JP6940404B2 - 核酸検出のための方法および組成物 - Google Patents
核酸検出のための方法および組成物 Download PDFInfo
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Description
本願は、2014年8月19日出願の米国特許仮出願第62/039,207号に基づく利益を主張する。同出願を参照により本明細書に援用する。
本明細書で引用する刊行物、特許、または特許出願はすべて、それらをそれぞれ具体的かつ個別に「参照により援用する」と示した場合と同様に参照により本明細書に援用される。
「ポリヌクレオチド」、「核酸」、および「オリゴヌクレオチド」という用語は互換的に使用され、ヌクレオチド(デオキシリボヌクレオチドまたはリボヌクレオチド)の任意の長さの重合体形態またはその類似体を指す。ポリヌクレオチドは任意の三次元構造を持ち、既知または未知の任意の機能を果たしてよい。ポリヌクレオチドの例としては以下が挙げられるが、これらに限定するものではない:遺伝子または遺伝子断片のコード領域または非コード領域、遺伝子間DNA、連鎖解析で定義された座位、エキソン、イントロン、メッセンジャーRNA(mRNA)、転移RNA、リボソームRNA、低分子干渉RNA(siRNA)、低分子ヘアピン型RNA(shRNA)、マイクロRNA(miRNA)、核小体低分子RNA、リボザイム、cDNA、組換えポリヌクレオチド、分岐ポリヌクレオチド、プラスミド、ベクター、任意配列の単離DNA、任意配列の単離RNA、核酸プローブ、アダプター、およびプライマー。ポリヌクレオチドはメチル化ヌクレオチドなどの修飾ヌクレオチドおよびヌクレオチド類似体を含んでよい。ヌクレオチド構造への修飾を行う場合、修飾は重合体の構成の前に付与しても後に付与してもよい。ヌクレオチドの配列にヌクレオチド以外の成分を挟んでもよい。ポリヌクレオチドを重合後にたとえば標識成分、タグ、反応性部分、または結合パートナーと結合することでさらに修飾してもよい。ポリヌクレオチドの配列を示す場合、他の指定がない限り、5’→3’の方向に記載する。
一側面では、本発明は、試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成する方法であって、標的ポリヌクレオチドの領域に対する全配列が得られる条件のもとに、反応混合物中で試料を核酸増幅反応に供する工程を含み、反応混合物は、(a)一本の鎖に5’→3’方向に配列A、リンカー配列D、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズするループプライマーと;(b)鋳型特異的プライマー伸長のための鋳型として機能する該標的ポリヌクレオチドに沿ってループプライマーの配列Bを5’→3’方向に伸長して該標的ポリヌクレオチドの相補配列を生成するポリメラーゼを含む、方法を提供する。
別の側面では、本発明は、試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成するための組成物であって、ループプライマーと順方向プライマーと逆方向プライマーとを含み、(a)ループプライマーは一本の鎖に5’→3’方向に配列A、リンカー配列、および配列Bを含み、(i)配列Aと標的ポリヌクレオチドの配列A’との配列相補性および(ii)配列Bと標的ポリヌクレオチドの配列B’との配列相補性(配列A’と配列B’は標的ポリヌクレオチドの5’→3’方向に位置する)によって標的ポリヌクレオチドに特異的にハイブリダイズし;(b)逆方向プライマーは標的ポリヌクレオチドで配列A’よりも5’側に位置する配列に対し配列相同性を示し;かつ(c)順方向プライマーはリンカー配列に含まれる配列に特異的にハイブリダイズする、組成物を提供する。
