JPH022934A - テンプレート−依存性核酸プロ−ブ再構成を用いたアッセイ - Google Patents

テンプレート−依存性核酸プロ−ブ再構成を用いたアッセイ

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Publication number
JPH022934A
JPH022934A JP63313658A JP31365888A JPH022934A JP H022934 A JPH022934 A JP H022934A JP 63313658 A JP63313658 A JP 63313658A JP 31365888 A JP31365888 A JP 31365888A JP H022934 A JPH022934 A JP H022934A
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Prior art keywords
probes
probe
nucleic acid
target
ligase
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JPH0634759B2 (ja
Inventor
Keith C Backman
ケイス・シー・バックマン
Chang-Ning J Wang
チャン−ニン・ジェイ・ウォン
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Biotechnica International Inc
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Biotechnica International Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6862—Ligase chain reaction [LCR]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays

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  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
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Abstract

(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。

Description

【発明の詳細な説明】 （産業上の利用分野） 本発明は核酸ハイブリダイゼーションアッセイの一般的
分野に関する。
（従来の技術） 核酸ハイブリダイゼーションはサンプル中の特定の核酸
の存在を検出するために用られる０例えば、ファルコウ
（Ｆａｌｋｏｗ）の米国特許筒４゜３５８．５３５号は
、ハイブリダイゼーションアッセイを開示しており、そ
のアッセイはシングルｔＭ　Ｄ　Ｎ　Ａをフィルターに
結合し；ラベルし；このフィルターにシングル鎖サンプ
ルＤＮＡを接触させ；そしてサンプルＤＮＡとラベルさ
れたプローブとのハイブリダイズをフィルター上で検出
することよりなる。
ホワイトレイ（Ｗｈｉｔｅｌｅｙ）らのＥＰＩ８５４９
４号は、診断用部分を持つ標的核酸配列を検出する方法
を開示しており、それによれば、サンプルは低ストリン
ジェントな条件下で該診断用部分と相補的なプローブで
処理され、次いでこのサンプルは高ストリンジェントな
条件下で隣接配列と相補的なプローブで処理される。こ
の診断用プローブおよび隣接プローブは共有結合されて
おり、そして結合したプローブは未結合プローブが除去
されたのち検出される。
ミュリス（Ｍｕｌｌｉｓ）の米国特許第４．６８３，２
０２号および４，６８３，１９５号は、相補核酸鎖をブ
ライマーで処理し、そしてこのブライマーをＤＮＡポリ
メラーゼで延長して所望核酸の合成のためのテンプレー
トを作製することにより、核酸配列を増幅する方法を開
示している。
上記米国特許４．６８３，１９５号は、この方法で増幅
