JP6558603B2 - デジタル検体分析 - Google Patents
デジタル検体分析 Download PDFInfo
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Description
この本出願は、2010年10月1日に出願された米国仮出願第61/388,937号、2010年5月21日に出願された米国仮出願第61/347,158号、2010年5月5日に出願された米国仮出願第61/331,490号、および2010年2月12日に出願された米国仮出願第61/304,163号(これらの内容は、各々それらの全体が参考として本明細書に援用される)に対する優先権を主張する。
本発明は、一般に、液滴ベースのデジタルPCR、およびそれを使用してターゲット核酸を分析するための方法に関する。
本発明は、例えば以下の項目を提供する。
(項目1)
単一の核酸テンプレートと前記テンプレート上の複数のターゲット部位に特異的な複数のプライマー対とを含む微小液滴。
(項目2)
前記液滴内で生産されたアンプリコンにハイブリダイズする複数のプローブをさらに含む、項目1に記載の微小液滴。
(項目3)
前記単一の核酸テンプレートがDNAまたはRNAである、項目1に記載の微小液滴。
(項目4)
ポリメラーゼ連鎖反応を行うための試薬をさらに含む、項目1に記載の微小液滴。
(項目5)
前記複数のプローブの構成員が検出可能標識を含有する、項目2に記載の微小液滴。
(項目6)
前記複数のプローブが、様々な濃度のプローブの1つ以上の群を含む、項目6に記載の微小液滴。
(項目7)
前記プローブの1つ以上の群の構成員それぞれが、同じ検出可能標識を含む、項目6に記載の微小液滴。
(項目8)
前記複数のプローブの構成員それぞれが、異なる検出可能標識を含む、項目5に記載の微小液滴。
(項目9)
前記検出可能標識が蛍光標識である、項目5に記載の微小液滴。
(項目10)
生体サンプル中の複数のターゲットを検出するための方法であって、
a)単一の核酸テンプレート、およびそれぞれが前記テンプレート上の複数のターゲット部位に特異的なプライマー対とプローブの不均一混合物をそれぞれが含む、1つ以上の微小液滴を形成する工程;
b)前記1つ以上の微小液滴内の前記核酸テンプレートを増幅する工程;および
c)前記1つ以上の微小液滴を分析する工程
を含む方法。
(項目11)
前記形成工程が、
a)単一の核酸テンプレートを含む第一の流体を供給すること;
b)それぞれが前記テンプレート上の複数のターゲット部位に特異的な複数のプライマーおよび複数のプローブを含む第二の流体を供給すること;
c)前記第一の流体と前記第二の流体を合体させて、前記単一の核酸テンプレートおよびプライマー対とプローブの不均一混合物を含む液滴を形成すること
を含む、項目10に記載の方法。
(項目12)
前記第一の流体および前記第二の流体が、前記流体に対する電場の存在下で合体される、項目11に記載の方法。
(項目13)
前記第一の流体および前記第二の流体が微小液滴である、項目11に記載の方法。
(項目14)
前記第二の流体が、ポリメラーゼ連鎖反応を行うための試薬をさらに含む、項目11に記載の方法。
(項目15)
前記単一の核酸テンプレートがDNAまたはRNAである、項目10に記載の方法。
(項目16)
前記分析工程が、前記1つ以上の微小液滴内の前記複数のターゲットの存在または不在を検出することを含む、項目10に記載の方法。
(項目17)
前記複数のプローブの構成員が、検出可能標識を含有する、項目10に記載の方法。
(項目18)
前記複数のプローブが、様々な濃度のプローブの1つ以上の群を含む、項目17に記載の微小液滴。
(項目19)
前記プローブの1つ以上の群の構成員それぞれが、同じ検出可能標識を含む、項目18に記載の微小液滴。
(項目20)
前記複数のプローブの構成員それぞれが、異なる検出可能標識を含む、項目17に記載の微小液滴。
(項目21)
前記検出可能標識が蛍光標識である、項目17に記載の微小液滴。
(項目22)
ターゲット核酸を分析するための方法であって、
単一ターゲット核酸と1つ以上の増幅試薬とを含有する液滴を形成する工程;
前記液滴内の前記ターゲットを増幅する工程;
前記ターゲットからのアンプリコンおよび前記ターゲットの変異体からのアンプリコンとを含有する液滴を排除する工程;および
ターゲットアンプリコンを分析する工程
を含む方法。
(項目23)
前記増幅工程が、ポリメラーゼ連鎖反応であり、および前記1つ以上の増幅試薬が、1つ以上のプライマー対を含む、項目22に記載の方法。
(項目24)
前記排除工程が、前記液滴をマイクロ流体チャネル内に流すことを含む、項目22に記載の方法。
(項目25)
前記分析工程が、検出可能に標識されたプローブへのハイブリダイゼーションにより前記アンプリコンを検出することを含む、項目22に記載の方法。
