JP5936304B2 - ゲノム核酸中の遺伝子異常を検出するためのアッセイ - Google Patents
ゲノム核酸中の遺伝子異常を検出するためのアッセイ Download PDFInfo
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- C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Description
a.標的配列を含有するゲノム核酸サンプルを標的配列に特異的なプローブと接触させ、ゲノム核酸および標的配列にハイブリダイズしたプローブから成る複合体を固相支持体上に形成させる(ここで、プローブは検出可能な標識を含有し、ゲノム核酸は核酸ハイブリダイゼーション以外の方法で固相支持体に固定され、そして、ゲノム核酸の標的配列の増幅は行われていない);そして
b.標識と固相支持体の結合を検出することによってゲノム核酸中の標的配列の存在を検出する。
a.ゲノム核酸サンプルを遺伝子異常に特異的なプローブと接触させ、(もしゲノム核酸中に遺伝子異常が存在すれば)ゲノム核酸およびプローブから成る複合体を固相支持体上に形成させる(ここで、ゲノム核酸は核酸ハイブリダイゼーション以外の方法で固相支持体に固定され、ゲノム核酸の標的配列の増幅は行われていない);
b.標識と固相支持体の結合を検出することによって遺伝子異常の存在を検出する。
a.遺伝子異常を含有するゲノム核酸サンプルを遺伝子異常に特異的な第1のプローブと接触させ、ゲノム核酸および第1のプローブから成る第1の複合体を固相支持体上に形成させる(ここで、プローブは検出可能な標識を含有し、ゲノム核酸は核酸ハイブリダイゼーション以外の方法で固相支持体に固定され、そして、ゲノム核酸の標的配列の増幅は行われていない);
b.ゲノム核酸サンプルを参照核酸に特異的な第2のプローブと接触させ、参照核酸および第2のプローブから成る第2の複合体を固相支持体上に形成させる(ここで、第2のプローブは検出可能な標識を含有する);
c.形成された第1の複合体の量の測定を、複合体と結合した第1のプローブの検出可能な標識を検出することによって行い、形成された第2の複合体の量の測定を、複合体と結合した第2のプローブの検出可能な標識を検出することによって行う;そして、
d.第1の複合体の量と第2の複合体の量を比較する(ここで、2つの複合体の量の差異は遺伝子異常を示す)。
a.遺伝子異常を含有するゲノム核酸サンプルを遺伝子異常に特異的な第1のプローブと接触させ、ゲノム核酸および第1のプローブから成る第1の複合体を固相支持体上に形成させる(ここで、プローブは検出可能な標識を含有し、ゲノム核酸は核酸ハイブリダイゼーション以外の方法で固相支持体に固定され、そして、ゲノム核酸の標的配列の増幅は行われていない);
b.ゲノム核酸サンプルを参照核酸に特異的な第2のプローブと接触させ、参照核酸および第2のプローブから成る第2の複合体を固相支持体上に形成させる(ここで、第2のプローブは検出可能な標識を含有する);
c.形成された第1の複合体の量の測定を、複合体と結合した第1のプローブの検出可能な標識を検出することによって行い、形成された第2の複合体の量の測定を、複合体と結合した第2のプローブの検出可能な標識を検出することによって行う;
d.第1および第2の複合体の量の比率を求める;そして
e.得られた比率を参照サンプル由来のゲノム核酸を用いて同様に得た比率と比較する(ここで、比率の差異は遺伝子異常を示す)。
a.個体由来のゲノム核酸サンプルを疾患に特異的な核酸配列と相補的なプローブと接触させ、(もしゲノム核酸が疾患に特異的な核酸配列を含有すれば)ゲノム核酸およびプローブから成る複合体を固相支持体上に形成させる(ここで、プローブは検出可能な標識を含有し、ゲノム核酸は核酸ハイブリダイゼーション以外の方法で固相支持体に固定され、そして、ゲノム核酸の標的配列の増幅は行われていない);
b.支持体に結合した検出可能な標識の量を検出することによって固相支持体上に形成された複合体の量を測定する;そして、
