JP5855195B2 - アドレス可能アレイでのリガーゼ検出反応を用いた核酸配列の相違の検出 - Google Patents
アドレス可能アレイでのリガーゼ検出反応を用いた核酸配列の相違の検出 Download PDFInfo
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- JP5855195B2 JP5855195B2 JP2014185507A JP2014185507A JP5855195B2 JP 5855195 B2 JP5855195 B2 JP 5855195B2 JP 2014185507 A JP2014185507 A JP 2014185507A JP 2014185507 A JP2014185507 A JP 2014185507A JP 5855195 B2 JP5855195 B2 JP 5855195B2
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Description
本発明は、連結反応相、捕捉反応相および検出反応相を用いて核酸中の核酸配列の相違を検出することに関する。連結反応相は第1オリゴヌクレオチドプローブと第2オリゴヌクレオチドプローブとの連結検出反応を利用する。第1プローブは標的配列特異的部分とアドレス可能アレイ(array:配列)特異的部分を有し、第2プローブは標的配列特異的部分と検出用標識を有する。捕捉反応相は、固定化捕捉オリゴヌクレオチド(少なくともこのいくつかはアドレス可能アレイ特異的部分に相補的である)アレイを有する固体支持物に連結したオリゴヌクレオチドプローブをハイブリダイズすることを含む。固体支持物にハイブリダイズした連結オリゴヌクレオチドの標識が検出反応相において検出される。
配列相違の検出
高度に多形的な座の大規模多量解析が、父親検定および法医学(Reynolds et al., Anal. Chem., 63:2-15(1991))、臓器移植のドナーとレシピエントの組み合わせ(Buyse et al., Tissue Antigens, 41:1-14(1993) and Gyllensten et al., PCR Meth. Appl, 1:91-98(1991))、遺伝疾患の診断、予後および出産前の相談(Chamberlain et al., Nucleic Acids Res., 16:11141-11156(1988) and L. C. Tsui, Human Mutat., 1:197-203(1992))および発ガン変異(Hollstein et al., Science, 253:49-53(1991))などについて個体の実際的な同定に必要である。さらに、核酸解析による感染疾患診断の費用効率はパネル試験における多重規模で直接的に変動する。これらの適用の多くは、時に密接なスペース座の多重性において単一塩基の相違の識別力に依存している。
固体支持物上に固定されたオリゴヌクレオチドの順位アレイがDNAを配列決定し、分別し、単離し、操作するために提案される。クローン一本鎖DNA分子の与えられた長さを持つすべての可能なオリゴヌクレオチドプローブへのハイブリダイゼーションが分子中に存在する対応相補的DNAセグメントを理論的に同定することが認められる。このようなアレイにおいて、各オリゴヌクレオチドプローブは、相違する予め定められた位置で固体支持物上に固定される。DNA分子におけるすべてのオリゴヌクレオチドセグメントはかかるアレイでもって観察される。
本発明は、複数の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の1以上を同定する方法に関する。この方法は連結反応相、捕捉反応相および検出反応相を含む。
本発明は、複数の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の1以上を同定する方法に関する。この方法は連結反応相、捕捉反応相および検出反応相を含む。
好ましくは熱ハイブリダイゼーション処理であるハイブリダイゼーション段階は、連結反応の接合部の識別し得るヌクレオチドを基にしたヌクレオチド配列の間を識別する。標的ヌクレオチド配列間の相違は、例えば、単一核酸塩基相違、核酸欠失、核酸挿入または核酸転座であり得る。一個以上の塩基が関与するこのような配列相違もまた検出できる。好ましくは、オリゴヌクレオチドプローブセットは、実質的に同じハイブリダイゼーション条件下で標的ヌクレオチド配列にハイブリダイズするように、実質的に同じ長さである。結果として、本発明の方法は、感染性疾患、遺伝的疾患および癌の検出を可能とする。環境監視、法医学および食物科学においても有用である。