(項目26)
前記分析工程が、前記排除工程で排除されなかった液滴からのアンプリコンに対して行われる、項目22に記載の方法。
(項目27)
前記形成工程が、
核酸を含む第一のサンプル流体のストリームを、流れているキャリア流体の2つの対向するストリームを交差するように流し、それによって、前記第一のサンプル流体を含む複数の第一の液滴を形成することであって、前記キャリア流体は前記サンプル流体と不混和性である、形成すること;および
前記第一のサンプル流体を含む複数の第一の液滴のそれぞれと、1つ以上の増幅試薬を含む第二の流体の部分とを合体させることであって、前記第二の流体の部分は場合により液滴である、合体させること
を含む、項目22に記載の方法。
(項目28)
前記キャリア流体が油である、項目27に記載の方法。
(項目29)
前記油が界面活性剤を含む、項目28に記載の方法。
(項目30)
前記界面活性剤がフッ素系界面活性剤である、項目29に記載の方法。
(項目31)
前記分析工程が、
野生型ターゲットのみを含有する液滴の数を決定すること;
前記ターゲットの変異体のみを含有する液滴の数を決定すること
を含む、項目22に記載の方法。
(項目32)
前記変異体のみを含有する液滴の存在が疾患の指標となる、項目31に記載の方法。
(項目33)
前記疾患が癌である、項目32に記載の方法。
(項目34)
前記変異体が対立遺伝子変異体である、項目31に記載の方法。
(項目35)
前記対立遺伝子変異体が一塩基多型である、項目34に記載の方法。
(項目36)
核酸サンプルを加工するための方法であって、
1つの核酸ターゲットを含む液滴を得る工程;
前記液滴内の前記核酸を増幅する工程;および
アンプリコンの不均一集団を含む液滴を、アンプリコンの均一集団を含有する液滴から分離する工程
を含む方法。
(項目37)
患者における癌の再発を検出するための方法であって、
平均して各液滴が患者サンプルから採取された単一ターゲット核酸を含む、サンプル液滴を形成する工程;
前記サンプル液滴を、チャネルを通して流す工程;
前記液滴内のターゲットを増幅する工程;
前記液滴内の増幅されたターゲットを検出する工程;
アンプリコンの不均一集団を含む液滴を排除する工程;および
排除されなかった液滴を分析して、再発の指標となる突然変異体対立遺伝子の存在を決定する工程
を含む方法。
(項目38)
前記形成工程が、
核酸を含むサンプル流体のストリームを、流れているキャリア流体の2つの対向するストリームを直行するように流すことであって、前記キャリア流体は前記サンプル流体と不混和性である、流すこと
を含む、項目37に記載の方法。
(項目39)
前記サンプルがヒト組織または体液である、項目37に記載の方法。
(項目40)
前記体液が、膿、痰、精液、尿、血液、唾液および脳脊髄液から成る群より選択される、項目39に記載の方法。
(項目41)
前記分析工程が、標識された捕捉プローブを使用して前記液滴から得られたアンプリコンを捕捉することを含む、項目37に記載の方法。
(項目42)
ターゲット核酸を分析するための方法であって、
各部分が単一ターゲット核酸を含有する複数の部分に第一の流体を区画化する工程;
前記部分中のターゲットを増幅する工程;
前記ターゲットからのアンプリコンおよび前記ターゲットの変異体からのアンプリコンを含有する部分を排除する工程;および
ターゲットアンプリコンを分析する工程
を含む、方法。
(項目43)
区画が、マイクロ流体デバイス内のチャンバを含む、項目42に記載の方法。
(項目44)
ターゲット核酸を分析するための方法であって、
単一ターゲット核酸を含有するサンプル液滴を形成する工程;
前記液滴内のターゲットを増幅する工程;
前記ターゲットからのアンプリコンおよび前記ターゲットの変異体からのアンプリコンを含有する液滴を排除する工程;および
ターゲットアンプリコンを分析する工程
を含む、方法。
(項目45)
前記第一の流体が第一の液滴内に含有され、および前記第二の流体がストリームの第一の部分であり、ならびにさらに、工程(c)が、前記第一の液滴を前記第一の部分と合体させることを含む、項目11に記載の方法。
(項目46)
前記第二の流体が第一の液滴内に含有され、および前記第一の流体がストリームの第一の部分であり、ならびにさらに、工程(c)が、前記第一の液滴を前記第一の部分と合体させることを含む、項目11に記載の方法。
