JP2011514163A - 増幅反応中の核酸分子を分析するための組成物及び方法 - Google Patents
増幅反応中の核酸分子を分析するための組成物及び方法 Download PDFInfo
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Abstract
【選択図】なし
Description
いくつかの実施形態では、本発明は対象となる標的核酸を分析するための検出技術を提供する。本明細書に記載するように、検出技術は必要に応じて定量的又は半定量的であり得る、リアルタイム検出能を有する。システム、組成物(例えば、キット、反応混合物等)、及び方法が提供される。システム、組成物及び方法は、他の既知の技術又は将来開発されるであろう技術と併用してもよい。いくつかの実施形態では、本発明は、例えば検出酵素を用いて検出するのに必要な最小構造(例えば二本鎖)を提供するフットプリントプローブの使用を含む検出システムを提供する。
本発明の理解を助けるために、いくつかの用語及び語句を以下に定義する。
本発明は、増幅された核酸、例えばPCRで増幅されたDNAを検出するための均質なリアルタイムアッセイに関する。いくつかの実施形態では、用いられるプローブはフルオロフォア等の検出可能な部分を含むが、いくつかの実施形態では、プローブはフルオロフォア及びクエンチャー部分等の相互作用検出系を含む。更に他の実施形態では、本発明の方法及びシステムは、分析物特異的プローブの切断産物を検出するよう構成されている検出系と共役した、非標識の分析物特異的プローブを使用する。
上述のように、本発明は酵素フットプリントプローブを使用する。二本鎖を認識する核酸修飾酵素用の認識フットプリントの同定は、FEN−1エンドヌクレアーゼ等の5’ヌクレアーゼについて本明細書に記載されている。しかしながら、本発明はこれらの酵素と共に使用するために設計されたフットプリントプローブに限定されない。当業者は、他の核酸修飾酵素の活性要件の分析に同じ原理を適用することができる。
ここでは、高融解温度を有するプライマーの存在下でさえ、また熱サイクルで用いられる「アニーリング温度」がフットプリントプローブのASRの計算Tm値(例えば最近接モデル及びDNA二本鎖形成のための公開されているパラメータ等の当該技術分野において標準的である方法を用いて計算される、Allawi and SantaLucia,Biochemistry,36:10581(1997)、及びSantaLucia,Proc Natl Acad Sci USA.,95(4):1460(1998))を優に上回る反応でさえも、短いフットプリントプローブを増幅アッセイで用い得ることを示す。本発明を任意の特定の作用機序に限定するものではないが、FEN−1酵素は計算Tm値を優に上回る温度で短いプローブのアニーリング及び切断を促進する因子であり得ると思われる。事実、本明細書に提供される実験データは、本発明の方法を実施できる温度が、用いられるプローブのASRの計算Tm値にほとんど依存しない、又は全く依存しないことを示す。
本発明の態様は、リアルタイムでPCRアッセイ等の標的増幅アッセイを検出するためのシステム及び方法を提供する。いくつかの実施形態では、本発明は検出アッセイ(例えば切断アッセイ)と組み合わせた標的増幅アッセイを実施するためのシステム、方法及びキットを提供し、前記検出アッセイは比較的短い(例えば6〜12塩基)の分析物特異的領域を有するプローブを用いる。好ましい実施形態では、これらのプローブは、検出試薬、例えばFEN−1ヌクレアーゼ等の切断試薬により有効に認識可能な二本鎖の最小長又はおよそ最小長であるプローブ/分析物二本鎖を提供するよう構成されており、その結果プローブの分析物特異的部分に対して配列中にミスマッチを有する標的にアニールしたプローブは、十分な効率で切断されない又は全く切断されない。かかる実施形態では、ミスマッチの標的核酸にハイブリダイズしたプローブからの検出可能な切断が、プローブの分析物特異的部分に完全に相補的である標的核酸にハイブリダイズしているプローブからの検出可能な切断に比べて減少しており、それによりこのアッセイがより高い特異性及び/又はより低いバックグラウンドを有する。
本発明の別の態様は、標準的な加水分解プローブに基づく方法と比べたとき、より迅速な増幅反応のリアルタイム検出を提供する。上で論じたように、TAQMAN型アッセイでは、プライマーがPCRのサイクルにおいて標的に沿って伸長したとき加水分解プローブを切断する。したがって、シグナル蓄積速度は、PCRの温度サイクリングに関連し、それにより制限される。