R1はHまたはCH3;
R2は(C=O)−O−R6、官能置換基を有するかまたは有しない脂肪族基、官能置換基を有するかまたは有しない芳香族基もしくは官能置換基を有するかまたは有しない混合脂肪族/芳香族基;
R3はO−アルキル、アルキルまたはハロゲン基;
R4はO−アルキル、アルキルまたはハロゲン基;
R5はO−アルキル、アルキルまたはハロゲン基;そして
R6は官能置換基を有するかまたは有しない脂肪族基、官能置換基を有するかまたは有しない芳香族基もしくは官能置換基を有するかまたは有しない混合脂肪族/芳香族基である〕。分子Aの例は、3−(トリメトキシシリル)プロピルメタクリレート、N−[3−(トリメトキシシリル)プロピル]−N'−(4−ビニルベンジル)エチレンジアミン、トリエトキシビニルシラン、トリエチルビニルシラン、ビニルトリクロロシラン、ビニルトリメトキシシランおよびビニルトリメチルシランを含む。
(i)R1はHまたはCH3、
R2は(C=O)、そして
R3はOHまたはCl
または
(ii)R1はHまたはCH3そして
R2は(C=O)−O−R4、官能置換基を有するかまたは有しない脂肪族基、官能置換基を有するかまたは有しない芳香族基もしくは官能置換基を有するかまたは有しない混合脂肪族/芳香族基;そして
R3はOH、COOH、NH2、ハロゲン、SH、COClまたは活性化エステルのような官能基;そして
R4は官能置換基を有するかまたは有しない脂肪族基、官能置換基を有するかまたは有しない芳香族基もしくは官能置換基を有するかまたは有しない混合脂肪族/芳香族基である〕。分子Bの例は、アクリル酸、アクリルアミド、メタクリル酸、ビニル酢酸、4−ビニル安息香酸、イタコン酸、アリルアミン、アリルエチルアミン、4−アミノスチレン、2−アミノエチルメタクリレート、塩化アクリロイル、塩化メタクリロイル、クロロスチレン、ジクロロスチレン、4−ヒドロキシスチレン、ヒドロキシメチルスチレン、ビニルベンジルアルコール、アリルアルコール、2−ヒドロキシエチルメタクリレートまたはポリ(エチレングリコール)メタクリレートを含む。
別の態様に従って、リンカー分子はその親水性/疎水性特性に基づいて選択され、ある受容体に対する合成ポリマーの提示を改善する。例えば、親水性受容体の場合、親水性リンカー分子は好ましくは受容体が合成ポリマーにより密接に近づくことを可能とする。
h,Editor,Escom Science Publishers:Leiden,The Netherlands pp.1078-80(1994)、
Egholm et al.,"Peptide Nucleic Acids (PNA).Oligonucleotide Analogues with an Achiral Peptide Backbone",J.Am.Chem.Soc.,114:1895-1897(1992)およびEgholm,et al.,"Recognition of Guanine and Adenine in DNA by Cytosine and Thymine Containing Peptide Nucleic Acids (PNA)",J.Am.Chem.Soc.,114:9677-9678(1992)、出典明示により本明細書の一部とする、に記載の方法を用いる。上記の合成図式は、5−プロピニルウラシル塩基成分を持つPNAモノマーの製造を説明するものである。まず、ヨード酢酸を用いて5−ヨードウラシルをアルキル化し、次いで、プロピニル基をPd/Cu触媒により塩基部分に結合させる。この図式中の残りの工程は、上記文献の方法に従う。これらのモノマーは、合成DNAおよびPNA鎖中に組み込むことができる。
テトラマーの番号付図式により、数字6つの列として各アドレスを略式表記できることに注意(例えば、下記表2の第2欄)。36テトラマーのユニークセット(表1)から設計される24量体アドレスの概念により、起こり得る構造は非常に多数であり得る。366=2,176,782,336。
これらのオリゴマーはそれぞれ、その5'末端に酸化ヘキサエチレンリンカーアームを含有し[P.Grossman,et al.,Nucl.Acids Res.,22:4527-4534(1994)、出典明示により本明細書の一部とする]、ガラススライドまたは別の材料の表面への結合に適したアミノ官能基を末尾に持つ。コンジュゲーション法は、遊離の表面官能基によって変わる[Y.Zhang, et al.,Nucleic Acids Res.,19:3929-3933(1991)およびZ.Guo, et al.,Nucleic Acids Res.,34:5456-5465(1994)、出典明示により本明細書の一部とする]。