c.形成された複合体の量を、同様の条件下でアッセイを行った参照サンプル由来のゲノム核酸を用いて形成された複合体の量と比較する(ここで、個体から形成された複合体の量と参照サンプルとの差異によって疾患が診断される)。
本発明は無傷細胞または核を必要とせずに固相支持体上で未増幅のゲノム核酸を検出するための方法を提供する。方法を使用して試験サンプル中の遺伝子異常、例えば点変異、転座、欠失、および重複を検出してもよい。方法を使用して、疾患の診断または予後診断を行ってもよい。
遺伝子異常は、ある生物の完全長遺伝子相補体またはその一部と、その生物の全染色体の正常な完全長遺伝子相補体との相違を反映しうる。例えば、遺伝子異常には染色体コピー数の変化(例えば異数性)もしくはその一部の変化(例えば欠失、重複、増幅);または染色体構造の変化(例えば転座、点変異)が含まれる。遺伝子異常により病的状態が引き起こされうる。癌のように生涯のうちで少数の細胞に起こる遺伝子異常を原因とする疾患もあるが、“遺伝病”という用語は最も一般的には、身体の全細胞に受胎の時から存在する疾患を言う。遺伝子異常は遺伝性のものと非遺伝性のものがある。
固相支持体を用いて共有結合または非共有結合によってゲノム核酸を固定してもよい。好ましい態様では、固相表面はビーズである。ある態様では、ビーズまたは微粒子は実質的に同一サイズである。他の態様では、ビーズまたは微粒子は同一サイズまたは複数サイズである。ある態様では、ビーズまたは微粒子は磁性であってもよい。これらのビーズまたは微粒子は、例えばポリスチレンまたはラテックスから成ってもよい。ビーズまたは微粒子は直径約0.1μm-10μmであるか、または大きければ直径50μm-100μmであってもよいが、より小さいビーズサイズおよびより大きいビーズサイズも可能である。
ゲノム核酸または参照核酸の固相支持体への固定は、検出可能標識を有するプローブへのゲノム核酸または参照核酸のハイブリダイゼーションの前、後、または同時に行ってもよい。核酸を支持体に共有結合または非共有結合によって固定してもよい。
プローブはゲノム核酸の少なくとも一部にハイブリダイズする能力がある。好ましい態様では、核酸プローブはThe BAC Resource Consortiumによる細菌人工染色体(BAC)一覧に提供されるヒトゲノム核酸セグメントの1個、数個、または全てから誘導される。当該分野では通常、これらのプローブをそのRPIまたはCTBクローン名で称する(Cheungら, Nature 409:953-958, 2001参照)。この一覧は、ヒトゲノム・ドラフト配列上の7,600個の細胞遺伝学的に定義されたランドマークを含有する(McPherson et al., Nature 409:934-41, 2001参照)。これらのランドマークは蛍光in situハイブリダイゼーションによって染色体バンドにマッピングされる大型インサートクローンであり、それぞれ、ゲノム配列上に位置する配列タグを含有する。これらのクローンは24個のヒト染色体全てを約1Mbの解像度で表す。BACゲノム・コレクションの供与源には BACPAC Resources Center(CHORI-Children’s Hospital Oakland Research Institute)、ResGen(Research Genetics(Invitrogen社を介する))、およびThe Sanger Center(英国)が含まれる。
核酸鎖間の相補性の度合いは、核酸鎖間のハイブリダイゼーションの効率および強度に有意な影響を及ぼす。これは核酸間の結合に依存する検出法において、特に重要である。ある態様では、プローブおよびゲノム核酸間の相補性は“部分的”であって、一部の核酸の塩基だけが塩基対合則に従ってマッチしていてもよい。別の態様では、プローブおよびゲノム核酸間の相補性は“完全な”、“全ての”、または“全くの”ものであってもよい。
本明細書で使用する“検出可能標識”とは、プローブに結合する分子、化合物、一群の分子、または一群の化合物で、ゲノム核酸または参照核酸にハイブリダイズしたプローブを同定するために用いられるものをいう。