したＤＮＡの検出を開示している。
（発明が解決しようとする課題） 本発明は、サンプル中の標的核酸配列の存在およびその
量を検出する方法を提供する。この方法は、過剰プロー
ブ配列の幾何級数的速度での迅速なテンプレート依存再
構成の繰り返しからなり、それにより、検出に利用され
る配列を急速に増大させ、そして究極的にアッセイの感
度を向上させる。本発明の方法は、標的配列が低濃度で
存在するかまたはサンプル中で極めてマイナーな成分と
して他の核酸配列と共に含まれる時に、特に有用である
。本発明の方法は、容易に自動化できるので診断用キッ
トきしての応用に特に魅力的である。
（課題を解決するための手段） 本発明は、一般にサンプル中の標的核酸配列の検出方法
であり、少なくとも四種のシングル鎖核酸プローブを化
学量論的過剰量で用いる。便宜のため、第一および第二
プローブを一次プローブと呼び、第二および第三プロー
ブを二次プローブと呼ぶ、これらのプローブは、次のよ
うな特性を有する。第一プローブは、標的核酸配列の鎖
の第一セグメントにハイブリダイズすることが出来る、
第二プローブは、標的核酸配列の同じ鎖の第二セグメン
トにハイブリダイズすることが出来る。第一および第二
プローブの選択は、これらの二種のプローブが標的配列
にハイブリダイズしたとき、第一プローブの３′末端の
第二プローブの５′末端への結合を可能ならしめるよう
に行うτ即ち、標的配列鎮の第一セグメントの５′末端
は、咳鎖の第二セグメントの３′末端と関連して位置し
、二つのプローブの結合を可能とする。第一プローブは
、第三プローブともハイブリダイズ可能であり、そして
第二プローブは第四プローブともハイブリダイズ可能で
ある。
アッセイは次のように行われる。標的が二重鎖である時
は、サンプルＤＮＡを、相補的な二つの標的類（第−標
的類および第二標的類）を含むシングル鎖ＤＮＡとして
用意する。四種のプローブをサンプルＤＮＡに四種のシ
ングル鎖として導入し、二つの一次プローブを第−標的
類にハイブリダイズさせ、そしてもし標的が二重鎖であ
る時は、二つの二次プローブを第二標的類にハイブリダ
イズさせる。次に、二つの一次プローブを連結（ライゲ
ート）シ、一次合成融合プローブ配列を形成し、さらに
二重鎖標的の場合には二次プローブを融合させ二次合成
融合プローブ配列を形成する。
ＤＮＡを変性させ、サンプル中の標的の量を実質的に二
倍にする。ハイブリダイゼーションのサイクルとして、
連結および変性を繰り返し、再構成された検出可能融合
プローブの量を幾何級数的速度で増大させる。標的がシ
ングル鎖である時は、二次プローブの標的Ｓｒｉは第二
サイクルまで存在しないが、その時点で一次合成融合プ
ローブ配列が二つの二次プローブのテンプレートとなり
、アッセイは上記のように進行する。上に述べた原理に
従えば、本発明はプローブ配列の再構成を可能ならしめ
て、検出される融合プローブ配列を幾何級数的速度で形
成する。迅速な再構成は、簡単な方法で、良好な感度を
提供する。好ましくは、サイクルは２０〜５０回繰り返
される。
さらに、第−標的類の第一セクションの５′末端は、効
率的連結、特に酵素的連結を提供するために、介在配列
の存在無しに、第−標的類の第二セクションの３′末端
に隣接（接続）し且つホスフェート結合で結合している
ことも好ましい、プローブにとっても標的にとっても、
好ましい核酸はＤＮＡである。相補配列を分離する好ま
しい方法は、熱変性、即ち融解（ｍｅｌｔｉｎｇ）であ
る、好ましくはプローブはｌＯ〜２００塩基長である。
第五、第六、等の追加プローブを用いて、これを同様に
して他のプローブに隣接してハイブリダイズおよび結合
させることもできる。しかしながら、四種のプローブで
充分であり、これが好ましい。
上記の方法は、感受性の検出システム、特に二種の異な
るプローブ上の標的剤の組合わせを含む系で用いること
が出来る０例えば、一つのプローブの上の標識剤として
、不溶性相への特異的結合成分（例えば、アビジン機能
を持たせた不溶性相に対するビオチン）を用い、他方の
プローブの標識剤に色素または蛍光色素を用いることが
できる。
不溶性相とサンプルを接触させて洗浄した後に、該相に
