JP4480380B2 - 分子タグ化システム - Google Patents
分子タグ化システム Download PDFInfo
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- JP4480380B2 JP4480380B2 JP2003350142A JP2003350142A JP4480380B2 JP 4480380 B2 JP4480380 B2 JP 4480380B2 JP 2003350142 A JP2003350142 A JP 2003350142A JP 2003350142 A JP2003350142 A JP 2003350142A JP 4480380 B2 JP4480380 B2 JP 4480380B2
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Description
1つの局面において、本発明は、分子集団から分子または分子亜集団を分類する方法を提供し、この方法は、以下の工程:
(a)タグのレパートリー由来のオリゴヌクレオチドタグを、分子集団中の各分子に結合する工程であって、この工程は、(i)この集団中の実質的に同じ分子または実質的に同じ分子亜集団が、結合した同じオリゴヌクレオチドタグを有し、そしてこの集団中の実質的にすべての異なる分子または異なる分子亜集団が、結合した異なるオリゴヌクレオチドタグを結合しているように、そして(ii)このレパートリー由来の各オリゴヌクレオチドタグが複数のサブユニットを包み、そしてこの複数のサブユニットのそれぞれが3から6ヌクレオチドまたは3から6塩基対の長さを有するオリゴヌクレオチドからなり、このサブユニットが最少に交差ハイブリダイズしているセットから選択されるように行われる工程;および
(b)このオリゴヌクレオチドタグとそれぞれの相補物とを特異的にハイブリダイズすることにより、この集団からこの分子または分子亜集団を分類する工程;
を包含する。
なおさらにより好ましい実施形態において、上記ポリヌクレオチドまたはポリヌクレオチド亜集団が、50から5000ヌクレオチドの範囲の長さを有する。なおさらにより好ましい別の実施形態において、上記微粒子が、ガラス微粒子、磁気ビーズ、グリシダルメタクリレート微粒子およびポリスチレン微粒子からなる群から選択される。なおさらにより好ましい実施形態において、上記微粒子の直径が1μmと100μmとの間である。さらにより好ましい別の実施形態において、上記固相支持体が、上記相補物の均一な集団を結合している複数の空間的に離れた表面領域を有する平面基板である。なおさらにより好ましい実施形態において、異なる上記の複数の空間的に離れた表面領域が、異なる上記相補物の均一な集団を有する。なおさらにより好ましい実施形態において、上記平面基板が、ガラス、シリコンおよびプラスチックからなる群から選択される。
−(M−L)n−
を含み、ここで、リン(V)結合基であり;
Mは、1〜20個の炭素原子と、酸素、窒素、およびイオウからなる群から選択される0〜10個のヘテロ原子とを有する、直鎖分子構造、環式分子構造、または分枝有機分子構造であり;そして
nは、3〜100の範囲にある。
この標的ポリヌクレオチドから、この標的ポリヌクレオチドをカバーする複数のフラグメントを生成する工程;
タグのレパートリー由来のオリゴヌクレオチドタグを、この複数のフラグメントのそれぞれに結合する工程であって、この工程は、(i)実質的にすべての同じフラグメントが、結合した同じオリゴヌクレオチドタグを有し、実質的にすべての異なるフラグメントが、異なるオリゴヌクレオチドタグを結合しているように、そして、(ii)このレパートリー由来の各オリゴヌクレオチドタグが複数のサブユニットを包含し、そしてこの複数のサブユニットのそれぞれが、3から6ヌクレオチドまたは3から6塩基対の長さを有するオリゴヌクレオチドからなり、このサブユニットが、最少に交差ハイブリダイズしているセットから選択されるように行われる、工程;
このオリゴヌクレオチドタグとそれぞれの相補物とを特異的にハイブリダイズすることによりこのフラグメントを分類する工程;
この複数のフラグメントのそれぞれの部分のヌクレオチド配列を決定する工程;および
このフラグメントの配列を対照することにより、この標的ポリヌクレオチドのヌクレオチド配列を決定する工程、
