masernvirusvakzinstamm und verfahren zu seiner absoluten identifizierung
EP92302004A EP0540135B1 (en) 1991-10-14 1992-03-10 Attenuated measles vaccine virus strain containing specific nucleotide sequence and a method for its absolute identification
PT92302004T PT540135E (pt) 1991-10-14 1992-03-10 Estirpe atenuada de virus da vacina do sarampo contendo uma sequencia nucleotidica especifica e um metodo para a sua identificacao absoluta
DE69231143T DE69231143T2 (de) 1991-10-14 1992-03-10 Spezifische Nukleotidsequenz enthaltender Masernvirusvakzinstamm und Verfahren zu seiner absoluten Identifizierung
ES92302004T ES2148164T3 (es) 1991-10-14 1992-03-10 Cepa atenuada de vacuna del virus del sarampion, que contiene una secuencia nucleotidica especifica y procedimiento para su identificacion.
US08/348,891 US5654136A (en) 1991-10-14 1994-11-25 Attenuated measles virus vaccine, containing specific nucleotide sequence and a method for its absolute identification
US08/905,817 US5824777A (en) 1991-10-14 1997-08-04 Attenuated measles virus vaccine containing specific nucleotide sequence and a method for its absolute identification
GR20000401965T GR3034278T3 (en) 1991-10-14 2000-08-30 Attenuated measles vaccine virus strain containing specific nucleotide sequence and a method for its absolute identification.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP3293625A JP3045581B2 (ja) 1991-10-14 1991-10-14 麻疹ワクチンウイルス株同定方法

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JPH05103665A JPH05103665A (ja) 1993-04-27
JP3045581B2 true JP3045581B2 (ja) 2000-05-29

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DE (1) DE69231143T2 (ja)
DK (1) DK0540135T3 (ja)
ES (1) ES2148164T3 (ja)
GR (1) GR3034278T3 (ja)
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WO1993021325A1 (en) * 1992-04-08 1993-10-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Wild-type measles virus glycoproteins: vaccine and detection method therefor
US6638482B1 (en) * 1993-11-01 2003-10-28 Nanogen, Inc. Reconfigurable detection and analysis apparatus and method
ATE226594T1 (de) * 1996-07-31 2002-11-15 Claude P Muller Peptide abgeleitet aus dem morbillivirus
CA2265554A1 (en) * 1996-09-27 1998-04-02 American Cyanamid Company 3' genomic promoter region and polymerase gene mutations responsible for attenuation in viruses of the order designated mononegavirales
JP4043054B2 (ja) * 1997-06-04 2008-02-06 財団法人阪大微生物病研究会 変異麻疹ウイルス抗原及びそれをコードする遺伝子
BR9909076A (pt) * 1998-03-26 2000-12-05 American Cyanamid Co Vìrus atenuado do sarampo, recombinantemente gerado, isolado, vìrus do sarampo, vìrus sincicial respiratório humano (rsv), subgrupo b, atenuado, recombinantemente gerado, isolado, o rsv, subgrupo b, vacina processo para imunização de um indivìduo para induzir proteção contra vìrus do sarampo, processo para imunização de um indivìduo para induzir proteção contra o rsv, subgrupo b, composição, processo para produção de vìrus do sarampo infeccioso atenuado, processo para produção de rsv infeccioso atenuado subgrupo b
US6875436B1 (en) * 1999-11-19 2005-04-05 The Kitasata Institute Method for producing cell-fushion type morbillivirus mutants
CA2359659C (en) 2000-01-31 2006-10-17 The Research Foundation For Microbial Diseases Of Osaka University Method for quality control of an attenuated varicella live vaccine
AU7948000A (en) * 2000-02-10 2001-08-20 Kitasato Inst Method of constructing temperature-sensitive morbilli virus
EP2110382A1 (en) * 2002-06-20 2009-10-21 Institut Pasteur Infectious cDNA of an improved vaccine strain of measles virus, use for immunogenic compositions
DK1375670T3 (da) 2002-06-20 2013-09-23 Pasteur Institut Rekombinante mæslingevira, der udtrykker epitoper af RNA-viras antigener, samt anvendelse af de rekombinante vira til fremstilling af vaccinesammensætninger
CA2432738A1 (en) 2003-02-26 2004-08-26 Philippe Despres New dengue and west nile viruses proteins and genes coding the foregoing, and their use in vaccinal, therapeutic and diagnostic applications
EP2420242A1 (en) 2010-08-20 2012-02-22 Lauer, Ulrich M. Oncolytic measles virus
CN104211769B (zh) * 2013-05-30 2018-08-03 中国科学院过程工程研究所 一种小分子抗体亲和肽及其应用

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US4617261A (en) * 1984-03-21 1986-10-14 Cetus Corporation Process for labeling nucleic acids and hybridization probes
JPS63307827A (ja) * 1987-06-08 1988-12-15 Kitasato Inst:The 安定化された生ウイルスワクチンおよびその製造法
AU7007491A (en) * 1990-02-02 1991-08-08 Schweiz. Serum- & Impfinstitut Bern Cdna corresponding to the genome of negative-strand rna viruses, and process for the production of infectious negative-strand rna viruses

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ES2148164T3 (es) 2000-10-16
PT540135E (pt) 2000-11-30
EP0540135B1 (en) 2000-06-07
GR3034278T3 (en) 2000-12-29
EP0540135A3 (en) 1993-12-08
KR930008138A (ko) 1993-05-21
EP0540135A2 (en) 1993-05-05
US5824777A (en) 1998-10-20
DE69231143T2 (de) 2000-10-19
KR950012759B1 (ko) 1995-10-21
JPH05103665A (ja) 1993-04-27
DK0540135T3 (da) 2000-08-07
DE69231143D1 (de) 2000-07-13
ATE193726T1 (de) 2000-06-15
US5654136A (en) 1997-08-05

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