ジップ 12(2-4-4-6-1-1)=24量体
5’−ATCG GGTA GGTA ACCT TGCG TGCG−3’
ジップ 14(4-4-6-6-3-1)=24量体
5’−GGTA GGTA ACCT ACCT CAGC TGCG−3’
ジップ 12(2-4-4-6-1-1)=24量体
5’−ATCG GGTA GGTA ACCT TGCG TGCG−3’
ジップ 14(4-4-6-6-3-1)=24量体
5’−GGTA GGTA ACCT ACCT CAGC TGCG−3’
ジップ 12(2-4-4-6-1-1)=24量体
5’−ATCG GGTA GGTA ACCT TGCG TGCG−3’
ジップ 3(3-6-5-2-2-3)=24量体
5’−CAGC ACCT GACC ATCG ATCG CAGC−3’
0を通してチャンバー4へテトラマーを加える。チャンバーをゆるめ、膜を90度回転させ、再度締める。テトラマーの第2ラウンドは、上記の減圧およびテトラー適用工程により行う。バルブ ブロックアッセンブリー(図25A−C)は、適当な横列への各テトラマーの経路となる。別法として、円柱状の多岐管(図26A−D)は、5横列(また縦列)に運送される前に6テトラマーの環状順列を可能とする。この設計はオリゴヌクレオチドを含まない領域により互いに離れているユニークな24量体をつくりだす。
(実施例)
固定化のための固体支持物は、ガラスであり、特に顕微鏡のスライドである。空間的なアドレス可能アレイにおける捕捉ヌクレオチドの固定化、すなわちガラス(例えば顕微鏡スライド)あるいはシリコン(例えばチップ)、膜(例えばナイロン膜)、ビーズ(例えばパラマグネチック ビーズまたはアガロース ビーズ)またはプラスチック支持物(例えばポリエチレン シート)などの他の支持物への固定化は、下記の5工程より構成される。
A.支持物のシラン処理
シラン処理剤がAPTSのとき、所望のアミノ官能性を直接導入した。官能基を既に含んでいる適当なシラン処理促進剤[例えば、重合アクリレート(M.Glad,et al.,"Use of Silane Monomers for Molecular Imprinting and Enzyme Entrapment in Polysiloxane-coated Porous Silica,"J.Chromatogr.347:11-23(1985);E.Hedborg,et al.,"Some Studies of Molecularly-imprinted Polymer Membranes in Combination with Field-effect Devices,"Sensors and Actuators A 37-38:796-799(1993);and M.Kempe,et al.,"An Approach Towards Surface Imprinting Using the Enzyme Ribonuclease A,"J.Mol.Recogn.8:35-39(1995)、出典明示により本明細書の一部とする)で表面を官能性化した3−(トリメトキシシリル)プロピル メタクリレート]の選択をするか、または[例えば、写真石版術(Fodor,et al.,"Ligt-Directed,Spatially Addressable Parallel Chemical Synthesis,"Science,251:767-773(1991);Fodor,et al.,"Multiplexed Biochemical Assays with Biological Chips,"Nature,364:555-556(1993)、出典明示により本明細書の一部とする)で使用される保護アミノ基の、局所的に光をあててる光脱保護を行った後に]所望の官能基を含む試薬でアミノ−官能性化表面を反応するか、いずれかにより他の官能基を導入できる。