色素もしくは蛍光色素が存在することは、合成的に融合
されたプローブの存在、従って、サンプル中の標的の存
在を示唆する。
本発明は、上記アッセイを実施するキットも提供するも
ので、このキットは、プローブ、リガーゼ、および該プ
ローブおよびリガーゼを別々に収容する上段とからなる
０本発明の方法を実施する装置は、標的配列、プローブ
およびリガーゼからなる混合物を保持する手段、および
該混合物の温度を変性温度から標的への１０−ブのハイ
ブリダイゼーションを可能とする温度へと循環させる手
段を含む、好ましくは、この温度は自動的に循環される
。
本発明の他の態様および利点は、以下の好ましい態様の
説明および特許請求の範囲の記載から理解されるであろ
う。
（好ましい態様） ■ 第１図はハイブリダイゼーションアッセイにおける各工
程を示す工程図である。
第２図は、再構成されるプローブの形成をサイクル数の
関数として示すグラフである。
方法 第１図は本発明を説明するもので、低濃度で存在するヌ
クレオチド配列を検出するためのハイブリダイゼーショ
ンアッセイでの工程を示している。
この方法で種々の工程を実施するために多くの方法が存
在することは、当業者に明らかであろう。
−１に、この工程は周知の技術、例えばマニアチスらの
、［モレキュラー・クローニングニア・ラボラトリ−・
マニュアル（ＭｏｌｅｃｕｌａｒＣｌｏｎｉｎｇ：Ａ　
　　ＬａｂｏｒａＬｏｒｙ　　　Ｍａｎｕａ　１）Ｊ　
　［コールド・スプリング・ハーバ−・ラボラトリ−（
ｃｏｌｄ　　ＳｐｒｉｎｇＨａｒｂｏｒ　　Ｌａｂｏｒ
ａｔｏｒｙ）、１８９２〕に記載されている技術で実施
可能である０例えば、二重鎖ＤＮＡは、８０〜１０５℃
で１〜５分間の熱変性（融解）でシングル鎖にすること
ができる。別法として、酵素的に鎖分離を行うこともで
きる。プローブまたはサブ−セグメントはオリゴヌクレ
オチドの合成のための標準的技術を用いて合成でき、ま
たは天然に存在するＤＮＡを消化してフラグメントを単
離することにより１ｇ製できる。ハイブリダイゼーショ
ンの条件は、関与するフラグメントの長さおよびホモロ
ジーの程度により変化するであろう、一般に、ウエトマ
ー（Ｗｅ　ｔｍａ　ｒ）ら、Ｊ９Ｍｏｌ、Ｂｉｏｌ、、
３１　：３４９−３７０　（１９６８）に記載されてい
る技術および条件を用いることができる。ヌクレオチド
リガーゼを用いるための適当な条件および技術は、周知
であり、市販リガーゼを使用できる。
本発明の方法には、必須ではないが好ましい態様が存在
する。特に、テンプレート依存性結合に関与する５′末
端が未だホスホリル化されていない場合は、他の５′末
端での結合が抑制されるように、該関与する５′末端の
みが標準的技術でホスホリル化されなければならない、
プローブの長さおよび配列の選択は、二つのプローブの
間違った結合が万−生じたとき（！！ＩＩち二つのプロ
ーブが意図する標的の直線配列を代表するように結合し
ないとき）に、相補プローブの末端が酵素的連結のため
に適切な様式で互いに隣接しないようにし、これらの過
誤結合したプローブが、相補プローブの結合のためのテ
ンプレートとして作用しないように選択される。好まし
くは、プローブは１０ないし２００塩基長である。
好ましいリガーゼは、少なくとも一つの好ましい特定の
反応条件下で、テンプレートに依存しないプローブの結
合を触媒する傾向のないものである０例えば、好ましい
結果は、容量を排除する溶質が高濃度に存在しない条件
でのＥ、ｃｏｌｉのＤＮＡリガーゼ（米国、バイオケミ
カル（Ｂｉ。
ｃｈｅｍｉｃａｌ）社から入手可能）またはＴ。
ＬｈｅｒｍｏｐｈｉｌｕｓのＤＮＡリガーゼで、あるい
は約５．０ｍＭのＡＴＰの存在下でのＴ４ＤＮＡリガー
ゼで得られる。チマーマン（Ｚｉｍｍｅ　ｒｍａ　ｎ）
ら、Ｐｒｏｃ、Ｎａ　Ｌ　１．Ａｃａｄ。
Ｓｃｉ、ＵＳＡ、８０．５８５２　（１９８３）；タカ
ハシ、Ｍ、およびウチダ、Ｔ、、Ｊ、Ｂｉ。
ｃｈｅｍ、１００，１２３　（１９８６）；およびフェ
レッティ　（Ｆｅｒｒｅｔ　ｉ）ら、Ｎｕｃｌ。
Ａｃ１ｄ　　Ｒｅｓ、、９．３６９５　（１９８１）を
参照。
リガーゼ酵素は、二重鎖ＤＮＡをその構成シングル鎖に