ハイブリダイズしたゲノム核酸、プローブ、および固相支持体複合体に導入された検出可能な標識を施与されたプローブの検出法は公知であり、標識の性質によって様々である。
ゲノム核酸の単離
この実施例のゲノム核酸は、乳癌に罹患していることが確認されている個体または乳癌に罹患していないことが確認されているコントロール個体由来のヒトHER-2遺伝子配列を含有するゲノムDNAである。個体の血清からDNAを抽出するか、またはQiagen社のEZ1 DNAキットを用いてパラフィン包埋組織からゲノムDNAを単離した。
ヒトHER-2遺伝子のある領域に相補的なFITC標識したプローブおよびCy-5で標識した17番染色体特異的シングルコピー配列(17-SSC)を用いて、血清またはパラフィン包埋組織サンプルから単離したビオチン化ゲノムDNAとハイブリダイズさせた。
5´ Cy5-TGTATTTATC CTCTCTCTAG CCATCCATAGC TGTAGCTGGC TCACTCACT 3´ (SEQ ID NO: 1)
ビオチン標識したゲノムDNAを含有するハイブリダイゼーション複合体をストレプトアビジン・コーティング・ビーズに捕捉した。非特異的結合を低減するために、コンジュゲーションに先立ってストレプトアビジン・コーティング・マイクロスフェア(Bangs Laboratories社、インディアナ州フィッシャーズ)をBlockAid(Invitrogen社、カリフォルニア州カールスバッド)および断片化サケ***DNA(100μg/mL)で順次処理した。5μlのストレプトアビジン・ビーズ(Bangs社、インディアナ州フィッシャーズ)を100μlのコンジュゲーション・バッファー(100mM Tris-HCL;pH 8.0、0.1% Tween 20;および1M LiCl)で1回洗浄し、20μlのコンジュゲーション・バッファーに再懸濁した。5μlのプローブ-DNA複合体をビーズに添加し、混合液を室温で撹拌しながら1時間インキュベートし、ビーズ-DNA複合体を生成させた。結合したビーズを10%ホルムアミド/0.2x SSCで1回、0.2x SSCで2回、洗浄する。ウサギ抗FITC抗体(BD Bioscience)を含有する溶液にビーズ複合体を再懸濁した。ビーズ複合体を2% BSA/リン酸緩衝食塩水(PBS)で3回洗浄し、4%ブロッキング・ミルクに再懸濁し、2% BSA/PBSで1回洗浄した。ビーズ複合体をAlexa-488標識したヤギ抗ウサギ抗体(BD Bioscience)を1:500の希釈率で含有する溶液に再懸濁し、暗所において室温で30分間回転撹拌した。次いで、Sorvall CW-2 Cell washerを用いてビーズ複合体を2% BSAで1回洗浄し、ビーズを沈殿させた。
FITC/Alexa-488およびCy-5からのシグナルの比率を測定した。この比率はHER-2:17-SSCの比を表す。コントロール個体およびコントロールサンプルから得られた結果に基づいて、2.14(平均値±3 SD)の比率をHER-2遺伝子増幅とみなした。
Claims (16)
- ゲノムDNA中の標的核酸の重複または欠失の存在または不存在を検出する方法であり、以下:
a.ゲノムDNAの試験サンプルを該標的核酸に特異的な第1のプローブと接触させ、該第1のプローブにハイブリダイズした該ゲノムDNAを含有する第1の複合体を形成させること(ここで、該プローブは検出可能な第1の標識を含有し、該ゲノムDNAの増幅は行われていない);
b.工程(a)において形成された該第1の複合体を、該ゲノムDNAを介して、核酸ハイブリダイゼーション以外の方法で固相支持体に固定すること;
c.該ゲノムDNAの試験サンプルを参照核酸に特異的な第2のプローブと接触させ、該第2のプローブにハイブリダイズした該ゲノムDNAを含有する第2の複合体を形成させること(ここで、該第2のプローブは検出可能な第2の標識を含有し、該第2のプローブは該第1のプローブと異なり該標的核酸に特異的ではなく、該第2の標識は該第1の標識と異なる);
d.工程(c)において形成された該第2の複合体を、該参照核酸を介して、核酸ハイブリダイゼーション以外の方法で固相支持体に固定すること;