を包含する。
1つまたはそれ以上の空間的に離れた領域を有する固相支持体;および
この1つまたはそれ以上の空間的に離れた領域の少なくとも1つにおいてこの固相支持体に共有結合されたオリゴヌクレオチドタグ相補物の均一な集団であって、このオリゴヌクレオチドタグ相補物は複数のサブユニットを含み、各サブユニットは3から6ヌクレオチドの長さを有するオリゴヌクレオチドからなり、そして各サブユニットは、最少の交差ハイブリダイズしているセットから選択される、オリゴヌクレオチドタグ相補物の均一な集団、
を含む。
オリゴヌクレオチドタグを、この集団の各ポリヌクレオチドに結合させる工程であって、この工程は、(i)実質的にすべての同じポリヌクレオチドが、結合した同じオリゴヌクレオチドタグを有し、実質的にすべての異なるポリヌクレオチドが、結合した異なるオリゴヌクレオチドタグを有しているように、そして(ii)各オリゴヌクレオチドタグが複数のサブユニットを包含し、そしてこの複数のサブユニットのそれぞれが、3から6ヌクレオチドの長さを有するオリゴヌクレオチドからなり、このサブユニットが、最少に交差ハイブリダイズしているセットから選択されるように行われる工程;
このオリゴヌクレオチドタグとそれぞれの相補物とを特異的にハイブリダイズすることにより、このポリヌクレオチドを分類する工程;
この分類されたポリヌクレオチドのそれぞれの部分のヌクレオチド配列を決定する工程;および
このポリヌクレオチドの配列の部分の頻度分布により、このポリヌクレオチド集団を分類する工程、
を包含する。
S1S2S3...Sn
からなる群から選択され、ここで、S1からSnのそれぞれは、3から6ヌクレオチドの長さを有するオリゴヌクレオチドからなり、そして最少に交差ハイブリダイズしているセットから選択されるサブユニットであり;そして
nは4から10の範囲にある。
S1S2S3...Sn
を有し、ここで、S1からSnのそれぞれは、3から6ヌクレオチドの長さを有するオリゴヌクレオチドからなり、そして最少に交差ハイブリダイズしているセットから選択されるサブユニットであり;そして
nは4から10の範囲にある。
ポリヌクレオチド混合物を含有する溶液を提供する工程であって、この混合物の各ポリヌクレオチドは、タグのレパートリー由来のオリゴヌクレオチドタグを結合しており、このレパートリー由来の各オリゴヌクレオチドタグは、複数のサブユニットを含み、この複数のサブユニットのそれぞれは、3から6ヌクレオチドの長さを有するオリゴヌクレオチドからなり、このサブユニットは、最少に交差ハイブリダイズしているセットから選択される工程;
このポリヌクレオチド混合物をサンプリングしてポリヌクレオチド亜集団を形成させる工程であって、ここで同じ配列の実質的にすべてのポリヌクレオチドは、結合した同じオリゴヌクレオチドタグを有し、異なる配列の実質的にすべてのポリヌクレオチドは異なるオリゴヌクレオチドタグを結合している、工程;および
このオリゴヌクレオチドタグとそれぞれの相補物との間に完全にマッチした二重鎖の形成を促進する条件下で、この亜集団と、このオリゴヌクレオチドタグの相補物を結合している1つまたはそれ以上の固相支持体とを接触させる工程、
を包含する。
この二本鎖DNAの末端に5’鎖を供給する工程であって、この工程は、このような5’鎖は、3種以下のヌクレオチドからなる第1の群から選択されるヌクレオチドから構成されるように、そしてこの5’鎖のあらかじめ決定された長さが、この第1の群には存在しない種類の第2のヌクレオチドによって規定されるように、行われる工程;および
この第2のヌクレオチドのヌクレオシド三リン酸の存在下で、この二本鎖DNAの末端を、T4 DNAポリメラーゼに曝露する工程;
を包含する。
mRNA分子集団からcDNAライブラリーを形成する工程であって、このcDNAライブラリー中の各cDNA分子は、結合したオリゴヌクレオチドを有し、この工程は、(i)実質的にすべての同じcDNA分子が、結合した同じオリゴヌクレオチドタグを有し、実質的にすべての異なるcDNA分子が、結合した異なるオリゴヌクレオチドタグを有しているように、そして(ii)各オリゴヌクレオチドタグが、複数のサブユニットを含み、そしてこの複数のサブユニットのそれぞれが、3から6ヌクレオチドの長さを有するオリゴヌクレオチドからなり、このサブユニットが、最少に交差ハイブリダイズしているセットから選択されるように行われる工程;