上述のように、リアルタイムPCRのためのプローブに基づく特異的検出化学の主な問題点の1つは、異なる分析物配列の各々について、高価な色素、クエンチャー、及び任意的にMGBを含む種々の特注プローブを使用する必要があることである。いくつかの実施形態では、本発明は、標識されたオリゴヌクレオチドを用いる二次検出反応に加えて、非標識の分析物特異的プローブを使用することを含むリアルタイム検出法を提供し、その結果高価な部分で標識された分析物特異的プローブを作製する必要がなくなる。
本発明の方法は、標的核酸の種類に限定されない。例えば、標的核酸としては、例えばRNAゲノムを有するウイルスから調製された核酸物質を挙げることができる。典型的には、RNA標的配列は逆転写酵素の作用によりcDNA分子に変換され、次いで核酸検出アッセイにより検出される。本発明の方法の組み込みにより、RNA標的配列の検出のダイナミックレンジは未だ実現不可能な幅に増加する。
この実施例は、INVADERアッセイ及びPCRの組み合わせから構成される定量アッセイについて記載する。INVADERアッセイは、短い分析物特異的領域(例えば11又は12塩基)を有するフットプリントプローブを用いて実施される。本発明のかかる短い酵素フットプリントプローブの使用により、INVADER−PCR組合せアッセイのダイナミックレンジが増加する。任意の特定の機序に限定されるものではなく、また本発明の実施に必須ではないが、INVADERアッセイ等の侵入的切断アッセイにおいて短い分析物特異的領域を有するプローブを使用することにより、標的検出のダイナミックレンジを増加させることができると考えられている。なぜなら切断されたプローブはPCR反応に干渉しないためである。例えば、切断されたプローブは、短いため、1)安定にハイブリダイズせず、それ故PCRプライマー伸長を阻害しない、そして2)PCR反応の一部として不適切に伸長されないと考えられている。
この実施例は、アッセイの種々の成分を試験するために、特定の成分を除く又は含むことを除いて、実施例1と同種のPCR−侵入的切断反応について記載する。この実施例では、以下の標的を使用した:U6 RNA;GA−21−DNA;第5因子DNA;及び第2因子DNA。以下の10×オリゴミックスを各標的のために調製した:4μMのリバースプライマー;4μMのフォワードプライマー;0.4μMの侵入的オリゴ(指示したように特定の条件では省略);6.7μMのプローブオリゴ;及び2.5μMのFRETオリゴ。以下の構成を有する10×反応緩衝液を各反応に用いた:100mMのMOPS、pH7.5;75mMのMgCl2;及び250μMのdNTP(指示したように特定の条件では省略)。200ng/μLのAfuFEN−1(指示したように特定の条件では省略);1.33ユニット/μLのGo Taqポリメラーゼ(天然Taqポリメラーゼ、Promega Corp.);80ユニット/μLのMMLV逆転写酵素(DNA標的では省略);及び7mM DTTから構成されていた40×酵素ミックスも各反応に用いた。
この実施例は、遺伝子型同定のためにPCR中に実施される侵入的切断アッセイにおける短い分析物特異的領域(この実施例では12塩基)を有するプローブの使用について記載する。この実施例における標的は第5因子である。第5因子のSNPを検出するための特異的プローブ、プライマー、侵入的オリゴヌクレオチド、及びFRETカセット配列を図5に示す。
Claims (82)
- 標的核酸を分析する方法であって、a)合成プローブ及びFEN−1エンドヌクレアーゼの存在下にて、前記合成プローブが増幅反応中に切断されて切断断片を生成する条件下で、標的核酸を増幅する工程であって、前記合成プローブが分析物特異的部分及び非標的部分を含むフットプリントプローブであり、前記非標的部分が前記標的核酸に対して実質的に非相補的であり、前記分析物特異的部分の長さが12ヌクレオチド以下であり、前記分析物特異的部分が前記標的核酸に対して相補的である最高12ヌクレオチドを含む、上記工程と;b)前記増幅反応中に前記切断断片を検出する工程と、を含む方法。
- 前記分析が、前記増幅反応中に前記切断断片を検出することにより前記標的核酸の存在を検出することを含む、請求項1に記載の方法。
- 前記分析が、前記標的核酸における多型の存在を同定することを含む、請求項1に記載の方法。
- 前記分析が、標的核酸が由来する生物を同定することを含む、請求項1に記載の方法。