核酸分子は、デオキシリボ核酸(DNA)および/またはリボ核酸(RNA)を包含する。核酸分子を合成することができ、または自然に存在する源から採取することができる。1つの実施形態では、様々な他の成分、例えばタンパク質、脂質および非テンプレート核酸、を含有する生体サンプルから核酸分子を単離する。動物、植物、細菌、真菌または任意の他の細胞性生物から得られる、任意の細胞性材料から核酸テンプレート分子を得ることができる。一定の実施形態では、単個細胞から核酸分子を得る。本発明において使用するための生体サンプルは、ウイルス粒子または調製物を含む。核酸分子を生物から直接得ることができ、または生物から得た生体サンプルから、例えば血液、尿、脳脊髄液、精液、唾液、痰、糞便および組織から、得ることができる。任意の組織または体液検体を本発明において使用するための核酸の源として使用することができる。培養細胞、例えば一次細胞培養物または細胞株、から核酸を単離することもできる。テンプレート核酸を得る細胞または組織は、ウイルスまたは他の細胞内病原体に感染している場合がある。サンプルは、生物検体、cDNAライブラリー、ウイルスまたはゲノムDNAから抽出された全RNAである場合もある。一定の実施形態において、核酸分子は、他のターゲット分子、例えばタンパク質、酵素、基質、抗体、結合剤、ビーズ、小分子、ペプチドまたは任意の他の分子、に応じて確定され、ターゲット分子を定量および/もしくは検出するための代用物として役立つ。
本発明の方法は、サンプル液滴を形成することを含み、この場合、ゼロのターゲット核酸分子を含有する液滴もあり、1つのターゲット核酸分子を含有する液滴もあり、および複数の核酸分子を含有することがあるまたはしないことがある液滴もある(上で定義したとおりの限界または終点希釈にそれぞれ対応する)。好ましい実施形態において、液滴内の分子の分布は、ポアソン分布に従う。しかし、液滴の非ポアソン負荷のための方法は当業者に公知であり、それらの方法としては、液滴の能動的選別、例えばレーザー誘導蛍光によるもの、または受動的な1対1負荷(one−to−one loading)によるものが挙げられるが、これに限定されない。後に続く説明は液滴のポアソン負荷を想定しているが、本発明は限界または終点希釈に準拠するDNA負荷量のすべての分布と両立できるので、そのような説明は非ポアソン負荷を排除することを意図したものではない。
本発明の方法は、各液滴内のターゲット核酸を増幅することをさらに含む。増幅は、核酸配列の追加のコピーの生産を指し、一般に、ポリメラーゼ連鎖反応または当該技術分野において周知の他の技術を用いて行われる(例えば、Dieffenbach and Dveksler、PCR Primer、a Laboratory Manual、Cold Spring Harbor Press、Plainview、N.Y.[1995])。増幅反応は、核酸分子を増幅する当該技術分野において公知の任意の増幅反応、例えば、ポリメラーゼ連鎖反応、ネステッドポリメラーゼ連鎖反応、リガーゼ連鎖反応(Barany F.(1991)PNAS 88:189−193;Barany F.(1991)PCR Methods and Applications 1:5−16)、リガーゼ検出反応(Barany F.(1991)PNAS 88:189−193)、鎖置換増幅、転写ベースの増幅システム、核酸配列ベースの増幅、ローリングサークル増幅および超分岐ローリングサークル増幅であり得る。
増幅後、増幅産物の検出のための検出モジュールに液滴を流す。液滴をオフチップで熱サイクルに付す実施形態については、液滴は、読み出しのために第二の流体回路−液滴生成のための流体回路(単数もしくは複数)と同じチップ上にあってもよいし、なくてもよい−への再注入を必要とし、または一定の実施形態では読み出しのために液滴を液滴生成に使用した元の流体回路に戻って再注入してもよい。当該技術分野において公知の任意の方法、例えばレポーターの存在または量の検出、を用いて、それらの液滴を個々に分析および検出することができる。一般に、前記検出モジュールは、1つ以上の検出装置と連通している。前記検出装置は、光学的もしくは電気的検出器またはこれらの組み合わせであり得る。適する検出装置の例としては、光導波路、顕微鏡、ダイオード、光刺激デバイス(例えば、レーザー)、光電子倍増管およびプロセッサ(例えば、コンピュータおよびソフトウェア)、ならびに特性、マーカーまたはレポーターのシグナル表示を検出するためにおよび選別モジュールでの測定または選別動作を決定および命令するために共働するこれらの組み合わせが挙げられる。検出モジュールおよび液滴中の増幅産物の検出方法についてのさらなる説明は、Linkら(米国特許出願第2008/0014589号、同第2008/0003142号、および同第2010/0137163号)およびRaindance Technologies Inc.の欧州特許出願公開第2047910号に示されている。
エマルジョン形式でのデジタルPCR性能を、参照遺伝子、分岐鎖ケト酸デヒドロゲナーゼE1(BCKDHA)、の系列希釈物を測定することによって検証した。液滴生成マイクロ流体チップを使用して、PCRマスターミックスと、1×プライマーと、BCKDHA用のプローブと、様々な濃度のヒトゲノムDNA混合物(1:1 NA14091とNA13705)との混合物を、フッ素化油中水型エマルジョン中の100万個を超える5.3pL液滴に区画化した。そのエマルジョンをオフチップで熱サイクルに付し、その後、各液滴の蛍光を読み出しチップにおいて蛍光によって分析した(図3参照)。