本発明の相補配列増幅スキームの例示的な概略図を図1に示す。RTループプライマーは3つの部分を含む。すなわち、汎用的な配列(配列Aと配列Bを結ぶ線で示す)、RTループプライマーの5’末端側に位置するmiRNA相補配列(配列A)、およびRTループプライマーの3’末端側に位置するmiRNA相補配列(配列B)である。RT反応は、このRTループプライマーの3’末端(配列B)から開始され、miRNA配列と汎用的配列の両方を含むハイブリッドcDNA鎖を生成する。特異的なループプライマーを用いるこのRTでは、RNAが標的の場合には逆転写酵素、DNAが標的の場合にはポリメラーゼによるプライマー伸長を利用する。ポリメラーゼは、配列Bのハイブリダイゼーション領域である標的ポリヌクレオチドの5’末端側の領域に対する相補配列の生成中、配列Aと標的ポリヌクレオチドのハイブリダイゼーションを低減する。RT後、汎用配列に相補的な順方向プライマーと、miRNAに特異的な配列に相補的な逆方向プライマーを用いて定量PCRでこのハイブリッドcDNAを定量する。
miRNAの配列hsa−let−7a−5p(UGAGGUAGUAGGUUGUAUAGUU)(受入番号MIMAT0000062、22nt))およびhsa−let−7c(UGAGGUAGUAGGUUGUAUGGUU(受入番号MIMAT0000064、22nt))をmiRBASEのサイトから入手した(http://www.mirbase.org/index.shtml)。hsa−let−7a−5pのグアニンをシトシンに置換してhsa−let−7x−testの配列を生成した(UGAGGUAGUACGUUGUAUAGUU、22nt)。報告ではこの3種の合成miRNAをlet−7a、let−7c、およびlet−7xと簡略化する。合成miRNAオリゴヌクレオチドとプライマーはIntegrated DNA Technologies(IDT)より購入した。プライマーの名称と配列(5’→3’方向に記載)は以下のとおりである。
RT反応溶液は合成miRNAオリゴヌクレオチド0.25μgとRTプライマー0.7μMを含有するものとした。RT緩衝剤、dNTP、MgCl2、RNaseOUT、およびSuperscript(登録商標)III RTはSuperscript(登録商標)III First-Strand Synthesis System(Invitrogen(商標)(Life Technologies)、18080-051)のキットから得た。RTを製造業者の指示に従い実施した。簡単に説明すると、10μlの反応溶液を、37℃、42℃または50℃で50分間、続いて75℃で15分間、Bio-Rad CFXの装置を用いてインキュベートした後、RT産物を4℃で保持した。
miRNAの定量の特異性を最適にするため、発明者らは図1に例示する新規方針を提案した。まず、40ntの汎用配列と5〜10ntのmiRNA特異的配列を含むプライマーを用いた逆転写によってハイブリッドcDNA鋳型を得た。次に、汎用的な順方向プライマーおよびmiRNA特異的な逆方向プライマーを用いて定量PCRを実施した。
この試験の特異性を、let−7aと1ヌクレオチドしか違わないlet−7cおよびlet−7xの合成miRNAを用いて評価した。まず、RTの特異性を評価する。RTは、let−7aと完全に一致するRTプライマー5+5を用いて行った。RT産物をCEによって調査した。結果は、図6(A〜C)に示すように、異なるmiRNA鋳型から同様の量のRT産物が生成されたことを示した。図6(A)ではlet−7a、図6(B)ではlet−7c、図6(C)ではlet−7xをRT鋳型として使用した。LMは20ntのRNAラダーマーカーを示す。
ループプライマーの代替的構造(ループの一部が折りたたまれヘアピン構造をとっている)の概略図の例を図9に示す。このプライマーは、5’側認識配列(配列A)と、5’側アーム配列(配列D)と、ステム(配列E・G)およびループ(配列F)を有するヘアピンと、3’側アーム配列(配列H)と、3’側認識配列(配列B)とを含む。ヘアピンによってループ構造は安定し、大部分の塩基が試料中の他の核酸との相互作用から隔離されるため、バックグラウンドシグナルが減少する。ステム構造を調節してシステムの特性を変更することができる。ループプライマーにヘアピン構造を導入してバックグラウンドシグナルを低減する例を図12に示す。
図10は、let7ファミリーの最初の5つのメンバー(let−7a〜e)を標的とする指定のループプライマーに基づいて7つの試験の交差反応性をRTおよび定量PCRで測定した分析結果を示す。hsa−let−7a−5p〜hsa−let−7e−5pの配列はmiRBASE(www.mirbase.org/)で得た。使用したRTプライマーおよび定量PCRプライマーを図10(A)に示す。let−7bとlet−7cそれぞれに対して2種類のループプライマーを設計した。