このオリゴヌクレオチドタグとそれぞれの相補物とを特異的にハイブリダイズすることにより、このcDNA分子を分類する工程;
この分類されたcDNA分子のそれぞれの部分のヌクレオチド配列を決定する工程;
この分類されたcDNA分子の配列の部分のヌクレオチド配列を、既知のcDNA分子の配列と比較することにより、新規なcDNA分子を同定する工程、
を包含する。
それらのそれぞれの相補物とオリゴヌクレオチドタグを特異的にハイブリダイズすることによりフラグメントを分類する、工程;(c)下記のように、好ましくは単一塩基配列決定方法により、多数の各フラグメントの一部のヌクレオチド配列を決定する工程;ならびに(d)標的ポリヌクレオチドのヌクレオチド配列を、フラグメントの配列を対照することにより決定する、工程。
オリゴヌクレオチドタグに関して本明細書中に用いられる「相補物」または「タグ相補物」は、オリゴヌクレオチドタグが特異的にハイブリダイズして完全にマッチした二重鎖または三重鎖を形成するオリゴヌクレオチドをいう。特異的ハイブリダイゼーションが三重鎖を生じる実施態様では、オリゴヌクレオチドタグは2本鎖または1本鎖のいずれかであることが選択され得る。従って、三重鎖が形成される場合、用語「相補物」は、1本鎖オリゴヌクレオチドタグの2本鎖相補物または2本鎖オリゴヌクレオチドタグの一本鎖相補物のいずれかを包含することを意味する。
本発明は、分子(特にポリヌクレオチド)をオリゴヌクレオチドタグを用いることにより標識および分類する方法を提供する。本発明のオリゴヌクレオチドタグは、サブユニットの最少に交差ハイブリダイズしているセットから選択される多数の「ワード」またはサブユニットを包含する。このようなセットのサブユニットは、2つより少なくミスマッチしたヌクレオチドを有する同じセットの別のサブユニットの相補物と二重鎖または三重鎖を形成し得ない。従って、二重鎖を形成するレパートリーの任意の2つのオリゴヌクレオチドタグの配列は、2ヌクレオチドの異なりより「厳密(close)」でない。特定の実施態様では、レパートリーの任意の2つのオリゴヌクレオチドタグの配列は、例えばサブユニットが3つより少なくミスマッチしたヌクレオチドを有する同じセットの別のサブユニットの相補物と二重鎖を形成し得ないように最少に交差ハイブリダイズしているセットを設計することなどにより、「さらに」離れることさえあり得る。このような実施態様では、より大きい特異性が達成されるが、タグの総レパートリーはより小さい。従って、一定の長さおよびワードサイズのタグについて、所望の特異性の程度と所望のレパートリーのサイズとの間で取引がされるに違いない。本発明は、配列決定、フィンガープリンティング、または他のタイプの分析のような並行操作のためにポリヌクレオチドを標識および分類するのに特に有用である。
任意の最少に交差ハイブリダイズしているセット用のサブユニットのヌクレオチド配列は、図3に図示した一般アルゴリズムに従い、そしてソースコードが付表Iに挙げられるプログラムminhxにより例示されたような簡単なコンピュータプログラムにより便利に計算される。minhxは、3種のヌクレオチドからなるサブユニットを有し、そして4の長さを有する全ての最少に交差ハイブリダイズしているセットを算定する。
オリゴヌクレオチドタグは、当該分野で周知の種々の反応性官能基により、多くの異なる種類の分子に結合し得る(例えば、Haugland,Handbook of Fluorescent Probes and Research Chemicals(Molecular Probes,Inc.,Eugene,1992);Khannaら、米国特許第4,318,846号など)。表IVは、オリゴヌクレオチドタグまたは目的の分子上に存在し得る、例となる官能基およびカウンターパート反応基を提供する。官能基およびカウンターパート反応体がともに反応する場合、いくつかの場合では活性化の後に結合基が形成される。さらに、以下により十分に記載されるように、タグは、選択された分子と同時に合成され、コンビナトリアルケミカルライブラリーを形成し得る。
−(M−L)n−