Linkら(米国特許出願第2008/0014589号、同第2008/0003142号、および同第2010/0137163号)、Andersonら(米国特許第7,041,481号および再発行番号41,780として再発行されたもの)およびRaindance Technologies Incの欧州特許出願公開第2047910号(これらのそれぞれの内容は、それら全体が参照により本明細書に援用されている)に記載されているような液滴ベースのデジタルPCR技術は、1ライブラリー液滴あたり単一のプライマー対を用いる。このライブラリー液滴を、プライマーを除いてゲノムDNAを含むすべてのPCR試薬を含有するテンプレート液滴と合体させる。テンプレート液滴とプライマーライブラリー液滴のマージ後、その新たな液滴は今やPCRを行うために必要なすべての試薬を含有する。その後、その液滴を熱サイクルに付してアンプリコンを生産する。1つの実施形態では、平均して1液滴あたり1未満の半数体が存在するようにテンプレートDNAをテンプレートミックスで希釈する。
10分間95℃
31サイクル
15秒間92℃
60秒間60℃ 。
位置づけられた読み取り(%):ヒトゲノムにマップされた全読み取りの百分率。
特異性:ターゲットを含むマップされた読み取りの百分率。前記ターゲットはすべてのアンプリコン配列を含むが、プライマー配列を含まない。
平均塩基網羅:ターゲット内の平均塩基網羅。前記ターゲットはすべてのアンプリコン配列を含むが、プライマー配列を含まない。
C1:少なくとも1x塩基網羅を有するターゲットの%。注記:非一意的シークエンシング読み取りがランダムにマップされる。
C20:少なくとも20x塩基網羅を有するターゲットの%。
C100:少なくとも100x塩基網羅を有するターゲットの%
塩基網羅(平均の0.2x):平均塩基網羅の少なくとも20%を有するターゲットの%。
伝統的なデジタルPCR法は、個々のターゲットに特異的な単一標識プローブの使用を含む。図7は、液滴ベースのデジタルPCRを用いるターゲット配列の一色検出を図示する概略図である。図7のパネルAに示すように、テンプレートDNAをフォワードプライマー(F1)およびリバースプライマー(R1)で増幅する。カラー1の蛍光体で標識されたプローブ(P1)は、ターゲット遺伝子配列(ターゲット1)に結合する。限界または終点希釈条件下でテンプレートDNAの希釈溶液で微小液滴を作製する。ターゲット配列を含有する液滴は蛍光を放射し、レーザによって検出される(パネルBおよびC)。ターゲット配列を含有するまたは含有しないマイクロカプセルの数を、ヒストグラムで示し(D)、定量した(E)。
同じ原理を用いて、選択的にスプライスされた転写産物を検出し、カウントした。RNA転写産物内のそれぞれのエキソンに特異的であるTaqManアッセイ物を設計することができる。RNAをcDNAにした後、それを液滴に1液滴あたり1コピー以下で封入することができる。この液滴は、それぞれのエキソンについての多重化TaqManアッセイ物も含有するであろう。それぞれのTaqManアッセイ物は、異なるプローブを含有するが、すべてのプローブに同じ蛍光色素が付いているだろう。それらの液滴を熱サイクルに付して、それぞれのTaqManアッセイ物についてのシグナルを生成させることとなる。サンプル中に多数のスプライス変異体がある場合、それらは、スプライシング事象に依存して異なる数のエキソンを含有するだろう。各液滴の蛍光強度は、存在するエキソンの数に依存して異なるだろう。異なる強度を有する液滴の数をカウントすることにより、サンプル中の異なるスプライス変異体の存在および存在度を同定することが可能であろう。
不均一サンプルが異なるコピーレベル数を有する成分を含有するかどうかを決定することが可能だろう。アッセイすべきコピー数変異体を染色体に沿って十分近い間隔で配置した場合、サンプルからのDNAをフラグメント化し、1液滴あたり1半数体ゲノム当量以下のレベルで液滴に封入することができよう。この液滴は、そのコピー数変異体に特異的なTaqManアッセイ物も含有するだろう。各液滴におけるシグナルの強度は、そのサンプルについての存在するコピー数変異体の数に依存するであろう。異なる強度の液滴の数のカウントは、特定のサンプル中の幾つの細胞が如何なるレベルのコピー数変異体を有するかというようなことを示すだろう。
