JP6740222B2 - 互いに消光する蛍光標識とのナノポアを基礎にしたポリマー分析 - Google Patents
互いに消光する蛍光標識とのナノポアを基礎にしたポリマー分析 Download PDFInfo
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Description
過去10年にわたり開発されてきたDNA配列決定技術は、生物科学に変革をもたらし、例えばLernerら、The Auk、127巻:4〜15頁(2010年);Metzker、Nature Review Genetics、11巻:31〜46頁(2010年);Holtら、Genome Research、18巻:839〜846頁(2008年);そして医療行為の多くの態様に変革をもたらす潜在性を有している、例えばVoelkerdingら、Clinical Chemistry、55巻:641〜658頁(2009年);Andersonら、Genes、1巻:38〜69頁(2010年);Freemanら、Genome Research、19巻:1817〜1824頁(2009年);Tuckerら、Am.J.Human Genet.、85巻:142〜154頁(2009年)。しかし、そのような潜在性を実現するには、1ラン当たりの配列決定コストの削減、試料調製の単純化、ランタイムの短縮、読取り長の増大、およびデータ解析の改善などを含む、対処しなければならない多くの課題が依然として存在し、例えば、Baker、Nature Methods、7巻:495〜498頁(2010年);Kircherら、Bioessays、32巻:524〜536頁(2010年);Turnerら、Annual Review of Genomics and Human Genetics、10巻:263〜284頁(2009年)。ナノポアを使用した単一分子配列決定は、これらの課題のいくつかに対処することができ、例えば、Maitraら、Electrophoresis、33巻:3418〜3428頁(2012年);Venkatesanら、Nature Nanotechnology、6巻:615〜624頁(2011年);しかしこの手法には、それ自体の一連の技術的難題、例えば信頼性あるナノポア製作、DNA移行速度の制御、ヌクレオチド識別、およびナノポアセンサーのラージアレイからの電気シグナルの検出などがある、例えば、Brantonら、Nature Biotechnology、26巻(10号):1146〜1153頁(2008年);Venkatesanら(前掲)。
(発明の要旨)
本発明は、マイクロ流体および/またはナノ流体デバイスにおけるポリヌクレオチドなどのポリマーの、光学的検出および分析を行うための方法、キット、およびシステムを対象とし;詳細には、本発明は、核酸のヌクレオチド配列を決定するためのナノポアを使用する方法およびシステムを含む。
一態様では、本発明は、下記のステップ:(a)ナノポアを通ってポリマーを移行させるステップであって、自由溶液中で隣接するモノマーの蛍光標識が互いの蛍光放出を実質的に消光するように(即ち、そのような標識は「消光状態」または「消光構成」にある)、ポリマーのモノマーが蛍光標識で標識され、かつ検出可能な蛍光シグナルが発生しないように、または検出可能なシグナルが実質的に発生しないように、ナノポアがそのボア内の蛍光標識を拘束状態に拘束するステップと;(b)ナノポアから出る際、かつ隣接する蛍光標識と消光構成を形成する前に、各モノマーの蛍光標識を励起するステップと;(c)出て行く蛍光標識によって発生した蛍光シグナルを測定して、蛍光標識が取着されるモノマーを識別するステップと;(d)蛍光シグナルの配列からポリマーのモノマー配列を決定するステップとを含む、ポリマーのモノマー配列を決定するための方法を含む。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
少なくとも1つのポリヌクレオチドのヌクレオチド配列を決定する方法であって、
ナノポアを通って少なくとも1つの一本鎖ポリヌクレオチドを移行させるステップであって、自由溶液中で隣接するヌクレオチドの蛍光標識が消光状態であるように、前記一本鎖ポリヌクレオチドのヌクレオチドを蛍光標識で標識し、前記ナノポアが、前記ナノポア内の前記蛍光標識を強制的に、検出可能なシグナルが実質的に発生しない拘束状態にするステップと、
前記ナノポアから出る際、かつ隣接するヌクレオチドと消光状態を形成する前に、各ヌクレオチドの前記蛍光標識を励起するステップと、
出て行く前記蛍光標識によって発生した蛍光シグナルを測定して、前記蛍光標識が取着される前記ヌクレオチドを識別するステップと、
蛍光シグナルの配列から前記ポリヌクレオチドのヌクレオチド配列を決定するステップとを含む方法。
(項目2)