ここで、Lはリンカー(linker)部分であり、そしてMは、広い範囲の化学構造から選択され得、不活性な非立体的に障害となるスペーサー部分として働くことから、他の成分に結合する分岐点、標識に結合するための部位:オリゴヌクレオチドに結合するための部位、あるいは治療標的にハイブリダイズまたは結合するための他の結合ポリマー:または溶解性、二重鎖および/または三重鎖形成の促進に影響を与える他の基を結合するための部位として働き得る反応性官能基を提供することまでの範囲の機能を提供するモノマー(例えば、インターカレーター、アルキル化剤など)である。このような線形ポリマー分子の配列およびその結果の組成は、BrennerおよびLerner(上記)により教示されたように、タグに結合するポリヌクレオチド内にコードされ得る。しかし、選択事象後、選択分子のタグを増幅し、次に配列決定する代わりに、タグそれ自体または付加コードセグメントは、目的の分子の放出後、例えば、タグ中の操作された部位の制限消化により、直接的に(いわゆる以下に記載の「単一塩基」アプローチを用いて)配列決定され得る。明らかに、タグ部位の同時合成と両立できる一連のケミストリー工程により生産される任意の分子は、コンビナトリアルライブラリーの生成に用いられ得る。
本発明のタグを用いるコンビナトリアルケミカルライブラリーは、好ましくは、Nielsenら(上記)で開示され、そして詳細な実施態様のために図4で図解された方法により調製される。簡単にいえば、固相支持体(例えば、CPG)は、タグを合成するために用いられるケミストリーおよびいくつかの選択プロセスを経る分子を合成するために用いられるケミストリーの両方に適合する切断可能なリンカーで誘導体化される。好ましくは、タグは、上記のようなホスホルアミダイトケミストリーを用いて、およびNeilsenら(上記)により推奨される改変(すなわち、メチル保護ホスファイトおよびホスフェート部分を有するDMT−5’−O−保護3’−ホスホルアミダイト−誘導体化サブユニットが、各合成サイクルに加えられる)により合成される。ライブラリー化合物は、好ましくは、Fmocまたは同等物(連続モノマーをカップリングする官能基をマスクする保護基)を有するモノマーである。DMTおよびFmoc保護基(本明細書中でサルコシンリンカーという)の両方を用いるケミストリーに対する適切なリンカーは、Brownら、J.Chem.Soc.Chem.Commun.、1989:891−893により開示され、この開示は、参考として援用される。
本発明で用いられる固相支持体は、広い種類の形態を有し得、例えば、微粒子、ビーズ、および膜、スライド、プレート、ミクロマシーンドチップ(micromachined chip)などが挙げられる。同様に、本発明の固相支持体は、広い種類の組成物を含み得、例えば、ガラス、プラスチック、シリコン、アルカンチオレート誘導体化金(alkanethiolate−derivatized gold)、セルロース、低架橋ポリスチレンおよび高架橋ポリスチレン、シリカゲル、ポリアミドなどが挙げられる。好ましくは、分離した粒子の集団のいずれかは、各々が同じタグ(および他はなし)への相補的配列の、均一のコーティング(または集団)を有するように用いられ、あるいは、単一支持体または数個の支持体は、各々が同じタグ(および他はなし)への相補的配列の、均一のコーティング(または集団)を含む、空間的に分離した領域で用いられる。後者の実施態様では、領域の面積は、特別な適用に従って変化し得、通常、数(例えば、3〜5)μm2から数百(例えば、100〜500)μm2の面積の領域範囲である。好ましくは、このような領域は、空間的に分離され、そのため隣接領域での事象(例えば、蛍光発光)により発生されるシグナルが、用いられる検出システムにより解明され得る。いくつかの適用では、1つより多いタグ相補物(例えば、同時配列分析、または別々にタグ化された分子を極めて近接に持ってくるための)の均一コーティングの領域を有することが、望ましくあり得る。
本発明の重要な局面は、同一のポリヌクレオチド(例えば、cDNAライブラリー由来)の集団の分類、ならびに各微粒子または領域が単一種のポリヌクレオチドのみを有するような微粒子あるいは固相支持体の分離領域へのそれらの結合である。この後者の条件は、タグのレパートリーをポリヌクレオチドの集団へ連結することにより、本質的に満たされ得る。次いで、連結産物は、クローン化され、増幅され、そしてサンプリングされる。サンプルが十分小さければ、以下により十分に説明するように、得られたライブラリーの実質的に全てのタグポリヌクレオチド結合体は、唯一である。すなわち、各ポリヌクレオチドは、唯一のタグを有し、逆も同様である。次いで、ポリヌクレオチドは、タグをその相補物にハイブリダイズすることにより分類される。