蛍光強度によるプローブの同定は、プローブ、特に、密なプローブパタンを有するより高プレックスの(higher−plex)アッセイのためのプローブ、の輝度の調整を必要とすることが多い。前のセクションにおいて、遺伝子コピー数アッセイ用のプローブは、非常によく分解されたピークを生じさせた(図11a)。明らかに、測定値の分解にコピー数アッセイにおける1つまたは多数のさらなるプローブを適応させる余地が存在するが、既存のアッセイ物への干渉を避けるために新たなプローブの蛍光強度を調整するための方法が求められる。本発明の1つの方法は、より高プレックスの反応における相対強度を最適化するための非常に単純な技術としてプローブおよびプライマー濃度を共に変化させることを含む。
本発明の1つの方法は、単一プローブカラー(すなわち蛍光体)を用いてより高プレックスのアッセイを行うことを含む。上で説明したように、様々な手段により、各強度レベルがDNAターゲットを一意的に同定するようにプローブ蛍光強度を調整することができる。例えば、ターゲットT1、T2、T3およびT4は、強度レベルI1、I2、I3およびI4によって一意的に同定され得る。理論により拘束されることを意図しないが、ターゲットの一意的同定のために可能な強度レベルの最大数は、異なる強度レベルの分解−すなわち、プローブの平均強度間の隔たりと比較した特定のプローブそれぞれについての強度の幅−に関連づけられ、ならびにプローブの数が増加するにつれて増す傾向がある空の液滴の強度にも関係づけられる。強度レベル数は、0、または1、または2、または3、または4、または10以下、または20以下、または50以下、または100以下であり得る。強度レベル数は、100より上であることもある。下に示す実施例においては、3ほどもの多さの強度レベルを実証する。
本発明の1つの態様を、棘筋萎縮症(SMA)についての幾つかの遺伝マーカーの定量の実例実証実験の実施にまとめた。SMAは、その重要な臨床的有用性とその複雑な遺伝的特質の両方のため、実例実証実験の1つに選択した。それは二番目に高頻度の致命的神経変性疾患であり、10,000のうち〜1の出生を襲う。SMAは、生存運動ニューロン1遺伝子(SMN1、Wirthらにより総説されている)内のエキソン7のホモ接合不在に、最も多くの場合、起因するが、この容態の重症度は、SMN2の遺伝子コピーの数によって変調され、1〜5コピー数で致死性から無症候性にわたる予後となる(Elsheikhらにより総説されている)。従って、SMN2コピー数の正確な定量は、臨床的予後および遺伝学カウンセリングに重量である。SMN1の大きな欠失とは別に、同じ遺伝子内の点突然変異または短い欠失/重複の数もSMAの症例の〜4%の原因である。総合SMAアッセイへの有意な工程において、ここで実証実験する多重化dPCRアッセイは、(SMN1および2についての)コピー数アッセイと高頻度SNPのもの(c.815A>G)についてのアッセイの両方を含む。
一定のSMA関連ターゲットについての9プレックスアッセイも、2色(FAMおよびVIC蛍光体を含有するプローブ)だけで実証した。最適化プライマーおよびプローブ濃度を除いて、アッセイ条件および実験手順は、上記5プレックスアッセイと同一であった。図15aは、プローブ濃度の最適化前の様々な液滴集団を2Dヒストグラムに示すものである。異なるターゲットの素性をその図自体に示す。本発明の1つの方法として、異なる集団の同定を、前のように、1つ以上のアッセイ物の選択的排除および/または追加によって行った。空の液滴に対応するクラスタと極めて近接していたc.815A遺伝子型についてのプローブを除き、集団の大部分は既に十分に分解されていた。プローブ濃度の最適化を3回繰り返した後、すべてのターゲット集団は互いに十分に分解され、空の液滴からも十分に分解され(図15b)。この実証実験では本発明の3つの方法に光を当てた:(1)9つのDNAターゲットを、従来のqPCRの能力をはるかに超えて、二次元ヒストグラムで一意的に同定した;(2)同じターゲットに対する1つまたは複数のプローブから生ずる色と強度の両方の何らかの組み合わせに基づいてターゲットDNA分子を区別した;および(3)様々な液滴集団間で増加された分解についての色および強度のパターンを最適化するようにプローブ濃度を変えることによって、ヒストグラム内のターゲット分子の相対位置を調整した。
前記SMA実施例において実証した多重化のレベルは、qPCRでの最大実行可能数を有意に超える9×であった。理論により拘束されることを望まないが、2つの主な制限は、アッセイ間の分解と、プローブの負荷量がより多い空の液滴の漸増蛍光強度とである。本発明の方法は、最大多重化のために異なるプローブの色および強度のパターンを最適化する上に、尚、個々の反応それぞれに対する適切な特異性を実現することを含む。液滴集団の長方形アレイを5および9プレックス反応について実証したが、もう1つの望ましいパターンは、密充填六角形アレイである。しかし、本発明はいずれの特定のアレイ戦略にも拘束されない。
