JP6234980B2 - 法医学的dnaの定量化のための改善された方法 - Google Patents
法医学的dnaの定量化のための改善された方法 Download PDFInfo
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Description
米国政府は、本発明における一括払いライセンスを有しており、米国司法省、司法プログラム局、国立司法研究所によって授与された(交付番号:NIJ 2008−DN−BX−K009)の条件により与えられるような適切な条件で他にライセンスを与えるために特許権者を必要とする限られた状況における権利を有している。
[関連出願]
配列ID番号:2は、配列5’−GCC TGA AAA GCT CCC GAT TAT−3’を有するTHO1リバースプライマー(Reverse Primer)である。
配列ID番号:3は、配列5’−GTC AGG AGA TCG AGA CCA TCC C−3’を有するAluフォワードプライマーである。
配列ID番号:4は、配列5’−TCC TGC CTC AGC CTC CCA AG−3’を有するAluリバースプライマーである。
配列ID番号:
5は、配列5’−GCC CGA TTT TGC GAC TTT GGA GGG C−3’を有するPV 92 プローブ1である。
配列ID番号:
6は、配列5’−CGC CTC AAA GTG CTG GGA TTA CAG GCG−3’を有するAluプローブ2である。
この実施例は、以下において用いられるシステムを記載する。
サブシステム(空気式サブシステム、温度サイクリングサブシステム、および分離および検出サブシステム)はラックマウント方式の耐久性を高められた工業用コンピュータによって制御される。このコンピュータは、標準サイズのデスクトップコンピュータの機能性を有しており、17インチのLCD表示装置、フルサイズのキーボード、およびマウスを含む。
バイオチップを通じての流体の流れは、流体チャネルの端部に配置されるポートに対する系統的な加圧によって達成される。毛状のバルブの破裂圧力未満の圧力が印加される場合、流体は、チャネルに沿って流出し、毛状のバルブで止まるだろう。バルブの破裂圧力よりも高い圧力が印加される場合、流体は、バルブを通じて流出するだろう。空気式系統は、また、膜を弁座に対して押しつけるための圧力の印加により、薄膜弁を閉じるために用いられる。薄膜弁の封止圧力は、適用される封止圧力に応じて増減する。選択されて出力に適用される5つの離散的な圧力レベルを供給するために、圧力は、小型の膜ポンプおよび圧力調整器によって生成される。本システムは、バイオチップ上のポートを通じて連結管に連結される8つの出力を提供する。空気式サブシステムは、所望の流れ制御を達成するためにコンピュータで制御される。このサブシステムは、バイオチップに対する特定の圧力レベルの系統的なアプリケーションを通じて、バイオチップ内の溶解およびPCRを実行するために流体の流れをもたらす。図10は、バイオチップの典型的な写真を示す。
温度サイクラーは、高性能のヒートシンクおよびファンアセンブリ(ヒートポンプ)上に取り付けられた高出力熱電モジュール(TEM)を含む。TEMと反応チャンバとの間の圧縮および効率的な熱の転送を供給するために、カバーによりバイオチップを締める。カバーに対する熱損失は、バイオチップとカバーアセンブリと間の絶縁材の層によって最小限にされる。TEMの表面および反応チャンバ内の温度センサは、設定値温度までの所望の迅速なランピングおよび前記設定値温度での安定度を可能にするためのフィードバックを行なう。TEM表面で測定された加熱/冷却レートは、21.6℃/秒および21.7℃/秒である。また、反応溶液の測定された加熱/冷却レートは、14.8℃/秒および15.4℃/秒である。反応溶液は、この温度サイクラー内で、急速の商用サイクラーと比較して7倍急速で加熱され冷却される。状態間の最小限の遷移時間は、バイオチップ内の反応溶液の迅速かつ制御された加熱/冷却を可能にする。図11および図12は、温度サイクラーの典型的な写真を示す。
高電圧接続は、計器のカバーに取り付けられ、カバーが閉まっている場合、バイオチップに接触される。レーザー励起蛍光サブシステムは、光学ビームパスまたはサブシステムコンポーネントに対して変更なしで計器に統合化される。ヒーターサブシステムは。チップ室内に取り付けられる。