5’−[G,W,W,W]9TGG−リンカー−微粒子。
5’−NRRGATCYNNN−3’
ここで、NはA、T、G、またはCのいずれか一つであり、Rはプリン含有ヌクレオチドであり、そしてYはピリミジン含有ヌクレオチドである。この特定のプライマーは、得られた2本鎖DNA中にBst Yl制限部位を作り、それは、Sal I部位とともに、例えばBam HIおよびXho I部位を用いたベクター中へのクローニングを容易にする。Bst YlおよびSal I消化の後、模範的な結合体は以下の形態を有する:
本発明は、DNA配列決定の従来の方法、例えば、Hultmanら、Nucleic Acids Research、17:4937−4946(1989)によって開示された方法とともに用いられ得る。しかし、複数のポリヌクレオチドの並行または同時の配列決定に関しては、以下の参考文献が挙げられる:Cheeseman、米国特許第5,302,509号; Tsienら、国際出願第WO 91/06678号; Rosenthalら、国際出願第WO 93/21340号; Canardら、Gene、148:1−6(1994); およびMetzkerら、Nucleic Acids Research、22:4259−4267(1994)。
本発明の目的は、タグおよびその相補物の特異的ハイブリダイゼーションによって、微粒子の表面上の同一分子、特に、ポリヌクレオチドを分類することである。一旦、このような分類が行われると、分子の存在またはそれらに対して行われる操作は、タグ化された分子の性質、微粒子が、分離して、または「バッチ」で検出されるかどうか、反復された測定が所望であるかどうかなどに応じて、多くの方法で検出され得る。代表的に、分類された分子は、例えば、薬物開発において、結合のためにリガンドに曝されるか、または、例えば、ポリヌクレオチド配列決定において化学的または酵素的プロセスに供される。これらの使用の両方において、多くの微粒子上でのこのような事象またはプロセスに対応する信号を同時に観察することがしばしば望まれる。分類された分子を担持する微粒子(本明細書において「ロードされた」微粒子と称する)が、このような大規模な並行操作に役立つ(例えば、Lamら(上記)に示されている)。
本発明のタグ化システムは、数キロベースまでの長さのポリヌクレオチドを配列決定するための単一塩基配列決定方法とともに用いられ得る。タグ化システムは、標的ポリヌクレオチドの何千ものフラグメントが、1つまたはそれ以上の固相支持体上に分類され、同時に配列決定され得ることを可能にする。この方法の好適な実施によると、各分類されたフラグメントの一部分が、上記のような走査システムまたは画像分析システムに関連する、顕微鏡スライドのような共通の基板に固定された何千ものロードされた微粒子のそれぞれにおいて、段階的に配列決定される。配列決定されたフラグメントの部分のサイズは、いくつかの要因、例えば、生成および分類されたフラグメントの数、標的ポリヌクレオチドの長さ、用いられた単一塩基方法の速度および正確さ、微粒子および/または同時にモニターされ得る別個の領域の数などに依存する。好適には、12〜50塩基が、各微粒子または領域で同定され、さらに好適には、18〜30塩基が、各微粒子または領域で同定される。この情報により、標的ポリヌクレオチドの配列が、重複する領域を介して12〜50塩基のフラグメントを対照することによって決定される(例えば、米国特許第5,002,867号に記載されている)。以下の引例は、所与の長さの標的ポリヌクレオチドを首尾良く再構築するために配列決定されなければならないフラグメントの部分を決定する際のさらなる指針を提供する:LanderおよびWaterman、 Genomics、2:231−239 (1988): Drmanacら、 Genomics、4:114−128 (1989): Bains、DNA Sequencing and Mapping、4: 143−150 (1993): Bains、Genomics、11:294−301 (1991): Drmanacら、J.Biomolecular Structure and Dynamics、8: 1085−1102 (1991): およびPevzner、J.Biomolecular Structure and Dynamics、7: 63−73 (1989)。