解離させるための工程で熱変性しないことも好ましい、
変性が温度の上昇で行われるときは、熱安定性リガーゼ
が好ましい、熱に安定な酵素の利点には試薬のコスト低
減、氏作の煩雑性の回避、添加すべき不所望成分の減少
（酵素はしばしばグリセロールを含むバッファー中に保
存される）、および試薬の保存期間の長期化の可能性が
含まれる。好ましい熱安定性リガーゼの例は、サーマス
・サーモフィラス（Ｔｈｅｒｍｕｓ　　Ｌｈｅｒｍｏｐ
ｈｉｌｕｓ）（例えばＡＴＣＣ２７６３４）から、タカ
ハシら、　　Ｊ、　　Ｂｉｏｌ、Ｃｈｅｍ、、２５９．
１００４１　（１９８３）の−船釣方法で精製されたリ
ガーゼである。
第１図は、Ｔ−Ｔ’　として示される標的二重鎖ＤＮＡ
配列を検出するハイブリダイゼーションアッセイを示す
、標的配列は、多（の無関係なりＮＡ配列を含むサンプ
ル中に存在する。
本発明は、Ｐ　、　−Ｐ　、’およびＰ２−Ｐ２′とし
て示されている二つの相補的プローブの対を、標準液中
に含むキットにも関する。これらのプローブは、標的配
列の種々の部位に相補的であるように選択される。詳細
には、Ｐ、は鎮ＴのセグメントＡに相補し；Ｐ２は鎖Ｔ
のセグメントＢに相補し；Ｐ１′は鎖Ｔ′のセグメンｌ
−Ａに相補し：そしてＰ２′は鎖Ｔ′のセグメントＢに
相補する。これらのプローブは選択的ハイブリダイゼー
ションを供給し、そしてサンプル中の他の成分から容易
に区別できる融合配列を生成するために、充分な長さに
なるよう選択される。そのために１０〜２００塩基のプ
ローブが満足なものであることを、本発明者らは見出し
た。最も好ましくは、プローブは１２ないし５０塩基の
長さである。
プローブは下記の反応を促すために大過剰量で供給され
る０例えば、プローブの濃度は、５０ｔｒｌの反応容量
中で好ましくは約１０１２〜１０１４分子である。
本発明の方法の１回のサイクルが第１Ａないし第１Ｄ図
憾示されている。先ず、第１Ａ図において、サンプルＤ
ＮＡが変性される０次に、ハイブリダイゼーションが行
われる（第１８図）、Ｔがサンプル中に存在すると、Ｔ
はＰ、およびＰ２と遭遇する可能性が比較的高く、こう
して第１８図に示される成分を形成する。同様に、Ｔ′
はＰ１′およびＰ２′と遭遇するであろう。
このサイクルの次の工程は、リガーゼの添加であり、こ
のリガーゼは隣接するプローブの末端を連結するであろ
う（第１Ｃ図）が、しかしながら、−Ｓにサンプル中の
ＤＮＡのプラント末端は連結しないであろう、連結の後
サンプルは変性条件に付され（第１Ｄ図）、融合プロー
ブＰ、−Ｐ２およびＰ、　　−Ｐ２’を生じる。この時
点からサンプルを、ハイブリダイゼーシランーライゲー
ションー変性の新たなサイクルへ送ることができる。
上記１回のサイクルの例に見られるとおり、サイクルの
開始時の一つの二重鎖テンプレートＴ１Ｔ　、　／から
サンプルが二つの二重鎖テンプレートへと増加する０次
のサイクルでの効率を理想的なものと仮定すると、これ
ら二つの合成二重鎖テンプレートおよび元の標的配列の
それぞれが、二つの二重鎖テンプレートを生じるであろ
う、第１表はこの状況をｎ回のサイクルについて示すも
のであり、ここでＸは第１回のサイクルの前のＴ−Ｔ、
対の数を示す。
第１表 サイクル数　Ｐ、−Ｐ２数　Ｐ、　　−Ｐ２’数１　・
　Ｘ ３　・　Ｘ ７　・　Ｘ １５　・　Ｘ １　・　Ｘ ３　・　Ｘ ７　・　Ｘ １５　・　Ｘ ｎ　　　　　（２ｎ−１）Ｘ　　　（２ｎ−１）Ｘ成分
Ｐ、−ｐ２（および所望によりＰｌ　−Ｐ２′）を検出
することができるので、繰り返しサイクルは検出感度を
一定の点まで向上させることができる。各サイクルに関
して、ＴまたはＴ′が不存在である時でも、プラント末
端の連結によってＰ、−Ｐ２又はＰ、　　−Ｐ２’が生
成する可能性は僅かではあるが蚤育実に存在する。この
現象が一回発生すると、この連結成分は出発時点でのＴ
またはＴ′の存在から区別することが不可能である。サ
イクル数を制限することは、そのような疑陽性の結果の
危険を減少させる。さらに、ある時点に達すると未融合
プローブが消費しつくされて、所望の反応を起こすこと
が不可能になり、そして融合プローブと未融合プローブ
とのハイブリダイズの可能性が殆ど無くなる（二つの融