- 前記分析が、前記標的核酸の量を検出することを含む、請求項1に記載の方法。
- 前記標的核酸がサンプルから単離されている、請求項1に記載の方法。
- 前記サンプルが、細胞サンプル、組織サンプル、流体サンプル、培養サンプル、及び環境サンプルから成る群から選択される、請求項6に記載の方法。
- 前記標的核酸が、動物、植物、細菌、ウイルス、及び真菌から成る群から選択される生物に由来する、請求項1に記載の方法。
- 前記標的核酸がDNAである、請求項1に記載の方法。
- 前記標的核酸がRNAである、請求項1に記載の方法。
- 前記増幅前に又は前記増幅と同時に前記RNAをDNAに逆転写する工程を更に含む、請求項10に記載の方法。
- 前記増幅がポリメラーゼ連鎖反応を含む、請求項1に記載の方法。
- 前記増幅がポリメラーゼを使用する、請求項1に記載の方法。
- 前記ポリメラーゼが熱安定性ポリメラーゼである、請求項13に記載の方法。
- 前記ポリメラーゼが5’から3’へのエキソヌクレアーゼ活性を欠いている、請求項13に記載の方法。
- 前記FEN−1エンドヌクレアーゼが熱安定性FEN−1エンドヌクレアーゼである、請求項1に記載の方法。
- 前記FEN−1エンドヌクレアーゼが古細菌種由来である、請求項1に記載の方法。
- 前記増幅が第1及び第2のプライマーオリゴヌクレオチドを使用する、請求項1に記載の方法。
- 前記プローブが切断される前に切断構造が形成され、前記切断構造がa)前記標的核酸の第1の領域における前記プローブ、及びb)第1の領域の下流に存在する前記標的核酸の第2の領域と会合する第2のオリゴヌクレオチドと、前記標的核酸との会合により形成される、請求項1に記載の方法。
- 第2の領域が第1の領域に隣接している、請求項19に記載の方法。
- 前記切断構造における第2のオリゴヌクレオチドの3’末端において少なくとも1個のヌクレオチドが、前記プローブと前記標的核酸とのハイブリダイゼーション領域と重複する、請求項19に記載の方法。
- 第2のオリゴヌクレオチドの3’末端ヌクレオチドが、前記切断構造における前記標的核酸に対して非相補的である、請求項21に記載の方法。
- 第2のオリゴヌクレオチドが前記増幅で用いられるプライマーでもある、請求項19に記載の方法。
- 前記プローブの前記標的結合部分が、前記標的核酸に対して相補的である11以下のヌクレオチドを含む、請求項1に記載の方法。
- 前記プローブの前記標的結合部分が、前記標的核酸に対して相補的である10以下のヌクレオチドを含む、請求項1に記載の方法。
- 前記プローブの前記標的結合部分が、前記標的核酸に対して相補的である9以下のヌクレオチドを含む、請求項1に記載の方法。
- 前記プローブの前記標的結合部分が、前記標的核酸に対して相補的である8以下のヌクレオチドを含む、請求項1に記載の方法。
- 前記プローブの前記標的結合部分が、前記標的核酸に対して相補的である7以下のヌクレオチドを含む、請求項1に記載の方法。
- 前記プローブの前記標的結合部分が、前記標的核酸に対して相補的である6以下のヌクレオチドを含む、請求項1に記載の方法。
- 前記プローブが標識されていない、請求項1に記載の方法。
- 前記プローブが非天然ヌクレオチドを含まない、請求項1に記載の方法。
- 前記プローブの前記非標的部分の長さが少なくとも10ヌクレオチドである、請求項1に記載の方法。
- 前記切断断片の検出が、1つ以上の前記切断断片を合成検出オリゴヌクレオチドと会合させることを含む、請求項1に記載の方法。
- 前記合成検出オリゴヌクレオチドがヘアピン構造を形成する自己相補性領域を有する、請求項33に記載の方法。
- 前記合成検出オリゴヌクレオチドが標識を含む、請求項33に記載の方法。
- 前記標識が蛍光標識である、請求項35に記載の方法。
- 前記合成検出オリゴヌクレオチドが蛍光クエンチャー部分を更に含む、請求項36に記載の方法。
- 前記切断断片が、前記合成検出オリゴヌクレオチドと会合したとき、前記FEN−1エンドヌクレアーゼにより切断可能な切断構造を形成する、請求項33に記載の方法。
- 前記検出が、前記合成検出オリゴヌクレオチドを含む前記切断構造を切断して、検出可能なシグナルを生成することを含む、請求項38に記載の方法。
- 合成対照標的核酸の既知の量も分析する、請求項1に記載の方法。
- 分析された合成対照標的核酸を用いて前記標的核酸の量を決定する、請求項40に記載の方法。