液滴ベースのマイクロフルイディクスを用いて、複数のターゲットを異なる方法により同時に測定することもできる。代替方法によると、アッセイ物を一意的に同定するための光学的標識と共に、プライマーおよびプローブを液滴に個々に負荷することができる。典型的に、前記光学的標識は、1つの蛍光体であるか、プローブ蛍光体とはスペクトル的に違う異なる蛍光体の組み合わせである。異なる光学的標識によって一意的に同定される異なるアッセイ物をそれぞれが含有する様々な異なるタイプの液滴を混合して液滴の「ライブラリー」にすることができる。次に、上の本発明の方法に従って、テンプレートDNAを含有する液滴とライブラリー液滴を1個ずつ合体させる。熱サイクリング後、テンプレートDNAを含有する幾つかの液滴は、プローブの放射波長でより明るい蛍光を呈示する。その後、これらのPCR(+)シグナルを生じさせる特異的ターゲットDNA分子を、光学的プローブによって同定する。1つの研究では、異なるKRAS突然変異または野生型KRASに特異的なTaqMan(登録商標)プローブおよび光学コードをそれぞれが含有する7つの異なるタイプの液滴(7員ライブラリー)のいずれか1つとゲノムDNAを含有する液滴とを1個ずつ融合させることによって、KRASコドン12における6つの共通突然変異を1回の実験で並行してスクリーニングした。
本発明の1つの方法は、一意的プローブシグネチャ(色および強度)から生ずる統計的に類似した液滴の集団を同定および特性づけするための、ならびに他のものからの液滴の1つの集団を識別するための、ヒストグラムベースのデータ提示および分析を含む。本発明のもう1つの方法は、光学的標識からの一意的シグネチャに基づいて液滴の集団を同定および選択するための、ヒストグラムベースのデータ提示および分析を含む。これらの方法についての一および二次元ヒストグラムの例を提供したが、本発明は、これに関して限定されない。上で説明したように、より多くの色を多重化にも光学的標識にも使用することとなることが予想される。従って、本発明の実施形態は、2より大きい、例えば3、または4、または10以下、または20以下の次元数のヒストグラムを含む。20より大きい次元数のヒストグラムも本発明に組み込まれる。
超高感度を必要とする用途、例えば豊富な野生型DNAの中での稀な突然変異についての検索、については、偽ポジティブ結果がDNAポリメラーゼ自体からのエラーから生ずることがある。例えば、初期熱サイクルうちの1つのサイクルの間に、ポリメラーゼは、野生型テンプレートからDNAの突然変異体鎖を合成することがあるだろう。このタイプのエラーは、突然変異体と野生型の間の差が非常に小さいとき、例えば一塩基多型(SNP)のとき、発生する可能性が最も高い。本発明のこの方法において、各液滴は、あったとしても単一のターゲット核酸しか含有しない。好ましい実施形態において、これは、終点希釈条件下で遂行される。野生型のターゲットである増幅産物を含有する液滴を、その野生型のターゲットにハイブリダイズするプローブから放出される蛍光体からの放射に基づいて検出する。変異体のターゲットを含有する液滴を、その変異体のターゲットにハイブリダイズするプローブから放出される蛍光体の放射に基づいて検出する。各液滴は、単一の核酸分子のみで出発するので、各液滴内の結果として生ずる増幅産物は、ターゲットについて均一であるか、ターゲットの変異体について均一である。
次に、分子の均一集団を含有する液滴のみに関して分析を行った。この分析は、カウンティング、すなわち、野生型ターゲットのみを含有する液滴の数の決定、および該ターゲットの変異体のみを含有する液滴の数の決定、に基づくものであり得る。そのような方法は、当該技術分野において周知である。例えば、Lapidusら(米国特許第5,670,325号および同第5,928,870号)ならびにShuberら(米国特許第6,203,993号および同第6,214,558号)(これらのそれぞれの内容は、その全体が参照により本明細書に援用されている)を参照のこと。
本発明の方法は、液滴が分子の均一な集団を含有するかまたは分子の不均一な集団を含有するかに基づく液滴の選別を含む。選別モジュールは、検出モジュール内での液滴問い合わせに関連して受け取るシグナルに依存して液滴のフローが1つ以上の他のチャネル、例えば枝チャネル、に入るように方向を変えることができるチャネルの接合部であり得る。典型的に、選別モジュールはモニターされ、および/または検出モジュールの制御下にあり、従って、選別モジュールは検出モジュールに応答することができる。選別領域は1つ以上の選別装置と連通しており、それらによる影響を受ける。
本発明の方法は、さらなる分析のために液滴から増幅ターゲット分子を放出させることをさらに含むことができる。液滴から増幅ターゲット分子を放出させる方法は、例えば、Linkら(米国特許出願第2008/0014589号、同第2008/0003142号、および同第2010/0137163号)およびRaindance Technologies Inc.の欧州特許出願公開第2047910号に示されている。