固体支持物の官能基はアミノ基であった。直径1mm、3.25mm離れているドットが5×5アレイであるプレハブマスクを使って、1−2%トリエチルアミン(生じた酸を洗浄するため)の入る無水ジメチルホルムアミド(“DMF”;Aldrich,Milwaukee,WI)中において、70 mg/ml ジスクシンイミジル アジピン酸 エステル(Hill,et al.,"Disuccinimidyl Esters as Bifunctional Crosslinking Reagents for Proteins,"FEBS Lett,102:282-286(1979);Horton,et al.,"Covalent Immobilization of Proteins by Techniques which Permit Subsequent Release,"Methods Enzymol.,pp.130-141(1987)、出典明示により本明細書の一部とする)を含む少量(典型的には0.2から10μl)の溶液をギルソンP−10ピペットで固体支持物に適用した。次いで、反応は、覆いをして室温で連続30分間進行さした。その後、さらにジスクシンイミジル アジピン酸 エステルを加えた。合計で1時間の反応後、支持物を無水DMFで洗浄し、減圧したデシケーター内で室温で乾燥した。
EDC活性化固体支持物以外の支持物に関して、上記プレハブマスクを再び使い、20mM KH2PO4,pH 8.3中の1 nmol/μl 5'アミノ修飾オリゴヌクレオチド(すなわち、Table2の配列)の少量液(0.2から1.0μl)を活性化支持物に適用した。反応は室温で続けて1時間行った。
E.固体支持物上の残存反応基の失活
ハイブリダイゼーション試験、およびGeneAmp In Situ PCR System 1000(商標登録)(Perkin Elmer,Applied Biosystems Division,Foster City,CA)(G.J.Nuovo,PCR in situ Hybridization,New York:Raven Press(2nd ed.1994)、出典明示により本明細書の一部とする)を用いる高速処理形態による捕捉オリゴヌクレオチドプローブ-捕捉オリゴヌクレオチドのハイブリッドの洗浄試験に関して、半自動なカスタム設計検定システムを作製した。そのシステムの一般フローチャートを図27に示す。そのシステムは、サンプル 充填装置およびマルチプル ポート システムを通じて、液貯蔵器のバッテリーおよび廃液貯蔵器につながるフロースルー ハイブリダイゼーション チャンバーからなる。液の流れはポンプで調節される。ポンプは、そのアッセブリーラインの末端に設置し、システムの液漏れおよび汚染を防ぐため、軽減圧保持条件下で操作する。ハイブリダイゼーション チャンバーおよび液貯蔵器は、GeneAmp In Situ PCR System 1000(商標登録)に正確に合うように設計しているので、ハイブリダイゼーションおよび検定の洗浄工程の間、温度は正確に調節され、維持される。
A.ハイブリダイゼーション チャンバー
ハイブリダイゼーション チャンバーとは、フロースルーの特性を調節するため手を加えたin situ PCR試薬保持システムである。保持システムは、ガラス顕微鏡スライド(76×25×1.2±0.02 mm)およびシリコンゴム膜を含む。それらは、薄いスレンレス スチール クリップでスライドに締め付けられている。内側にある金属クリップの卵形縁により、スライドにシリコンの円盤の端を圧縮する。このスライドは、ハイブリダイゼーション プローブおよび洗浄液の保持を確実し、水および気体のシールをしっかりとするのに充分な力をもつ。保持体積はおよそ50 μlである。固定化捕捉オリゴヌクレオチドのアレイは、シリコンの円盤でカバーするスライド(おおよそ13mm×15mm)の中心部分に保持される。異なる部分の集合は、in situ PCRシステムの製造業者により供給される集合用手段で容易に行われる。一旦、集合させると、ハイブリダイゼーションの入口と出口は、12"チュービングの2本の針 25G3/4およびマルチプル サンプル ルアー アダプター(Becton Dickinson,Rutherford,NJ)を挿入することによりつくられる。プローブ標的ハイブリッドの洗浄の間のアップおよびアクロス(up-and-across)の流型を確実にするため、針を斜めに挿入する。
相違する洗浄溶液を含む貯蔵器は、GeneAmp In Situ PCR System 1000(商標登録)の熱ブロックの垂直スロットに合うようにカスタム設計された。各貯蔵器は、プレハブ シリコン ガスケット(Nunc,Inc.,Napierville,IL)を含む2つのガラス顕微鏡チャンバースライド(25×75×1mm)から成り、それらはシリコン シーラント(Dow Corning,Midland,MI)を使って互いに接着していた。出口は、シリコン ガスケットに通す12"ロング チュービングの針 21G3/4およびマルチプル サンプル ルアー アダプター(Becton Dickinson,Rutherford,NJ)の挿入によりつくられた。チュービングのない二番目の針21G3/4は、気体の入口をつくるためにシリコン ガスケットに通して挿入した。液貯蔵器は、漏れがなく、熱ブロックのスロット内に当てはまる。その熱ブロックで貯蔵器は、含まれる液への熱伝導を良く確保する金属板に締め付けて固定される。各貯蔵器の体積は約2mlである。