ヘアピンループプライマーを用いた様々な試験結果を図11に示す。miRNA(hsp−let−7a−5p)の使用量を2.5×1010−250コピー/RT反応から変動させた。研究した範囲内では、試験は優れた直線性を示し、定量PCRシステムの効率は約86%であった。
(実施例9:ヘアピンを含むループプライマーを用いたバックグラウンドシグナル低減の検証)
本発明は以下のものに関する:
[1] 試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成する方法であって、該標的ポリヌクレオチドの該領域に対する全配列を生成する条件のもとに、反応混合物中で該試料を核酸増幅反応に供する工程を含み、該反応混合物は、
(a)一本の鎖に5’→3’方向に配列A、リンカー配列D、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズする、ループプライマーと;
(b)鋳型特異的プライマー伸長のための鋳型として機能する該標的ポリヌクレオチドに沿って該ループプライマーの該配列Bを5’→3’方向に伸長して該標的ポリヌクレオチドの相補配列を生成するポリメラーゼと
を含む、方法。
[2] 試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成する方法であって、該標的ポリヌクレオチドの該領域に対する全配列を生成する条件のもとに、該試料をループプライマーと順方向プライマーと逆方向プライマーとポリメラーゼとを含む核酸増幅反応に供する工程を含み、反応混合物は、
(a)一本の鎖に5’→3’方向に配列A、リンカー配列D、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズする該ループプライマーと;
(b)鋳型特異的プライマー伸長のための鋳型として機能する該標的ポリヌクレオチドに沿って該ループプライマーの該配列Bを5’→3’方向に伸長して該標的ポリヌクレオチドの相補配列を生成する該ポリメラーゼと;
(c)該標的ポリヌクレオチド内で該配列A’または該配列B’よりも5’側に位置する配列と配列相同性を示す該逆方向プライマーと;
(d)該ループプライマーに相補的な配列に特異的にハイブリダイズする該順方向プライマーと
を含む、方法。
[3] 項目1の方法で得られる産物を逆方向プライマーおよび必要に応じて順方向プライマーの存在下で増幅する工程をさらに含み、該逆方向プライマーおよび該順方向プライマーは、それぞれ増幅産物および前記ループプライマーに対して配列相補性を示す、項目1に記載の方法。
[4] 前記順方向プライマーは前記リンカー配列に含まれる配列に特異的にハイブリダイズする、項目3に記載の方法。
[5] 前記逆方向プライマーは前記標的ポリヌクレオチドの前記配列A’または前記配列B’より5’側に位置する部分に相補的な配列に特異的にハイブリダイズする、項目3に記載の方法。
[6] 前記核酸増幅の産物を検出する工程をさらに含む、項目2または3に記載の方法。
[7] 前記検出工程は前記反応混合物に含まれ前記産物に相補的な配列を有するプローブからのシグナルを検出する工程を含む、項目6に記載の方法。
[8] 前記配列Aは2nt〜約10ntの長さであり、前記配列Bは2nt〜約10ntの長さである、項目1または2に記載の方法。
[9] 前記配列Aと前記配列Bの合計の長さは約5nt〜約20ntである、項目1または2に記載の方法。
[10] 前記配列Aと前記配列Bの合計の長さは前記標的ポリヌクレオチドに特異的にハイブリダイズして前記ループプライマーを伸長させるのに十分な長さである、項目1または2に記載の方法。
[11] 最適に整列した場合、前記配列Bと前記配列Aを直線状に連結した配列は、前記配列A’と前記配列B’を直線状に連結した配列と少なくとも80%の相補性を有する、項目1または2に記載の方法。
[12] 前記配列Bと前記配列Aを直線状に連結した配列は前記配列A’と前記配列B’を直線状に連結した配列と少なくとも90%の相補性を有する、項目1または2に記載の方法。
[13] 前記配列A’の3’末端は前記配列B’から1nt〜約5nt以内にある、項目1または2に記載の方法。