- a)標的核酸と、b)増幅プライマーと、c)ポリメラーゼと、d)FEN−1エンドヌクレアーゼと、e)分析物特異的部分及び非標的部分を含む非標識合成プローブであって、前記非標的部分が前記標的核酸に対して実質的に非相補的であり、前記分析物特異的部分の長さが12ヌクレオチド以下であり、前記分析物特異的部分が前記標的核酸に対して相補的である最高12ヌクレオチドを含む非標識合成プローブとを含む組成物。
- 前記組成物が反応混合物である、請求項42に記載の組成物。
- 前記組成物がキットである、請求項42に記載の組成物。
- 前記キットが、標的核酸、増幅プライマー、ポリメラーゼ、FEN−1エンドヌクレアーゼ、及び非標識合成プローブの1以上を収容している複数の容器を備える、請求項44に記載の組成物。
- 前記標的核酸が、動物、植物、細菌、ウイルス、及び真菌から成る群から選択される生物に由来する、請求項42に記載の組成物。
- 前記標的核酸がDNAである、請求項42に記載の組成物。
- 前記標的核酸がRNAである、請求項42に記載の組成物。
- 逆転写酵素を更に含む、請求項42に記載の組成物。
- 前記ポリメラーゼが熱安定性ポリメラーゼである、請求項42に記載の組成物。
- 前記ポリメラーゼが5’から3’へのエキソヌクレアーゼ活性を欠いている、請求項50に記載の組成物。
- 前記FEN−1エンドヌクレアーゼが熱安定性FEN−1エンドヌクレアーゼである、請求項42に記載の組成物。
- 前記FEN−1エンドヌクレアーゼが古細菌種由来である、請求項42に記載の組成物。
- 前記標的核酸の存在下にて前記プローブと共に切断構造を形成するよう構成されている第2のオリゴヌクレオチドを更に含み、前記切断構造が、a)前記標的核酸の第1の領域における前記プローブ、及びb)第1の領域の下流にある前記標的核酸の第2の領域と会合する第2のオリゴヌクレオチドと、前記標的核酸との会合により形成される、請求項42に記載の組成物。
- 第2の領域が第1の領域に隣接している、請求項54に記載の組成物。
- 前記切断構造における第2のオリゴヌクレオチドの3’末端において少なくとも1個のヌクレオチドが、前記プローブと前記標的核酸とのハイブリダイゼーション領域と重複している、請求項54に記載の組成物。
- 第2のオリゴヌクレオチドの3’末端ヌクレオチドが、前記切断構造における前記標的核酸に対して非相補的である、請求項54に記載の組成物。
- 前記プローブの前記分析物特異的部分が、前記標的核酸に対して相補的である11以下のヌクレオチドを含む、請求項42に記載の組成物。
- 前記プローブの前記分析物特異的部分が、前記標的核酸に対して相補的である10以下のヌクレオチドを含む、請求項42に記載の組成物。
- 前記プローブの前記分析物特異的部分が、前記標的核酸に対して相補的である9以下のヌクレオチドを含む、請求項42に記載の組成物。
- 前記プローブの前記分析物特異的部分が、前記標的核酸に対して相補的である8以下のヌクレオチドを含む、請求項42に記載の組成物。
- 前記プローブの前記分析物特異的部分が、前記標的核酸に対して相補的である7以下のヌクレオチドを含む、請求項42に記載の組成物。
- 前記プローブの前記分析物特異的部分が、前記標的核酸に対して相補的である6以下のヌクレオチドを含む、請求項42に記載の組成物。
- 前記プローブが標識されていない、請求項42に記載の組成物。
- 前記プローブが非天然ヌクレオチドを含まない、請求項42に記載の組成物。
- 前記プローブの前記非標的部分の長さが少なくとも10ヌクレオチドである、請求項42に記載の組成物。
- 前記プローブの前記非標的部分に対して相補的である領域を有する合成検出オリゴヌクレオチドを更に含む、請求項42に記載の組成物。
- 前記合成検出オリゴヌクレオチドがヘアピン構造を形成する自己相補性領域を有する、請求項67に記載の組成物。
- 前記合成検出オリゴヌクレオチドが標識を含む、請求項67に記載の組成物。
- 前記標識が蛍光標識である、請求項69に記載の組成物。
- 前記合成検出オリゴヌクレオチドが蛍光クエンチャー部分を更に含む、請求項70に記載の組成物。
- 請求項42に記載の組成物を含むシステム。
- 検出器を更に含む、請求項72に記載のシステム。
- 前記検出器が蛍光シグナルを検出する、請求項73に記載のシステム。
- a)標的核酸と、b)増幅プライマーと、c)ポリメラーゼと、d)FEN−1エンドヌクレアーゼと、e)分析物特異的部分及び非標的部分を含む非標識合成プローブであって、前記非標的部分が前記標的核酸に対して実質的に非相補的である非標識合成プローブと、を含む組成物。