液貯蔵器、サンプル充填装置およびハイブリダイゼーション チャンバーは、液の単向的な流れを手動で制御できるマルチプル ポート システムを通じて連結される。そのシステムは、互いに雄-雌結合で連結するルアー アダプター(Kontes Scientific Glassware/Instruments,Vineland,NJ)をともなう一連の3方向ナイロン ストップコックからなる。液貯蔵器からの雌ルアー アダプターは、雄どうしをつなぐルアー アダプター結合器(Biorad,Richmond,CA)を通じてマルチ ポート 雌 ルアー アダプターと連結する。サンプル充填装置は、液貯蔵器につながるポートおよびハイブリダイゼーション チャンバーに連結するポート間に位置する。それは、ルアー アダプターを通じてマルチ ポート システムに直接つながる1ml シリンジ(Becton Dickinson,Franklin Lakes,NJ)からなる。液の流れは、所望の方向にストップコックのつまみを回転させることにより手動で制御できる。
ハイブリダイゼーション チャンバーからの出口チュービングは、ルアー アダプター(Becton Dickinson,Franklin Lakes,NJ)をともなう20ml シリンジからなる廃液貯蔵器につながる。そのプランジャーは固定位置に確保されている。ポンプは、12"ロングチュービングである針21G3/4およびプランジャーのゴム ガスケットに通じるマルチプル サンプル ルアー アダプターの挿入により連結する。ポンプが稼働すると、ハイブリダイゼーション チャンバーを通して液体貯蔵器から廃液貯蔵器へ液を流すシリンジ内で僅かに減圧が生じる。
ぜん動性ポンプP−1(Pharmacia,Piscataway,NJ)は、システムを通じて液の流れを制御するのに利用された。システム内を僅かに減圧するためにポンプはアッセンブリーラインの末端に設置した。ポンプの入口チュービングは、3方向ナイロン ストップコックを通して廃液貯蔵器の出口チュービングへつながる。この構造により廃液貯蔵器内の減圧解放は重力により容易に排水を行う。
異なる捕捉オリゴヌクレオチドの捕捉特異性を調べるために、6つのテトラマー中3つ(すなわち、24のヌクレオチド中12)が共通である2つの捕捉オリゴヌクレオチドプローブを用いてハイブリダイゼーション実験を行った。本実施例では、異なる捕捉オリゴヌクレオチドを区別するのが最も難しい場合を示す。一般的に、共通のテトラマーがより少ない方の捕捉オリゴヌクレオチドを選び、それを用いてアドレス可能なアレイ上にある異なる増幅産物を分離する。
捕捉オリゴヌクレオチド−オリゴヌクレオチドプローブハイブリッドを洗浄した後、シリコンディスク、針および金属カバークリップをガラス顕微鏡スライドから取り去り、残りの液体をキムワイプ(Kimberly-Clark、Roswell、GA)で吸収した。捕捉オリゴヌクレオチドプローブをリン・イメージ剤(Molecular Dynamics、Sunnyvale、CA)を用いて視覚化し定量した。ガラス顕微鏡スライドをリン・イメージ剤スクリーンに21時間あてた後、試験した異なる固体支持物についてデータを集積した。得られた像を図28に示す。定量データは表4Aおよび4Bに示す。
ポリマーを文献の方法を用いてスライド上に配置した。Barnard,et al.「A Fibre-optic Sensor With Discrete Sensing Sites」Nature 353:338-40(1991);Bonk,et al.「Fabricarion of Patterned Sensor Arrays With Aryl Azides on a Polymer-coated Imaging Optical Fiber Bundle」Anal.Chem.66:3319-20(1994);Smith,et al.「Poly-N-acrylylpyrrolidone--A New Resin in Peptide Chemistry」Int.J.Peptide Protein Res.13:109-12(1979)。これらは出典明示により本明細書の一部とする