[14] 前記標的ポリヌクレオチドはDNA分子である、項目1または2に記載の方法。
[15] 前記標的ポリヌクレオチドはRNA分子である、項目1または2に記載の方法。
[16] 前記標的ポリヌクレオチドは非コードRNA分子である、項目1または2に記載の方法。
[17] 前記非コードRNA分子は、成熟マイクロRNA分子、マイクロRNA前駆体分子、初期マイクロRNA分子、低分子干渉RNA(siRNA)分子、piwi結合RNA(piRNA)分子、piwiRNA分子、長鎖非コードRNA(lncRNA)分子、リボソームRNA(rRNA)分子、および低分子ヘアピン型RNA(shRNA)分子からなる群より選択される、項目16に記載の方法。
[18] 前記標的ポリヌクレオチドは100nt未満の長さである、項目1または2に記載の方法。
[19] 前記標的ポリヌクレオチドは50nt未満の長さである、項目1または2に記載の方法。
[20] 前記リンカー配列は、1つ以上のバーコード配列;1つ以上の制限酵素認識配列;1つ以上のオリゴヌクレオチドプローブ結合配列またはその相補体;配列決定プライマーがアニールする1つ以上の配列またはその相補体;およびそれらの組み合わせからなる群より選択される、1つ以上の配列要素を含む、項目1または2に記載の方法。
[21] 前記リンカー配列は複数の異なるループプライマーに共通の汎用的な配列を含む、項目1または2に記載の方法。
[22] 前記リンカー配列はヘアピン型構造を有する、項目1または2に記載の方法。
[23] 試料中の少数アレルすなわち対応する多数アレルと単一の塩基位置が異なる配列多様体の存在を検出する方法であって、該配列多様体を含む少数アレルと多数アレルの領域がループプライマー対を用いて増幅される条件のもとに、反応混合物中で該試料を核酸増幅反応に供する工程を含み、該反応混合物は、
(a)一本の鎖に5’→3’方向に配列A1、リンカー配列D1、および配列B1を含み、(i)該配列A1と該少数アレルの配列A1’との配列相補性および(ii)該配列B1と該少数アレルの配列B1’との配列相補性(該配列A1’と配列B1’は該少数アレルの5’→3’方向に位置する)によって該少数アレルに特異的にハイブリダイズする第一のループプライマーと;(b)一本の鎖に5’→3’方向に配列A2、リンカー配列D2、および配列B2を含み、(i)該配列A2と該多数アレルの配列A2’との配列相補性および(ii)該配列B2と該少数アレルの配列B2’との配列相補性(該配列A2’と該配列B2’は該多数アレルの5’→3’方向に位置する)によって該多数アレルに特異的にハイブリダイズする第二のループプライマーと;(c)鋳型特異的プライマー伸長のための鋳型として機能する各アレルに沿って該第一のループプライマーの該配列B1と該第二のループプライマーの該配列B2を5’→3’方向に伸長して各アレルの相補配列を生成するポリメラーゼとを含む、方法。
[24] 試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成するための組成物であって、ループプライマーと順方向プライマーと逆方向プライマーとを含み、
(a)該ループプライマーは一本の鎖に5’→3’方向に配列A、リンカー配列、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズし;
(b)該逆方向プライマーは該標的ポリヌクレオチドで該配列A’よりも5’側に位置する配列に対し配列相同性を示し;かつ
(c)該順方向プライマーは該リンカー配列に含まれる配列に特異的にハイブリダイズする、組成物。
[25] 前記逆方向プライマーまたは前記順方向プライマーの伸長により生成された前記標的ポリヌクレオチドに相補的な配列に対して配列相補性を有する検出プローブをさらに含む、項目24に記載の組成物。
[26] 前記配列Aは2nt〜約10ntの長さであり、前記配列Bは2nt〜約10ntの長さである、項目24に記載の組成物。
[27] 前記配列Aと前記配列Bの合計の長さは約5nt〜約20ntである、項目24に記載の組成物。
[28] 前記配列Aと前記配列Bの合計の長さは前記標的ポリヌクレオチドに特異的にハイブリダイズして前記ループプライマーを伸長させるのに十分な長さである、項目24に記載の組成物。