合プローブの不所望なハイブリダイズの可能性に反して
）。
第２図はサイクル数の関数として、混合物中に存在する
融合プローブの検出可能数を描いた曲線である。Ｘ（最
初に存在する標的プローブの数）に応じて、再構成され
た融合プローブの数は、上記計算に従って、あるレベル
まで幾何級数的に増大し、そのレベルで増加の速度は劇
的に低下するであろう、この関係をスタンダードにたい
してプロットし、そして一定のレベルに達するまでに何
回のサイクルが必要かを決定することにより、最初に存
在した標的の量を決定することが可能である。
Ｃ１実施例１ 標準的方法により、四種のデオキシリボ核酸オリゴマー
を調製した。このオリゴマーは次の配列を有していた： Ｐ、＝　　５’ＧＧＧＣ；ＡＴＣＣＴＣＴＡＧＡＧＴＣ
ＧＡＣＣＴＧＣＡ　　３’ Ｐ２＝　　５’ＡＡＴＴＣＧＡＧＣＴＣＧＧＴＡＣＣＣ
３’ Ｐ　、’　＝５’　　ＧＧＴＣＧＡＣＴＣＴＡＧＡＧＧ
ＡＴＣＣＣＣ３’ Ｐ２’　＝５’　ＧＧＧＴＡＣＣＧＡＧＣＴＣＧ　　３
’Ｐ、およびＰ２はプラスミドｐＵｃ１８のポリリンカ
ー碩域の一つのストランド上で隣接する配列であり、Ｐ
１′およびＰ２′は、その相補ストランドの上で隣接す
る配列である。
プローブＰ１′およびＰ２はポリヌクレオチドキナーゼ
およびＡＴＰで処理してそれらの５′末端をホスホリル
化した。プローブＰ１はターミナルトランスフェラーゼ
とα３２Ｐ−ｄＣＴＰで処理して、その３′末端を放射
線標識した。
Ｄ、実施例２ サンプルとして、３（１＋Ｍのトリス塩酸ｐ１８，０゜
１００ｓ＋ＭＮａ　Ｃｌ、　　１．　２ｓＭＥＤＴＡ、
　　４．　０＋ＭＭｇＣＩ　２，１．０ｍＭジチオスレ
イトール９５０ｐ７ｍｌウシ血清アルブミン、２０ｐｇ
／ｍｌのＨｅＬａ　　ＤＮＡ＋２０ｐｇ／ｎｄ非特異的
ＤＮＡ　（例えば、次の２０マー：　５’　−ＡＴＣＧ
ＡＴＡＣＡＴＣＡＧＧＡＡＴＡＴＴ−３’　）、各々１
　ｐｇ　／　ｍｉの実施例１のプローブおよびＥｃｏＲ
ｒ開裂部位で直線化された種々の量のρＵＣ１８プラス
ミドＤＮＡを含む種々のサンプルを調製した。これらの
サンプルの５０ｐ！アリコートを次の工程で処理した＝
（ａ）ＤＮＡ変性のための１００℃、１分間の加熱；（
ｂ）ＤＮＡ再生を行うための３７”Ｃ，１分間のインキ
ュベート： （ｃ）　　Ｅ、ｃｏ　Ｉ　１ＤＮＡリガ一ゼ５０単位の
添加（単位は酵素の製造元、米国バイオケミカル・コー
ポレーション（Ｂｉｏｃｈｅｍｉｃａｌ　　Ｃｏｒｐ＊
ｒａＬｉｏｎ）の定めた単位による）：（ｄ）　　適切
に並んだプローブの結合を図るための、３７℃、１分間
のインキュベート。
工程（ａ）ないしくｄ）を２０〜５０回繰り返した６反
６混合物から一定量を取り出し、残存リガーゼ活性を失
活させて保存した。この保存物をポリアクリルアミドゲ
ル電気泳動およびオートラジオグラフィーで分析した。
結合物質の検出可能量の出現の時間（サイクル数で表し
て）は、反応系に最初に存在した標的分子の数に強く相
関した。
他の態様は、特許請求の範囲により定められる。
例えば、ＤＮＡと同様にＲＮＡを用いることもできる。
実施例では、ＨｅＬａのＤＮＡおよび非特異的オリゴヌ
クレオチドを添加して、サンプル中に存在する恐れのあ
るヌクレアーゼによる分解からプローブを保護した。し
かしながら、このことは本発明の必須要件ではない。
【図面の簡単な説明】
第１Ａ図、第１８図、第１Ｃ図および第１Ｉ）図は、各
々本発明のハイブリダイゼーションアッセイにおける各
工程を順に示す工程図である。 第２図は、再構成されたプローブの形成をサイクル数の
関数として示すグラフである。

Claims (1)

  1. 【特許請求の範囲】 １、サンプル中の標的核酸を検出する方法において、 （ａ）サンプルの核酸をシングル鎖核酸として用意し； （ｂ）サンプル中に少なくとも四種の核酸プローブを用
    意し、ここで、 ｉ）前記プローブの第一および第二のプローブは一次プ
    ローブであり、そして第三および第四のプローブは二次
    的核酸プローブであり； ｉｉ）前記第一プローブは標的核酸の第一鎖の第一セグ
    メントにハイブリダイズすることの出来るシングル鎖で