捕捉オリゴヌクレオチド固定化に関する別法を用いて、ポリマーで被膜したスライドがアドレス可能なオリゴヌクレオチドプローブを捕捉する能力について、試験を行った。3−(トリメトキシシリル)プロピルメタクリレートを用いてシラン化した後、モノマーをスライド上でポリマー化した。1つには、ポリエチレングリコール含有クロスリンカーを用いてCOOH官能基のついたポリマー層を形成させ、他方には、ポリエチレングリコール−メタクリル酸モノマーをスライド上でポリマー化しOH官能基を形成させた。実施例1のEDC活性化法を用いてCOOH官能基のついたスライドを活性化した。
膜支持物を用いて異なる捕捉オリゴヌクレオチドの捕捉特異性を調べるために、捕捉オリゴヌクレオチドプローブ12および14(表3)を用いてハイブリダイゼーション実験を行った。
ガラススライド(Fisher Scientific、Extra thick microslides、スリガラス商品番号#12-550-11)を濃NH4OH−H2O2−H2O(1:1:5、v/v/v)水溶液中、80℃で5分間インキュベートし、蒸留水で濯いだ。二度目のインキュベートは濃HCl−H2O2−H2O(1:1:5、v/v/v)水溶液中80℃で5分間行った。J〓nsson,et al.「Absorption Behavior of Fibronectin on Well Characterized Silica Surfaces」J.Colloid Interface Sci.90:148-163(1982)参照。これは出典明示により本明細書の一部とする。スライドを完全に蒸留水、メタノールおよびアセトンで濯ぎ、室温で自然乾燥した。
実施例8により調製した洗浄済スライドを24−48時間、室温で、2.6mlの3−メタクリロイルオキシプロピルトリメトキシシラン(Aldrich Chemical Company,Inc.Milwaukee,Wis.商品番号#23,579-2)、0.26mlトリエチルアミンおよび130mlトルエンからなる溶液中でインキュベートした。E.Hedborg,et al.、Sensors Actuators A,37-38:796-799(1993)参照。これは出典明示により本明細書の一部とする。スライドを完全にアセトン、メタノール、蒸留
水、再びメタノール、再びアセトンで濯ぎ、室温で自然乾燥させた。図31参照。
実施例8により調製した洗浄済スライドを15分間、室温で、12mlジクロロジメチルシランおよび120mlトルエンからなる溶液中でインキュベートした。スライドを完全にアセトン、メタノール、蒸留水、再びメタノール、および再びアセトンで濯ぎ、自然乾燥させた。
2.2gポリ(エチレングリコール)メタクリル酸(Aldrich Chemical Company,Inc.Milwaukee,Wis.商品番号#40,953-7)(平均分子量〜306g/mol)および50gの2,2'−アゾビス(2−メチルプロピオニトリル)の3.5mlアセトニトリル溶液を氷上で冷却し、3分間アルゴン気流下で脱気した。次の工程はアルゴン雰囲気下グローブボックス中で行った。5−15滴のポリマー化混合物を、実施例8および9により調製したメタクリル酸誘導体化ガラススライドに配置した。メタクリル酸誘導体化ガラススライドおよびポリマー化混合物を、実施例10によりシラン化した第2のガラススライドで覆い、2つのガラススライドを押し合わせ、クリップで固定した。スライドは続けて真空デシケーターに移した。ポリマー化は55℃で熱的に始まるか、または366nmで光学的に始まった。図32参照。
0.5gアクリル酸(Aldrich Chemical Company,Inc.Milwaukee,Wis.商品番号#14,723-0)、1.83gトリメチロールプロパンエトキシレート(14/3EO/OH)トリアクリレート(Aldrich Chemical Company,Inc.Milwaukee,Wis.商品番号#23,579-2)および50mgの2,2'−アゾビス(2−メチルプロピオニトリル)の3.5mlアセトニトリル溶液を氷上で冷却し、3分間アルゴン気流下で脱気した。次の工程は実施例11に記載したようにグローブボックス中で行った。スライドは続けて真空デシケーターに移し、実施例11に記載のようにポリマー化した。図33参照。