[29] 最適に整列した場合、前記配列Bと前記配列Aを直線状に連結した配列は前記配列A’と前記配列B’を直線状に連結した配列と少なくとも80%の相補性を有する、項目24に記載の組成物。
[30] 前記配列Bと前記配列Aを直線状に連結した配列は前記配列A’と前記配列B’を直線状に連結した配列と少なくとも90%の相補性を有する、項目24に記載の組成物。
[31] 前記配列A’の3’末端は前記配列B’から1nt〜約5nt以内にある、項目24に記載の組成物。
[32] 前記標的ポリヌクレオチドはDNA分子である、項目24に記載の組成物。
[33] 前記標的ポリヌクレオチドはRNA分子である、項目24に記載の組成物。
[34] 前記標的ポリヌクレオチドは非コードRNA分子である、項目24に記載の組成物。
[35] 前記非コードRNA分子は、成熟マイクロRNA分子、マイクロRNA前駆体分子、初期マイクロRNA分子、siRNA分子、piRNA分子、piwiRNA分子、lncRNA分子、rRNA分子、およびshRNA分子からなる群より選択される、項目34に記載の組成物。
[36] 前記リンカー配列は、1つ以上のバーコード配列;1つ以上の制限酵素認識配列;1つ以上のオリゴヌクレオチドプローブ結合配列またはその相補体;配列決定プライマーがアニールする1つ以上の配列またはその相補体;およびそれらの組み合わせからなる群より選択される1つ以上の配列要素を含む、項目24に記載の組成物。
[37] 前記リンカー配列は複数の異なるループプライマーに共通の汎用的な配列を含む、項目24に記載の組成物。
[38] 前記組成物は容器に入っている、項目24に記載の組成物。
[39] 前記容器はウェル、プレート、チューブ、チャンバー、フローセル、またはチップである、項目38に記載の組成物。
[40] 前記組成物は無水形態である、項目24に記載の組成物。
[41] ループプライマーと順方向プライマーと逆方向プライマーとポリメラーゼとを含む、試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成するための反応混合物であって、
(a)該ループプライマーは一本の鎖に5’→3’方向に配列A、リンカー配列、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズし;
(b)該逆方向プライマーは該標的ポリヌクレオチドで該配列A’よりも5’側に位置する配列に対し配列相同性を示し;かつ
(c)該順方向プライマーは該リンカー配列に含まれる配列に特異的にハイブリダイズする、反応混合物。
[42] 前記逆方向プライマーまたは前記順方向プライマーの伸長により生成された前記標的ポリヌクレオチドに相補的な配列に対して配列相補性を有する検出プローブをさらに含む、項目41に記載の反応混合物。
[43] 前記配列Aは2nt〜約10ntの長さであり、前記配列Bは2nt〜約10ntの長さである、項目41に記載の反応混合物。
[44] 前記配列Aと前記配列Bの合計の長さは約5nt〜約20ntである、項目41に記載の反応混合物。
[45] 前記配列Aと前記配列Bの合計の長さは前記標的ポリヌクレオチドに特異的にハイブリダイズして前記ループプライマーを伸長させるのに十分な長さである、項目41に記載の反応混合物。
[46] 最適に整列した場合、前記配列Bと前記配列Aを直線状に連結した配列は前記配列A’と前記配列B’を直線状に連結した配列と少なくとも80%の相補性を有する、項目41に記載の反応混合物。
[47] 前記配列Bと前記配列Aを直線状に連結した配列は前記配列A’と前記配列B’を直線状に連結した配列と少なくとも90%の相補性を有する、項目41に記載の反応混合物。
[48] 前記配列A’の3’末端は前記配列B’から1nt〜約5nt以内にある、項目41に記載の反応混合物。
[49] 前記標的ポリヌクレオチドはDNA分子である、項目41に記載の反応混合物。
[50] 前記標的ポリヌクレオチドはRNA分子である、項目41に記載の反応混合物。
[51] 前記標的ポリヌクレオチドは非コードRNA分子である、項目41に記載の反応混合物。