    あり； ｉｉｉ）前記第二プローブは、前記標的核酸配列の第一
    鎖の第二セグメントにハイブリダイズすることの出来る
    シングル鎖であり； ｉｖ）標的の第一鎖の第一セグメントの５′末端は該標
    的の第一鎖の第二セグメントの３′末端との相対的位置
    関係において、前記第一および第二プローブが前記標的
    核酸の第一鎖にハイブリダイズされた場合に、第一プロ
    ーブの３′末端の第二プローブの５′末端への結合を可
    能ならしめる位置に存在し； ｖ）第三プローブは第一プラスミドにハイブリダイズ可
    能であり；そして ｖｉ）第四プローブは第二プローブにハイブリダイズ可
    能であり；そして （ｃ）次の工程： ｉ）該複数のプローブをサンプル中の核酸とハイブリダ
    イズさせ； ｉｉ）ハイブリダイズしたプローブを連結して再構成さ
    れた融合プローブ配列を形成し；ｉｉｉ）サンプル中の
    ＤＮＡを変性させる；からなるサイクルを繰り返し行っ
    て、再構成された融合第一および融合第二プローブの量
    を増加させ；そして （ｄ）再構成された融合プローブ配列を検出する； ことを特徴とする、サンプル中の標的核酸を検出する方
    法。 ２、標的配列の第一鎖の第一セグメントの５′末端が、
    介在する塩基を有すること無く、標的配列の第一鎖の第
    二セグメントの３′末端に隣接し且つ共有結合している
    、請求項１記載の方法。 ３、プローブを酵素で連結させる請求項１記載の方法。 ４、プローブをリガーゼで連結させる請求項３記載の方
    法。 ５、リガーゼがバクテリアのリガーゼである、請求項４
    記載の方法。 ６、リガーゼがＥ．ｃｏｌｉのＤＮＡリガーゼまたはサ
    ーマス・サーモフィラス（Ｔｈｅｒｍｕｓ　ｔｈｅｒｍ
    ｏｐｈｉｌｕｓ）のＤＮＡリガーゼである、請求項５記
    載の方法。７、核酸プローブがＤＮＡである請求項１記
    載の方法。 ８、標的核酸配列がＤＮＡである請求項１記載の方法。 ９、融合したプローブ核酸が標的配列から熱変性により
    分離される、請求項１記載の方法。 １０、前記サイクルが少なくとも２回繰り返される、請
    求項１記載の方法。 １１、前記サイクルが２０ないし５０回繰り返される、
    請求項１０記載の方法。 １２、第二プローブの５′末端がホスホリル化されてお
    り、第一プローブの５′末端はホスホリル化されていな
    い、請求項１記載の方法。 １３、標的配列が工程（ａ）の前に二重鎖である、請求
    項１記載の方法。 １４、プローブの少なくとも一種が標識剤でラベルされ
    ている、請求項１記載の方法。 １５、一次プローブの両方が標識剤でラベルされている
    、請求項１４記載の方法。 １６、二次プローブの両方が標識剤でラベルされている
    、請求項１４記載の方法。 １７、プローブの少なくとも一種が色素または蛍光色素
    でラベルされている、請求項１４記載の方法。 １８、プローブの少なくとも一種が不溶性相への特異的
    結合成分でラベルされている、請求項１４記載の方法。 １９、前記各プローブ、核酸リガーゼおよび該プローブ
    を該核酸リガーゼと分離して収納する手段からなる、請
    求項１記載の方法の実施に用いるキット。 ２０、前記標的配列、前記各プローブおよびリガーゼか
    らなる混合物を保持する手段および該混合物の温度を前
    記サンプルの中の核酸を変性させる第一温度と各プロー
    ブの標的へのハイブリダイゼーションを可能ならしめる
    第二温度との間で繰り返し変化させる手段を含んでなる
    、請求項１記載の方法を実施するための装置。 ２１、温度変化手段が自動的に温度を変化させる手段を
    含む、請求項２０記載の装置。
JP63313658A 1987-12-11 1988-12-12 テンプレート−依存性核酸プロ−ブ再構成を用いたアッセイ Expired - Fee Related JPH0634759B2 (ja)

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