- 標的核酸を分析する方法であって、請求項75に記載の組成物を準備する工程と、増幅反応中に前記プローブと前記標的核酸との間に切断構造を形成する工程と、前記プローブを前記FEN−1エンドヌクレアーゼで切断して、前記プローブの前記非標的部分を含む切断産物を生成する工程と、前記切断産物を検出する工程とを含む方法。
- 標的核酸を分析する方法であって、a)合成プローブ及びFEN−1エンドヌクレアーゼの存在下にて、前記合成プローブが増幅反応中に切断されて切断断片を生成する条件下で、標的核酸を増幅する工程であって、前記合成プローブが前記FEN−1エンドヌクレアーゼのためのフットプリントプローブであり、前記フットプリントプローブが分析物特異的部分及び非標的部分を含み、前記非標的部分が前記標的核酸に対して実質的に非相補的であり、前記増幅反応が等温反応である場合、前記フットプリントプローブの前記分析物特異的部分が、前記等温反応を実施する温度より少なくとも5℃低い前記標的に対する計算Tm値を有し、又は前記増幅反応が熱サイクル反応である場合、前記フットプリントプローブの前記分析物特異的部分が、前記熱サイクルで用いられる最低温度より少なくとも5℃低い前記標的に対する計算Tm値を有し、前記フットプリントプローブが副溝バインダー部分を含まない、上記工程と、b)前記増幅反応中に前記切断断片を検出する工程と、を含む方法。
- 前記フットプリントプローブの前記分析物特異的部分が、前記等温反応を実施する温度より少なくとも8℃低い前記標的核酸に対する計算Tm値を有し、又は前記増幅反応が熱サイクル反応である場合、前記フットプリントプローブの前記分析物特異的部分が、前記熱サイクルで用いられる最低温度より少なくとも8℃低い前記標的核酸に対する計算Tm値を有する、請求項77に記載の方法。
- 前記フットプリントプローブの前記分析物特異的部分が、前記等温反応を実施する温度より少なくとも10℃低い前記標的に対する計算Tm値を有し、又は前記増幅反応が熱サイクル反応である場合、前記フットプリントプローブの前記分析物特異的部分が、前記熱サイクルで用いられる最低温度より少なくとも10℃低い前記標的に対する計算Tm値を有する、請求項77に記載の方法。
- 標的核酸を分析する方法であって、
a)核酸二本鎖を含む構造を認識する5’ヌクレアーゼを選択する工程と、
b)前記5’ヌクレアーゼのためのフットプリント二本鎖長を決定する工程と、
c)合成フットプリントプローブ及び前記5’ヌクレアーゼの存在下にて、前記合成プローブが標的増幅反応中に切断されて切断断片を生成する条件下で、標的核酸を増幅する工程であって、前記合成プローブが分析物特異的部分及び非標的部分を含み、前記非標的部分が前記標的核酸に対して実質的に非相補的であり、前記分析物特異的部分が前記5’ヌクレアーゼ酵素のための前記フットプリント二本鎖長より長くない前記標的核酸とのプローブ−標的二本鎖を形成する工程と、
d)前記増幅反応中に前記切断断片を検出する工程と、
を含む方法。 - 前記標的増幅反応がポリメラーゼ連鎖反応である、請求項80に記載の方法。
- 前記5’ヌクレアーゼが、天然FEN−1エンドヌクレアーゼ、改変型FEN−1エンドヌクレアーゼ、及び少なくとも1種のFEN−1エンドヌクレアーゼの少なくとも一部を含むキメラタンパク質から成る群から選択される、請求項80に記載の方法。
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HK1150171A1 (en) | 2011-11-04 |
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EP2274448B1 (en) | 2013-09-18 |
KR101419980B1 (ko) | 2014-07-15 |
CN102301000B (zh) | 2015-04-29 |
JP5651022B2 (ja) | 2015-01-07 |
BRPI0908748A2 (pt) | 2015-07-28 |
WO2009117327A2 (en) | 2009-09-24 |
EP2274448A2 (en) | 2011-01-19 |
WO2009117327A3 (en) | 2009-12-23 |
CA2718011C (en) | 2015-05-19 |
US20090253142A1 (en) | 2009-10-08 |
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