次に続くのは、上で詳述した様々な実験についての実験の詳細である。
ここで使用したすべてのTaqMan(登録商標)プライマーおよびプローブを表2にリストする。表中に参考文献による別の注記がない限り、プライマーおよびプローブは、Applied Biosystems Inc.(ABI)からの「Custom TaqMan(登録商標)Assay Design Tool」で設計し、ABI(カリフォルニア州カールズバッド)を通じて調達した。プローブを6−カルボキシフルオレセイン(FAM、λ励起494nm\λ放射494nm)またはVIC(商標)(ABIから、λ励起538nm\λ放射554nm)で標識した。
幾つかの遺伝子ターゲット、BCKDHAおよびSMN2、について、プライマー対の間にわたる配列(表2参照)を含有するプラスミドDNAを合成し(ドイツ、レーゲンスブルクのGeneArt)、GeneArt標準ベクター(2.5kb)にクローニングした。アッセイに影響を及ぼし得る一切のDNAスーパーコイル化を回避するために、SfiIでの制限消化によってターゲットフラグメントをクローニングベクターから放出させた。簡略化のために、本文全体を通してこれらの遺伝子フラグメントを「プラスミドDNA」と呼ぶ。多重化反応の実証実験のために異なる遺伝子フラグメントのストリングも合成し(GeneArt)、GeneArt標準ベクターにクローニングした。それを本文では「人工染色体」と呼ぶ。この場合はフラグメントを隣接EcoRV部位での制限消化によって互いに分離した。細胞株(表3参照;ニュージャージー州カムデンのCoriell)から既に精製された形態でヒトDNAを得、使用前に製造業者(カリフォルニア州カールズバッドのInvtrogen)の説示に従ってK7025−05ネブライザーでフラグメント化した。Nanodrop 2000分光光度計(デラウェア州ウィルミントンのThermo Scientific)を用いて260nmでの吸収を測定することにより、DNA濃度を定量した。
従来のソフトリソグラフィーによってマイクロ流体チップを製造した。6インチシリコンウェハ上にSU−8ネガティブフォトレジスト(マサチューセッツ州ニュートンのMicroChem Corp.)をスピンコートし、OAI Hybralign Series 200アライナー(カリフォルニア州サンホゼのOAI)でのコンタクトリソグラフィーによりフォトマスク(オレゴン州バンドンのCAD/Art Services)から流体形状を転写することによって、成形用マスターを作製した。チップは、そのチップの外部ポートから機能領域に流体を移送するための低い流体力学的抵抗を有する深いチャネル(100±10um)と液滴操作および検出のための浅いチャネル(20±1um)である、2つの深度を有するチャネルを含有した。SU−8フォトレジスト2100および2025を深いおよび浅いチャネルにそれぞれ使用した。ポリジメチルシロキサン(PDMA)(Sylgard(登録商標)184、ミシガン州ミッドランドのDow Corning)チップを注文設計の金型ハウジング内でネガティブマスターから成形した。AutoGlow(商標)酸素プラズマシステム(アリゾナ州フェニックスのGlow Research)での表面活性化、続いて即座の圧着により、それらのチップの流体側にガラス・カバー・スライドを永久接着した。疎水性表面を作るために、100uLの溶剤中の18gのシランの混合物として調製したFC−3283(ミネソタ州セントポールの3M Specialty Materials)に溶解した1H,1H,2H,2H−パーフルオロデシルトリクロロシラン(マサチューセッツ州ワードヒルのAlfa Aesar)に〜2分間、それらのマイクロ流体チャネルを暴露した。
一方は液滴生成用および他方は熱サイクリング後の蛍光読み出し用である2つの異なるマイクロ流体デバイスを使用した。液滴生成チップは、この時点以降「キャリア油」と呼ぶ、エマルジョン安定化界面活性剤を伴う不活性フッ素化油(REBキャリア油;マサチューセッツ州レキシントンのRainDance Technologies)に懸濁されたテンプレートDNAおよびPCRマスターミックスの均一なサイズの水性液滴のエマルジョンを生じさせた。十字形のマイクロ流体交差部、すなわち「ノズル」、内で液滴を生成させた。図3aに示すように、典型的な動作のもとで、水性相は、右からノズルに流れ込み(160uL/時)、上部および下部からのキャリア油のフロー(750uL/時の全油)に合流し、11kHzの速度で4pLの液滴を生じさせた。交差部でのチャネル幅は、水溶液流入口については15um、油流入口については12.5の測定値であり、および流出口では15umが40umに広がっていた。特注OEMポンプ(イリノイ州ノースブルックのIDEX Corporation)によってフローを駆動した。