e.形成された該第1の複合体の量の測定を、該第1の複合体に結合した該第1の標識を検出することによって行い、形成された該第2の複合体の量の測定を、該第2の複合体に結合した該第2の標識を検出することによって行うこと;
f.該第2の複合体の量に対する該第1の複合体の量の比率を求めること;
g.得られた比率を、参照サンプル由来のゲノムDNAを用いて同様に得た比率と比較すること(ここで、該比率の増加は重複を示し、該比率の減少は欠失を示す)
を含む上記方法。 - 該参照サンプルを正常な個体から得る、請求項1記載の方法。
- 該固相支持体が結合対の第1のメンバーを含有し、該ゲノムDNAが結合対の第2のメンバーを含有し、結合対メンバーの結合によって該ゲノムDNAが該固相支持体に固定される、請求項1又は2に記載の方法。
- 該ゲノムDNAが固相支持体に共有結合によって固定される、請求項1〜3のいずれか一項に記載の方法。
- 該固相支持体がビーズ、マイクロウェル・プレート、またはガラス表面である、請求項1〜4のいずれか一項に記載の方法。
- 該結合対がリガンド-受容体、ホルモン-受容体、または抗原-抗体である、請求項3〜5のいずれか一項に記載の方法。
- 該結合対がビオチンおよびストレプトアビジンまたはストレプトアビジンの変異体である、請求項3〜6のいずれか一項に記載の方法。
- 前記第1又は第2のプローブがオリゴヌクレオチド、ゲノムDNA、RNA、またはペプチド核酸である、請求項1〜7のいずれか一項に記載の方法。
- 該第1のプローブおよび該第2のプローブの長さが少なくとも50ヌクレオチドである、請求項1〜8のいずれか一項に記載の方法。
- 前記第1又は第2の標識がフルオロフォア、ナノ粒子、同位元素、化学発光化合物、酵素、またはハプテンである、請求項1〜9のいずれか一項に記載の方法。
- 前記第1又は第2の複合体をフローサイトメトリーによって固相支持体上で検出する、請求項1〜10のいずれか一項に記載の方法。
- 前記第1又は第2のプローブの検出可能標識に結合する標識された試薬を検出することによって前記第1又は第2の複合体を検出する、請求項1〜11のいずれか一項に記載の方法。
- 該標識された試薬が検出可能標識に特異的な標識された抗体である、請求項12に記載の方法。
- 該試験サンプルが細胞、組織、体液、糞便、パラフィン包埋組織、細胞ライセート、または組織ライセートを含む、請求項1〜13のいずれか一項に記載の方法。
- 該参照核酸が染色体中のハウスキーピング遺伝子またはシングルコピー配列である、請求項1〜14のいずれか一項に記載の方法。
- 該固相支持体が結合対の第1のメンバーから成り、該ゲノムDNAが結合対の第2のメンバーから成り、結合対メンバーの結合によって該ゲノムDNAが該固相支持体に固定される、請求項1〜15のいずれか一項に記載の方法。
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CN107523616A (zh) | 2017-12-29 |
WO2009073345A4 (en) | 2009-09-24 |
WO2009073345A2 (en) | 2009-06-11 |
CN107523616B (zh) | 2021-05-25 |
EP2227562A4 (en) | 2011-01-19 |
US20090142755A1 (en) | 2009-06-04 |
BRPI0819841A2 (pt) | 2019-09-24 |
JP2011505137A (ja) | 2011-02-24 |
CA2707219A1 (en) | 2009-06-11 |
US8093063B2 (en) | 2012-01-10 |
CN101925677A (zh) | 2010-12-22 |
CN101925677B (zh) | 2017-08-15 |
EP2227562A2 (en) | 2010-09-15 |
WO2009073345A3 (en) | 2009-07-30 |
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