前記ポリヌクレオチドのヌクレオチドが、FRET対の第2のメンバーで標識され、それぞれの第2のメンバーは、前記メンバーが取着される前記ヌクレオチドを示すFRETシグナルを生成し、前記ポリヌクレオチドのヌクレオチドは、前記ナノポアを出る際に、それぞれの第2メンバーが前記FRET対の第1のメンバーのFRET距離内を通るように、前記ナノポアに隣接して位置決めされた前記FRET対の前記第1のメンバーの傍を順次通り、
励起する前記ステップが、前記FRET距離内にある前記FRET対の前記第1および第2のメンバーの間にFRETが生じるように、前記第1のメンバーを第1の波長の光ビームに曝露して、前記ナノポアから出て行く前記ヌクレオチドを示す第2の波長のFRETシグナルを発生させることを含む、項目1に記載の方法。
(項目3)
前記ナノポアが固相膜内に配置され、前記FRET対の前記第1のメンバーが、前記ナノポアに隣接する前記固相膜に取着される、項目2に記載の方法。
(項目4)
前記ナノポアがタンパク質ナノポアであり、前記FRET対の前記第1のメンバーが前記タンパク質ナノポアに取着される、項目2に記載の方法。
(項目5)
前記FRET対の前記第1のメンバーがドナーであり、前記FRET対の前記第2のメンバーがアクセプターである、項目2からA4までに記載の方法。
(項目6)
前記ドナーが量子ドットである、項目5に記載の方法。
(項目7)
前記アクセプターが蛍光有機色素である、項目5に記載の方法。
(項目8)
曝露する前記ステップが、前記ドナーを、全内部反射励起からのエバネッセント波に曝露することを含む、項目5に記載の方法。
(項目9)
前記ナノポアが脂質二重層に埋め込まれる、項目1に記載の方法。
(項目10)
前記ナノポアが、複数の実質的に同一のナノポアを含むナノポアアレイ内にある、項目A1に記載の方法。
(項目11)
前記ナノポアアレイの前記ナノポアが、タンパク質ナノポアである、項目10に記載の方法。
(項目12)
前記ナノポアアレイが、第1のチャンバーを第2のチャンバーから分離する固相膜を含み、前記固相膜は、その内部に固定化された前記タンパク質ナノポアをそれぞれが有するアパーチャーの平面アレイを含む、項目11に記載の方法。
(項目13)
ポリマーのモノマー配列を決定するための方法であって、
(a)ナノポアを通ってポリマーを移行させるステップであって、自由溶液中で隣接するモノマーの蛍光標識が実質的に消光した状態であるように、前記ポリマーのモノマーを蛍光標識で標識し、検出可能な蛍光シグナルがその内部で実質的に発生しないように、前記ナノポアが、そのボア内で蛍光標識を拘束状態に拘束するステップと、
(b)前記ナノポアから出る際、かつ隣接する蛍光標識と消光状態を形成する前に、各モノマーの前記蛍光標識を励起するステップと、
(c)出て行く前記蛍光標識によって発生した蛍光シグナルを測定して、前記蛍光標識が取着される前記モノマーを識別するステップと、
(d)蛍光シグナルの配列から前記ポリマーのモノマー配列を決定するステップと
を含む方法。
(項目14)
前記ポリマーのモノマーが、FRET対の第2のメンバーで標識され、それぞれの第2のメンバーは、前記メンバーが取着される前記モノマーを示すFRETシグナルを生成し、前記ポリマーのモノマーは、前記ナノポアを出る際に、それぞれの第2のメンバーが前記FRET対の第1のメンバーのFRET距離内を通るように、前記ナノポアに隣接して位置決めされた前記FRET対の前記第1のメンバーの傍を順次通り、
励起する前記ステップが、前記FRET距離内にある前記FRET対の前記第1および第2のメンバーの間にFRETが生じるように、前記第1のメンバーを第1の波長の光ビームに曝露して、前記ナノポアから出て行く前記ヌクレオチドを示す第2の波長のFRETシグナルを発生させることを含む、項目13に記載の方法。
(項目15)
前記ナノポアがタンパク質ナノポアであり、前記FRET対の前記第1のメンバーが、前記タンパク質ナノポアに取着されたドナーであり、前記FRET対の前記第2のメンバーが、モノマーに取着されたアクセプターである、項目14に記載の方法。
(項目16)
前記ドナーが量子ドットであり、前記アクセプターが、互いに消光する組から選択される蛍光有機色素である、項目15に記載の方法。
本発明は、様々な修正および代替形態を受け得るが、それらの詳細を図面に例として示しており、これより詳細に記述する。しかし、本発明を、記述される特定の実施形態に限定しようとするものではないことを理解すべきである。それどころか、本発明の精神および範囲内に入る全ての修正例、均等物、および代替例を包含するものである。例えば、本発明の特定のナノポアのタイプおよび数、特定の標識、FRET対、検出スキーム、製作手法は、例示の目的で示される。しかし本開示は、その他のタイプのナノポア、ナノポアのアレイ、およびその他の製作技術を利用して本明細書で論ずるシステムの様々な態様を実現することができるので、この点に限定するものではないことを理解すべきである。