好適には、標的ポリヌクレオチドの長さは、1キロベース〜50キロベースである。より好適には、長さは、10キロベース〜40キロベースである。LanderおよびWaterman(上記)は、配列決定されるフラグメントの数(すなわち、サンプルサイズ)、各フラグメントから得られた配列情報の量、および標的ポリヌクレオチドが、ギャップがない部分的な配列、すなわち、「アイランド」から再構築され得る可能性の間の相互関係に関する指針を提供する。本発明において、所与のサンプルサイズおよびフラグメント配列のサイズで得られ得る最大のポリヌクレオチドサイズを以下に示す。
本発明は、本発明の種々の実施態様を実施するためのキットを含む。好適には、本発明のキットは、固相支持体に結合されたタグ相補物のレパートリーを含む。さらに、本発明のキットは、対応するタグのレパートリー(例えば、ポリヌクレオチドを増幅して分類するためのプライマーとして、またはポリヌクレオチドを増幅して分類するために用いられ得るクローニングベクターの要素として)を含み得る。好適には、タグ相補物のレパートリーは、微粒子に結合される。キットはまた、酵素的プロセシング、検出ケミストリー(例えば、蛍光タグまたは化学ルミネセンスタグ)などのための適切な緩衝液、使用説明書、プロセシング酵素(例えば、リガーゼ、ポリメラーゼ、トランスフェラーゼなど)を含み得る。配列決定のための重要な実施態様において、キットはまた、プロセシングのためにロードされた微粒子を固定するための、アビジン化された顕微鏡スライドのような基板を含み得る。
cDNAライブラリーにおける新規なポリヌクレオチドは、上記のように微粒子に結合されたcDNA分子のライブラリーを構築することによって、同定され得る。次いで、ライブラリーの大きな画分、またはライブラリー全体でさえ、部分的に並行に配列決定され得る。mRNAの単離、およびおそらく、Soaresら、Proc. Natl. Acad. Sci.、91:9228−9232 (1994)、または同様の引例によって教示されるように、その集団の正規化の後、以下のプライマーが、従来のプロトコルを用いて、逆転写酵素で第1鎖の合成のためのポリAテールにハイブリダイズされ得る:
(pUC19由来の多重標的ポリヌクレオチドの分類)
3つの標的ポリヌクレオチドタグ結合体の混合物を、以下のように得る:まず、以下の6つのオリゴヌクレオチドを合成し、対として組み合わせ、タグ1、タグ2およびタグ3を形成する。
(SV40フラグメントの並行配列決定)
表Iから選択される9つの4−ヌクレオチドサブユニットからなる36マーのタグのレパートリーを、上記のような、分裂または混合手段によって、タグおよびタグ相補物を別々に合成することによって調製する。Sma I/Hind III消化M13mp19に連結可能なように、レパートリーを合成する。従って、実施例Iと同様に、1組のオリゴヌクレオチドはAの添加で開始し、9回の分裂および混合合成が続く。このオリゴヌクレオチドを、表Iのサブユニットに対応して3’−ホスホルアミダイト誘導体化4マーによりサブユニットで伸張する。次いで、Sma I認識部位(GGG) の半分、2つのCおよび5’−モノホスフェートを、例えば、Clontech Laboratories (Palo Alto、CA)から入手可能であるPhosphate−ON試薬を用いて、ヌクレオチド毎に添加することで合成を完了する。他方の組のオリゴヌクレオチドは、3つのC(Sma I認識部位の一部)および2つのGの添加で開始し、9回の分裂および混合合成が続く。このオリゴヌクレオチドを、表Iのサブユニットの相補物に対応して、3’−ホスホルアミダイト誘導体化4マーにより伸張する。Hind III認識部位および5’−モノホスフェートのヌクレオチド毎の添加により合成を完了する。合成支持体からの分離後、オリゴヌクレオチドを以下の二重鎖の形成を可能にする条件下で混合する:
Claims (10)
- 集団中のポリヌクレオチドにオリゴヌクレオチドタグを結合させる方法であって、該方法は、以下の工程:
ポリヌクレオチドの集団のサイズよりも大きいサイズを有するオリゴヌクレオチドタグのレパートリーを供給する工程であって、該レパートリーは、以下の形態のオリゴヌクレオチド:
S1S2S3...Sn