特注の顕微鏡での従来の落射蛍光顕微鏡法により、蛍光読み出しを行った。20mW、488nmレーザー源(Cyan;カリフォルニア州サニーヴェールのPicarro)を2×拡大し、対物レンズ(20×/0.45NA;日本の株式会社ニコン(Nikon)によってマイクロ流体チャネルに焦点を合わせた。2つのバンド・パス・フィルターが、対物レンズによって集められた蛍光を識別した:FAMおよびVIC蛍光体についてそれぞれ512/25nmおよび529/28nm(ニューヨーク州ロチェスターのSemrock)。2つのH5784−20光電子倍増管(Hamamatsu、日本)により蛍光を検出し、USB−6259データ取得カード(テキサス州オースチンのNational Instruments)を用いて200kHzのサンプリング速度で概して記録した。後の分析の前に7点二次Savitzky−Golayアルゴリズムによりデータトレースを平滑化した。蛍光読み出しと当時に、850nm LED(TSHG6200;コネチカット州シェルトンのVishay Semiconductors)からの背面照明で同じ対物レンズと、蛍光検出および撮像のために光路を分離するためのショート・パス・フィルタと、Guppy CCDカメラ(マサチューセッツ州ニューベリーポートのAllied Vision Technologies)とによって、液滴を撮像した。画像にすじが入らないように短い照明パルス(5〜20マイクロ秒)で液滴を撮像した。
液滴事象を閾値より上の蛍光強度の継続的バーストと解釈する特注LabViewソフトウェア(テキサス州オースチンのNational Instruments)でデータを分析した。シグナル対ノイズ比は一般に相当高く、シグナルレベルは日ごとに一致しており、従って、50mVの固定閾値を主として用い、他の状況では閾値を目視によって設定した。VIC蛍光体とFAM蛍光体の両方について液滴事象ごとにピーク蛍光強度を記録した。熱サイクリング中に液滴の多少の合体が、概して2個の無損傷液滴間の孤立した事象として発生して、「ダブレット」を形成した。ダブレットおよび稀なより大きい合体事象を蛍光バーストの継続期間に基づいてデータセットから容易に濾過した。
他の文献、例えば特許、特許出願、特許公開公報、ジャーナル、本、論文、ウェブコンテンツ、の参照および引用を本開示全体を通して行った。すべてのそのような文献は、あらゆる意味でそれら全体が参照により本明細書に援用されている。
本発明の精神または本質的特徴を逸脱することなく他の特定の形態で本発明を具現することができる。従って、上述の実施形態は、すべての点で、本明細書に記載する本発明を制限するものではなく例証するためのものであると解釈すべきである。
Claims (13)
- 核酸を分析するための方法であって、
マイクロチャネル内に、核酸と遺伝子座特異的プライマーとを含む水性流体を供給する工程;
油の対向伝播するストリーム内に前記水性流体を流して、複数の水性液滴を形成する工程であって、前記複数の水性液滴の各々が、単一の核酸と、複数の前記遺伝子座特異的プライマーとを含む、工程;
前記複数の水性液滴の各々において増幅反応を行い、前記複数の水性液滴の各々における前記単一の核酸の2以上の遺伝子座に対応するアンプリコンを前記複数の水性液滴の各々において生成する工程;
前記複数の水性液滴から前記アンプリコンを放出させる工程;および
前記アンプリコンを分析して、前記核酸のハプロタイプを決定する工程
を含む方法。 - 前記核酸が、生物の血液、尿、脳脊髄液、精液、唾液、痰、糞便または組織から得られる、請求項1に記載の方法。
- 前記核酸が、ゲノムDNA、cDNAまたはRNAを含む、請求項1に記載の方法。
- 前記核酸が基質に結合される、請求項1に記載の方法。
- 前記水性流体が、ポリメラーゼと複数のデオキシヌクレオチドをさらに含む、請求項1に記載の方法。
- 前記核酸と遺伝子座特異的プライマーが、マイクロ流体制御下の前記水性流体において組み合わされる、請求項1に記載の方法。
- 前記油が、フルオロカーボン油を含む、請求項1に記載の方法。
- 前記油が界面活性剤を含む、請求項1に記載の方法。
- 分析が、同じ前記液滴中で生じたアンプリコンを検出することを含む、請求項1に記載の方法。
- 分析がシークエンシングを含む、請求項1に記載の方法。
- 前記ハプロタイプを疾患を検出するための指標として用いることをさらに含む、請求項1に記載の方法。
- 前記疾患が癌であり、前記遺伝子座特異的なプライマーが、既知の癌バイオマーカーと関連する遺伝子座にハイブリダイズする、請求項11に記載の方法。
- 前記ハプロタイプを、薬物療法への応答を評価するための指標として、または、細菌もしくはウイルス感染の薬物耐性を同定するための指標として用いることをさらに含む、請求項1に記載の方法。
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