本発明の態様に関する指針は、その関連ある部分が参照により本明細書に組み込まれる、例えば、Cao,Nanostructures&Nanomaterials(Imperial College Press,2004);Levinson,Principles of Lithography,Second Edition(SPIE Press,2005);Doering and Nishi, Editors,Handbook of Semiconductor Manufacturing Technology,Second Edition(CRC Press,2007);Sawyer et al,Electrochemistry for Chemists,2nd edition(Wiley Interscience,1995);Bard and Faulkner,Electrochemical Methods:Fundamentals and Applications,2nd edition(Wiley,2000);Lakowicz,Principles of Fluorescence Spectroscopy,3rd edition(Springer,2006);Hermanson,Bioconjugate Techniques,Second Edition(Academic Press,2008);などを含む、当業者に周知の多くの入手可能な参考文献および論文に見出される。
ナノポアおよびナノポア配列決定
ナノポアおよび分析物に関する標識
移行速度
キット
定義
Claims (11)
- 少なくとも1つのポリヌクレオチドのヌクレオチド配列を決定する方法であって、
ナノポアを通って少なくとも1つの一本鎖ポリヌクレオチドを移行させるステップであって、前記一本鎖ポリヌクレオチドの異なる種類のヌクレオチドを互いに消光する組由来の異なる蛍光標識で標識し、前記ナノポアが、前記ナノポア内の前記蛍光標識を強制的に、検出可能なシグナルが実質的に発生しない拘束状態にするように寸法決めされたボアを有し、前記ナノポアが、1から4nmの直径を有するボアを有するタンパク質ナノポアであり、前記互いに消光する組のそれぞれの蛍光標識は、(i)同じ前記組のうちのいずれの他方の蛍光標識の蛍光も、かかる標識が自由溶液中でポリヌクレオチドの隣接するヌクレオチドに取着されているときはいつでも、消光し、(ii)非消光状態において明確な蛍光シグナルを発生する、ステップと、
前記ナノポアから出る際、かつ隣接するヌクレオチドと消光状態を形成する前に、各ヌクレオチドの前記蛍光標識を励起するステップと、
出て行く前記蛍光標識によって発生した蛍光シグナルを測定して、前記蛍光標識が取着される前記ヌクレオチドを識別するステップと、
蛍光シグナルの配列から前記ポリヌクレオチドのヌクレオチド配列を決定するステップとを含む方法。 - 前記ポリヌクレオチドのヌクレオチドが、FRET対の第2のメンバーで標識され、それぞれの第2のメンバーは、前記メンバーが取着される前記ヌクレオチドを示すFRETシグナルを生成し、前記ポリヌクレオチドのヌクレオチドは、前記ナノポアを出る際に、それぞれの第2メンバーが前記FRET対の第1のメンバーのFRET距離内を通るように、前記ナノポアに隣接して位置決めされた前記FRET対の前記第1のメンバーの傍を順次通り、
励起する前記ステップが、前記FRET距離内にある前記FRET対の前記第1および第2のメンバーの間にFRETが生じるように、前記第1のメンバーを第1の波長の光ビームに曝露して、前記ナノポアから出て行く前記ヌクレオチドを示す第2の波長のFRETシグナルを発生させることを含む、請求項1に記載の方法。 - 前記ナノポアが固相膜内に配置され、前記FRET対の前記第1のメンバーが、前記ナノポアに隣接する前記固相膜に取着される、請求項2に記載の方法。
- 前記FRET対の前記第1のメンバーが前記タンパク質ナノポアに取着される、請求項2に記載の方法。
- 前記FRET対の前記第1のメンバーがドナーであり、前記FRET対の前記第2のメンバーがアクセプターである、請求項2に記載の方法。
- 前記ドナーが量子ドットである、請求項5に記載の方法。
- 前記アクセプターが蛍光有機色素である、請求項5に記載の方法。
- 曝露する前記ステップが、前記ドナーを、全内部反射励起からのエバネッセント波に曝露することを含む、請求項5に記載の方法。
- 前記ナノポアが脂質二重層に埋め込まれる、請求項1に記載の方法。
- 前記ナノポアが、複数の実質的に同一のナノポアを含むナノポアアレイ内にある、請求項1に記載の方法。
- 前記ナノポアアレイが、第1のチャンバーを第2のチャンバーから分離する固相膜を含み、前記固相膜は、その内部に固定化された前記タンパク質ナノポアをそれぞれが有するアパーチャーの平面アレイを含む、請求項10に記載の方法。
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