からなり、ここで、S1からSnのそれぞれは、3〜6ヌクレオチドの長さを有するサブユニットであり、かつサブユニットのセットから選択され、該サブユニットのヌクレオチド配列は、該セットのサブユニットと、該セットの任意の他のサブユニットの相補物との間に形成される二重鎖が少なくとも2つのミスマッチを含むように選択され、そして
nは4から10の範囲にある、工程;
該ポリヌクレオチドの集団に該オリゴヌクレオチドタグのレパートリーを連結して、タグ−ポリヌクレオチド結合体の集団を形成する工程;および
異なるポリヌクレオチドを有する試料中の少なくとも80%のタグ−ポリヌクレオチド結合体が、異なるオリゴヌクレオチドタグを有するように、該タグ−ポリヌクレオチド結合体の集団の試料を取る工程、
を包含する、方法。 - 空間的に離れた領域を有する固相支持体であって、該領域各々は、オリゴヌクレオチドタグ相補物の共有結合された集団を含み、該領域各々は、特定の配列を有する唯一のタイプのタグ相補物を含むようになっており、
該オリゴヌクレオチドタグ相補物は、以下の形態:
S1S2S3...Sn
であり、ここで、S1からSnのそれぞれは、3〜6ヌクレオチドの長さを有するサブユニットであり、かつサブユニットのセットから選択され、該サブユニットのヌクレオチド配列は、該セットのサブユニットと、該セットの任意の他のサブユニットの相補物との間に形成される二重鎖が少なくとも2つのミスマッチを含むように選択され、そして
nは4から10の範囲にある、支持体。 - 前記固相支持体が、複数の微粒子であり、前記空間的に離れた領域各々が、単一の微粒子である、請求項2に記載の支持体。
- 前記空間的に離れた領域の各々は、固体支持体上のアレイ上の特定の位置である、請求項2に記載の支持体。
- 前記オリゴヌクレオチドタグ相補物が、ほぼ等しい安定性の完全にマッチした二重鎖を形成するようにさらに選択される、請求項2に記載の支持体。
- オリゴヌクレオチドタグのレパートリーであって、該レパートリーは、以下の形態のオリゴヌクレオチド:
S1S2S3...Sn
からなり、ここで、S1からSnのそれぞれは、3〜6ヌクレオチドの長さを有するサブユニットであり、かつサブユニットのセットから選択され、
該セット中のサブユニットのヌクレオチド配列は、該セットのサブユニットと、該セットの任意の他のサブユニットの相補物との間に形成される二重鎖が少なくとも2つのミスマッチを含むように選択され、そして
nは4から10の範囲にある、レパートリー。 - 前記オリゴヌクレオチドタグがクローニングベクターの挿入物である、請求項6に記載のオリゴヌクレオチドタグのレパートリー。
- 1つまたはそれ以上の固相支持体上にポリヌクレオチドの混合物からのポリヌクレオチドを分類する方法であって、該方法は、以下の工程:
(a)オリゴヌクレオチドタグを、該ポリヌクレオチド混合物中の各ポリヌクレオチドに結合させて、タグ−ポリヌクレオチド結合体の集団を形成する工程であって、異なるポリヌクレオチドを有する試料中の少なくとも80%のタグ−ポリヌクレオチド結合体に、異なるオリゴヌクレオチドタグが結合しており、
各オリゴヌクレオチドタグは、複数のサブユニットを含み、該複数のサブユニットのそれぞれは、3から6ヌクレオチドの長さを有するオリゴヌクレオチドからなり、該サブユニットは、特定のセットから選択され、該セットのサブユニットと該セットの他のあらゆる別のサブユニットの相補物との間で形成される二重鎖は、少なくとも2つのミスマッチを含む、工程;
(b)空間的に離れている固相支持体の集団に結合された該オリゴヌクレオチドタグのそれぞれの相補物を提供する工程であって、該支持体の集団は、別個の配列を有する相補物のレパートリーを含み、該空間的に離れている固相支持体各々は、唯一の配列の相補物を含む、工程;ならびに
(c)該タグ化ポリヌクレオチドの集団を該1つまたはそれ以上の支持体と混合することにより、該タグ化ポリヌクレオチドの該オリゴヌクレオチドタグとそれぞれの相補物とを特異的にハイブリダイズし、それにより、該タグ化ポリヌクレオチドを、該集団から該空間的に離れた固相支持体上における同一ポリヌクレオチドの亜集団へと分類する工程、
を包含する、方法。 - 前記固相支持体が微粒子である、請求項8に記載の方法。
- 前記固相支持体が、平面基板上に複数の空間的に離れた表面領域を含む、請求項8に記載の方法。
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