0.55gポリ(エチレングリコール)メタクリレート(Aldrich Chemical Company,Inc.Milwaukee,Wis.商品番号#40,953,7)、1.64gトリメチロールプロパンエトキシレート(14/3EO/OH)トリアクリレート(Aldrich Chemical Company,Inc.Milwaukee,Wis.商品番号#23,579-2)および50mgの2,2'−アゾビス(2−メチルプロピオニトリル)の3.5mlアセトニトリル溶液を氷上で冷却し、3分間アルゴン気流下で脱気した。次の工程は実施例11に記載したようにグローブボックス中で行った。スライドは続けて真空デシケーターに移し、実施例11に記載のようにポリマー化した。図34参照。
Claims (16)
- 捕捉オリゴヌクレオチドのコレクションであって、
該コレクションの捕捉オリゴヌクレオチドの各タイプは、1以上の捕捉オリゴヌクレオチドの結合に好適なアレイ位置を有する固体支持物上に結合し、16より多いヌクレオチドを有し、かつ該コレクション中の捕捉オリゴヌクレオチドの別のタイプのヌクレオチド配列と並べた場合に少なくとも25%のヌクレオチドにおいて相違するヌクレオチド配列を含んでおり、
該コレクション中の各捕捉オリゴヌクレオチドは、同一のハイブリダイゼーション条件下で捕捉オリゴヌクレオチドの相補的ヌクレオチド配列を含む核酸分子とハイブリダイズし、
該各タイプの捕捉オリゴヌクレオチドが、該個体支持物上の相違するアレイ位置で結合される、
捕捉オリゴヌクレオチドのコレクション。 - 該コレクション中の各オリゴヌクレオチドプローブが、24以下のヌクレオチドを含む、請求項1のコレクション。
- 球体の群であって、該群の各球体が、捕捉オリゴヌクレオチドのコレクションからの捕捉オリゴヌクレオチドの1以上のタイプを含む、球体群であって、該コレクションの捕捉オリゴヌクレオチドの各タイプは、16より多いヌクレオチドを有し、かつ該コレクション中の捕捉オリゴヌクレオチドの別のタイプのヌクレオチド配列と並べた場合に少なくとも25%のヌクレオチドにおいて相違するヌクレオチド配列を含んでおり、
該コレクション中の各捕捉オリゴヌクレオチドは、同一のハイブリダイゼーション条件下で相補的ヌクレオチド配列を含んでいる核酸分子とハイブリダイズする、
球体の群。 - 該球体が、プラスチック、セラミック、金属、樹脂、ゲル、ガラス、シリコンおよびこれらの組み合わせ体からなる群より選ばれる材料でつくられる、請求項3の球体の群。
- リンカーが該球体に該捕捉オリゴヌクレオチドを連結する、請求項3−4いずれか一項記載の球体の群。
- 該球体がオレフィン、アミノ、ヒドロキシル、シラノール、アルデヒド、ケト、ハロ、アシルハライドまたはカルボキシル基で官能化されている、請求項3−4いずれか一項記載の球体の群。
- 該球体が、3−アミノプロピルトリエトキシシラン、3−アミノプロピルメチルジエトキシシラン、3−アミノプロピルジメチルエトキシシラン、3−アミノプロピルトリメトキシシラン、N−(2−アミノエチル)−3−アミノプロピルメチルジメトキシシラン、N−(2−アミノエチル−3−アミノプロピル)トリメトキシシラン、アミノフェニルトリメトキシシラン、4−アミノブチルジメチルメトキシシラン、4−アミノブチルトリエトキシシラン、アミノエチルアミノメチルフェネチルトリメトキシシランおよびこれらの混合物からなる群より選ばれるアミン化合物との反応により、アミノ基で官能化されている、請求項6の球体の群。
- 該球体が、オレフィン含有シランで官能化されている、請求項3−7いずれか一項記載の球体の群。
- オレフィン含有シランが、3−(トリメトキシシリル)プロピルメタクリレート、N−[3−(トリメトキシシリル)プロピル]−N'−(4−ビニルベンジル)エチレンジアミン、トリエトキシビニルシラン、トリエチルビニルシラン、ビニルトリクロロシラン、ビニルトリメトキシシラン、ビニルトリメチルシランおよびこれらの混合物からなる群より選ばれる、請求項8の球体の群。
- 該球体が、オレフィン含有モノマーで重合化される、請求項3−7いずれか一項記載の球体の群。
- オレフィン含有モノマーが、官能基を含む、請求項10の球体の群。
- オレフィン含有モノマーが、アクリル酸、メタクリル酸、ビニル酢酸、4−ビニル安息香酸、イタコン酸、アリルアミン、アリルエチルアミン、4−アミノスチレン、2−アミノエチルメタクリレート、塩化アクリロイル、塩化メタクリロイル、クロロスチレン、ジクロロスチレン、4−ヒドロキシスチレン、ヒドロキシメチルスチレン、ビニルベンジルアルコール、アリルアルコール、2−ヒドロキシエチルメタクリレート、ポリ(エチレングリコール)メタクリレートおよびこれらの混合物からなる群より選ばれる、請求項10の球体の群。