[52] 前記非コードRNA分子は、成熟マイクロRNA分子、マイクロRNA前駆体分子、初期マイクロRNA分子、siRNA分子、piRNA分子、piwiRNA分子、lncRNA分子、rRNA分子、およびshRNA分子からなる群より選択される、項目51に記載の反応混合物。
[53] 前記リンカー配列は、1つ以上のバーコード配列;1つ以上の制限酵素認識配列;1つ以上のオリゴヌクレオチドプローブ結合配列またはその相補体;配列決定プライマーがアニールする1つ以上の配列またはその相補体;およびそれらの組み合わせからなる群より選択される1つ以上の配列要素を含む、項目41に記載の反応混合物。
[54] 前記リンカー配列は複数の異なるループプライマーに共通の汎用的な配列を含む、項目41に記載の反応混合物。
[55] 前記反応混合物は容器に入っている、項目41に記載の反応混合物。
[56] 前記容器はウェル、プレート、チューブ、チャンバー、フローセル、またはチップである、項目55に記載の反応混合物。
[57] 前記反応混合物は無水形態である、項目41に記載の反応混合物。
[58] キットの形態に梱包された項目24の組成物。
[59] 項目58に記載のキットの使用法であって、標的ポリヌクレオチドと前記ループプライマーと前記順方向プライマーと前記逆方向プライマーと検出可能量の増幅産物を生成するポリメラーゼとを含む反応混合物中で核酸増幅反応を実施する工程を含み、該標的ポリヌクレオチドは約100nt未満の長さである、使用法。
[60] 試料中の標的ポリヌクレオチドを検出するシステムであって、
(a)試料で検出反応を実施するようにとの顧客の要求を受けるよう構成されたコンピュータと;
(b)項目37に記載の反応混合物中で核酸増幅反応を実施して増幅産物を生成する増幅系と;
(c)増幅産物量に対応する検出シグナルの検出結果を含む報告書を受取人に送る報告書作成部と
を含む、システム。
[61] 前記受取人は前記顧客である、項目60に記載のシステム。
[62] 1つ以上のプロセッサで実行すると試料中の標的ポリヌクレオチドを検出する方法を実施するコードを含む、コンピュータ可読媒体であって、該方法は、
(a)試料で検出反応を実施するようにとの顧客の要求を受ける工程と;
(b)項目40に記載の反応混合物中で核酸増幅反応を実施して増幅産物を生成する工程と;
(c)増幅産物量に対応する検出シグナルの検出結果を含む報告書を作成する工程と
を含む、媒体。
[63] 試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を、該標的ポリヌクレオチドの該領域に対する全配列を生成する条件のもとに、単一の反応混合物中で生成する工程をさらに含み、該反応混合物は、
(a)一本の鎖に5’→3’方向に配列A、リンカー配列D、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズするループプライマーと;
(b)鋳型特異的プライマー伸長のための鋳型として機能する該標的ポリヌクレオチドに沿って該ループプライマーの該配列Bを5’→3’方向に伸長して該標的ポリヌクレオチドの相補配列を生成するポリメラーゼと;
(c)該標的ポリヌクレオチド内で該配列A’または該配列B’よりも5’側に位置する配列と配列相同性を示す逆方向プライマーと;
(d)該ループプライマーに相補的な配列に特異的にハイブリダイズする順方向プライマーと
を含む、項目2に記載の方法。
[64] 標的ポリヌクレオチドと前記ループプライマーと前記順方向プライマーと前記逆方向プライマーと検出可能量の増幅産物を生成するポリメラーゼとを含む反応混合物中で核酸増幅反応を実施する工程をさらに含み、該標的ポリヌクレオチドは約100nt未満の長さであり、該核酸増幅反応のサイクル閾値(CT)は30未満である、項目59に記載の方法。
[65] 試料中の少数アレルすなわち対応する多数アレルと単一の塩基位置が異なる配列多様体の存在を検出する方法であって、該配列多様体を含む該少数アレルと該多数アレルの領域をループプライマー対を用いて増幅する条件のもとに、複数の反応混合物中で該試料のうち複数の部分を複数の核酸増幅反応に供する工程を含み、第一の反応混合物は第一のループプライマーとポリメラーゼを含み、第二の反応混合物は第二のループプライマーとポリメラーゼを含み、さらに、