- 該球体が、アクリル酸、アクリルアミド、メタクリル酸、ビニル酢酸、4−ビニル安息香酸、イタコン酸、アリルアミン、アリルエチルアミン、4−アミノスチレン、2−アミノエチルメタクリレート、塩化アクリロイル、塩化メタクリロイル、クロロスチレン、ジクロロスチレン、4−ヒドロキシスチレン、ヒドロキシメチルスチレン、ビニルベンジルアルコール、アリルアルコール、2−ヒドロキシエチルメタクリレート、ポリ(エチレングリコール)メタクリレート、およびその混合物からなる群から選ばれるモノマーと、アクリル酸、メタクリル酸、ビニル酢酸、4−ビニル安息香酸、イタコン酸、アリルアミン、アリルエチルアミン、4−アミノスチレン、2−アミノエチルメタクリレート、塩化アクリロイル、塩化メタクリロイル、クロロスチレン、ジクロロスチレン、4−ヒドロキシスチレン、ヒドロキシメチルスチレン、ビニルベンジルアルコール、アリルアルコール、2−ヒドロキシエチルメタクリレート、ポリ(エチレングリコール)メタクリレート、メチルアクリレート、メチルメタクリレート、エチルアクリレート、エチルメタクリレート、スチレン、1−ビニルイミダゾール、2−ビニルピリジン、4−ビニルピリジン、ジビニルベンゼン、エチレングリコールジメタクリレート、N,N'−メチレンジアクリルアミド、N,N'−フェニレンジアクリルアミド、3,5−ビス(アクリロイルアミド)安息香酸、ペンタエリスリトールトリアクリレート、トリメチロールプロパントリメタクリレート、ペンタエリスリトールテトラアクリレート、トリメチロールプロパンエトキシレート(14/3EO/OR)トリアクリレート、トリメチロールプロパンエトキシレート(7/3EO/OR)トリアクリレート、トリメチロールプロパンプロポキシレート(1PO/OR)トリアクリレート、トリメチロールプロパンプロポキシレート(2PO/OH)トリアクリレートおよびこれらの混合物からなる群より選ばれるモノマーと一緒に重合化される、請求項10の球体の群。
- 固体支持物上のコレクション中の各捕捉オリゴヌクレオチドのタイプが、異なるヌクレオチド配列を有する、請求項3−13いずれか一項記載の球体の群。
- 該コレクション中の各捕捉オリゴヌクレオチドが、24以下のヌクレオチドを含む、請求項3−14いずれか一項記載の球体の群。
- 該コレクション中の1以上の捕捉オリゴヌクレオチドが、相補的ヌクレオチド配列を含む核酸分子とハイブリダイズされる、請求項3−15いずれか一項記載の球体の群。
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JP4294732B2 (ja) | 2009-07-15 |
JP5634937B2 (ja) | 2014-12-03 |
AU2799797A (en) | 1997-09-10 |
EP2573101A1 (en) | 2013-03-27 |
JP4890411B2 (ja) | 2012-03-07 |
EP2332958B1 (en) | 2016-04-20 |
EP0920440A2 (en) | 1999-06-09 |
EP2573101B1 (en) | 2016-04-20 |
JP2014236750A (ja) | 2014-12-18 |
CA2244891C (en) | 2008-12-30 |
EP1958955A1 (en) | 2008-08-20 |
JP2008064765A (ja) | 2008-03-21 |
EP2368897B1 (en) | 2016-10-19 |
WO1997031256A2 (en) | 1997-08-28 |
EP2332958A1 (en) | 2011-06-15 |
EP2574617B1 (en) | 2016-04-20 |
JP2011154043A (ja) | 2011-08-11 |
EP2332957B1 (en) | 2015-04-08 |
EP0920440B1 (en) | 2012-08-22 |
EP2368897A1 (en) | 2011-09-28 |
EP1958955B1 (en) | 2013-09-04 |
EP0920440A4 (en) | 2004-08-25 |
JP2001519648A (ja) | 2001-10-23 |
EP2332957A1 (en) | 2011-06-15 |
CA2244891A1 (en) | 1997-08-28 |
AU735440B2 (en) | 2001-07-05 |
EP2574617A1 (en) | 2013-04-03 |
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