(a)該第一のループプライマーは一本の鎖に5’→3’方向に配列A1、リンカー配列D1、および配列B1を含み、(i)該配列A1と該少数アレルの配列A1’との配列相補性および(ii)該配列B1と該少数アレルの配列B1’との配列相補性(該配列A1’と該配列B1’は該少数アレルの5’→3’方向に位置する)によって該少数アレルに特異的にハイブリダイズし;
(b)該第二のプライマーは一本の鎖に5’→3’方向に配列A2、リンカー配列D2、および配列B2を含み、(i)該配列A2と該多数アレルの配列A2’との配列相補性および(ii)該配列B2と該少数アレルの配列B2’との配列相補性(該配列A2’と該配列B2’は該多数アレルの5’→3’方向に位置する)によって該多数アレルに特異的にハイブリダイズし;かつ
(c)ポリメラーゼは鋳型特異的プライマー伸長のための鋳型として機能する各アレルに沿って該第一のループプライマーの該配列B1または該第二のループプライマーの該配列B2を5’→3’方向に伸長して各アレルの相補配列を生成する、方法。
Claims (16)
- 試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成する方法であって、該標的ポリヌクレオチドの該領域に対する全配列を生成する条件のもとに、反応混合物中で該試料を核酸増幅反応に供する工程を含み、該反応混合物は、
(a)一本の鎖に5’→3’方向に配列A、リンカー配列D、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズする、ループプライマーと;
(b)鋳型特異的プライマー伸長のための鋳型として機能する該標的ポリヌクレオチドに沿って該ループプライマーの該配列Bを5’→3’方向に伸長して該標的ポリヌクレオチドの相補配列を生成するポリメラーゼと
を含み、前記リンカー配列Dが、少なくとも5ヌクレオチド長のステム配列を有するヘアピン構造を含み、前記ステム配列がその全長にわたり完全に相補的である、前記方法。 - 請求項1の方法で得られる産物を、逆方向プライマーおよび順方向プライマーの存在下で増幅する工程をさらに含み、該逆方向プライマーが、配列A'又はB’に対して5’である標的ポリヌクレオチドの一部に相補的である配列に特異的にハイブリダイズし、及び該順方向プライマーが、リンカー配列Dに含まれる配列に特異的にハイブリダイズする、請求項1に記載の方法。
- 前記核酸増幅の産物を検出する工程をさらに含み、そしてここで前記検出工程、前記産物に相補的な配列を有する反応混合物中のプローブからのシグナルを検出する、請求項2に記載の方法。
- 前記配列Aは2nt〜10ntの長さであり、前記配列Bは2nt〜10ntの長さである、請求項1〜3のいずれか一項に記載の方法。
- 前記配列Aと配列Bの合計の長さは5nt〜20ntである、請求項1〜4のいずれか一項に記載の方法。
- 最適に整列した場合、前記配列Bと前記配列Aを直線状に連結した配列は、前記配列A’と前記配列B’を直線状に連結した配列と少なくとも80%の相補性を有する、請求項1または2に記載の方法。
- 配列A’の3’末端と、配列B’の5’末端との間に1nt〜5ntが位置する、請求項1〜6のいずれか一項に記載の方法。
- 前記標的ポリヌクレオチドは非コードRNA分子であり、そして前記非コードRNA分子は、成熟マイクロRNA分子、マイクロRNA前駆体分子、初期マイクロRNA分子、低分子干渉RNA(siRNA)分子、piwi結合RNA(piRNA)分子、piwiRNA分子、長鎖非コードRNA(lncRNA)分子、リボソームRNA(rRNA)分子、および低分子ヘアピン型RNA(shRNA)分子からなる群より選択される、請求項1〜7のいずれか一項に記載の方法。
- 前記リンカー配列Dは、1つ以上のバーコード配列;1つ以上の制限酵素認識配列;1つ以上のオリゴヌクレオチドプローブ結合配列またはその相補体;配列決定プライマーがアニールする1つ以上の配列またはその相補体;およびそれらの組み合わせからなる群より選択される、1つ以上の配列要素を含む、請求項1〜8のいずれか一項に記載の方法。
- 試料中の少数アレルすなわち対応する多数アレルと単一の塩基位置が異なる配列多様体の存在を検出する方法であって、該配列多様体を含む少数アレルと多数アレルの領域がループプライマー対を用いて増幅される条件のもとに、反応混合物中で該試料を核酸増幅反応に供する工程を含み、該反応混合物は、
(a)一本の鎖に5’→3’方向に配列A1、リンカー配列D1、および配列B1を含み、(i)該配列A1と該少数アレルの配列A1’との配列相補性および(ii)該配列B1と該少数アレルの配列B1’との配列相補性(該配列A1’と配列B1’は該少数アレルの5’→3’方向に位置する)によって該少数アレルに特異的にハイブリダイズする第一のループプライマーと;(b)一本の鎖に5’→3’方向に配列A2、リンカー配列D2、および配列B2を含み、(i)該配列A2と該多数アレルの配列A2’との配列相補性および(ii)該配列B2と該少数アレルの配列B2’との配列相補性(該配列A2’と該配列B2’は該多数アレルの5’→3’方向に位置する)によって該多数アレルに特異的にハイブリダイズする第二のループプライマーと;(c)鋳型特異的プライマー伸長のための鋳型として機能する各アレルに沿って該第一のループプライマーの該配列B1と該第二のループプライマーの該配列B2を5’→3’方向に伸長して各アレルの相補配列を生成するポリメラーゼとを含み、
ここで前記リンカー配列D1及びD2が、各々少なくとも5ヌクレオチド長のステム配列を有するヘアピン構造を含み、前記ステム配列がその全長にわたり完全に相補的である、前記方法。 - 試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成するための組成物であって、ループプライマーと順方向プライマーと逆方向プライマーとを含み、
(a)該ループプライマーは一本の鎖に5’→3’方向に配列A、リンカー配列、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズし;
(b)該逆方向プライマーは該標的ポリヌクレオチドで該配列A’よりも5’側に位置する配列に対し配列相同性を示し;かつ
(c)該順方向プライマーは該リンカー配列に含まれる配列に特異的にハイブリダイズし、ここで前記リンカー配列Dが、少なくとも5ヌクレオチド長のステム配列を有するヘアピン構造を含み、前記ステム配列がその全長にわたり完全に相補的である、組成物。 - 前記逆方向プライマーまたは前記順方向プライマーの伸長により生成された前記標的ポリヌクレオチドに相補的な配列に対して配列相補性を有する検出プローブをさらに含む、請求項11に記載の組成物。
- 前記組成物は無水形態である、請求項11又は12に記載の組成物。
- ループプライマーと順方向プライマーと逆方向プライマーとポリメラーゼとを含む、試料中の標的ポリヌクレオチドに含まれる領域に相補的な配列を生成するための反応混合物であって、
(a)該ループプライマーは一本の鎖に5’→3’方向に配列A、リンカー配列D、および配列Bを含み、(i)該配列Aと該標的ポリヌクレオチドの配列A’との配列相補性および(ii)該配列Bと該標的ポリヌクレオチドの配列B’との配列相補性(該配列A’と該配列B’は該標的ポリヌクレオチドの5’→3’方向に位置する)によって該標的ポリヌクレオチドに特異的にハイブリダイズし;
(b)該逆方向プライマーは該標的ポリヌクレオチドで該配列A’よりも5’側に位置する配列に対し配列相同性を示し;かつ
(c)該順方向プライマーは該リンカー配列に含まれる配列に特異的にハイブリダイズし、ここで当該リンカー配列Dが少なくとも5ヌクレオチド長のステム配列を有するヘアピン構造を含み、前記ステム配列がその全長にわたり完全に相補的である、反応混合物。 - 前記逆方向プライマーまたは前記順方向プライマーの伸長により生成された前記標的ポリヌクレオチドに相補的な配列に対して配列相補性を有する検出プローブをさらに含む、請求項14に記載の反応混合物。
- 前記反応混合物は無水形態である、請求項14又は15に記載の反応混合物。
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US20230129799A1 (en) | 2023-04-27 |
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ES2832748T3 (es) | 2021-06-11 |
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