温度サイクリングサブシステムは、サイクル番号、残りの工程所要時間、およびカレントブロックおよび溶液温度を含む装置ステータスをユーザに提供する。ユーザフィードバックは、キーボードを介して供給される。実行されたデータはすべて、制御コンピュータに格納され、イーサネットによってプロセスデータベースに転送される。計器上の分離および検出の間、制御コンピュータは、実行中であるステップを示す。さらに、分離チャネル電流および基板温度を含む16個のレーンおよびプロセスパラメータの各々のためのリアルタイムエレクトロフォレトグラムが表示される。機載コンピュータは、年次メンテナンスまでの残り時間、システム電源投入時自己診断テスト(POST)の結果、および故障または即時のメンテナンスを必要とする任意のサブシステムの名前について、ユーザに警告する。
この実施例は、TH01型ローカスプローブを用いて、マイクロ流体ピコグリーン分析によるDNA定量化を実証する。
単一複製のヒトのチロシン水酸化酵素遺伝子、THO1(スワンゴ(Swango)ら「法医学的試料における核DNAの量および品質を評価するための多重qPCR分析の発展的な検証(Developmental validation of a multiplex qPCR assay for assessing the quantity and quality of nuclear DNA in forensic sample)」(2007年)、国際法医遺伝学会、170巻、1版、35〜45ページ)を標的とするために使用されたプライマー対は次のとおりだった。
TH01型フォワードプライマー:5’−AGG GTA TCT GGG CTC TGG−3’(配列ID番号:1)
TH01型リバースプライマー:5’−GCC TGA AAA GCT CCC GAT TAT−3’(配列ID番号:2)
9947AゲノムDNA(MCLab、サウスサンフランシスコ(カリフォルニア))のストック10ng/マイクロリットルは、反応混合に対して4マイクロリットル量におけるDNAの適正量を追加することにより、標準曲線を生成するために用いられた。この標準曲線は、未知の(ヒト/ヒト以外の)ゲノムDNA試料にフィットするデータに用いるためのゲノムDNA − 0ng、0.4ng、1ng、4ng、10ng、20ngおよび40ng − の7つの異なる濃縮物を含んだ。標準曲線試料は、4回繰り返して解析された。増幅は、[93℃で4秒、58℃で15秒、70℃で7秒]の28サイクルおよび70℃で90秒の最後の伸長反応によって追従された、93℃における20秒の活性化により始動された。完了時間は、約17分だった。
この実施例は、Aluローカスプローブを用いて、マイクロ流体ピコグリーン分析によってDNA定量化を実証する。
Aluフォワードプライマー:5’−GTC AGG AGA TCG AGA CCA TCC C−3’(配列ID番号:3)
Aluリバースプライマー:5’−TCC TGC CTC AGC CTC CCA AG−3’(配列ID番号:4)
高速のPCRサイクリングプロファイル反応および定量化は、93℃での20秒の活性化の改善された増幅プロトコルを備えた実施例2において記載されたように、[93℃で4秒、58℃で15秒、70℃で7秒]の15サイクルおよび70℃で90秒の最後の伸長反応によって追従された。完了時間は、約10分だった。計器からの投入DNA対相対蛍光単位(RFU)のプロットは、R2=0.999を有する(図15)。図16は、レーン変位の機能としてレーザー検出から出力されたRFUデータである。励起の間に、TH01型反応により用いられるものと比較して、振幅によってレーザーパワーの強度を弱めたフィルターは、色素の光退色を回避するために必然的に見出された。OD4減光フィルターは200mWに設定されたレーザーパワー、原寸大の30%に設定された青色のPMTのゲイン、0に設定された赤色、黄色および緑色のゲイン、および5Hzに設定されたリフレッシュレートとともに用いられた。レーザーパワーの設定およびフィルターの組み合わせにて、効果的なレーザーパワーは、実施例2の10%である。このデータは、増幅の間のサイクル数がさらに低減されたことを示唆する。
この実施例は、サイバーグリーンI(SYBR Green I)分析によってDNA定量化を実証する。
この実施例は、分子ビーコンを用いて、混成分析によって事前の増幅をしないで、DNA定量化を実証する。
この実施例は、直接混成分子ビーコン分析の還元反応時間を実証する。
この実施例は、ヒト口腔スワブDNAを定量化するために、直接混成分子ビーコン分析を実証する。
この実施例は、直接混成分子ビーコン分析の特異性を実証する。記載されるように、ヒト以外のDNAが精製された。実施例6の標準曲線から、バクテリア、犬、および、鶏DNAからの蛍光信号が、再び推定され、UV吸光度から得られた値と比較された。さらに、既知のヒト口腔スワブのDNA試料は、これらの異なるバックグラウンドDNAにより混入された。
この実施例は、法医学的データベース試料による定量化の必要性をなくすことを実証する。
この実施例は、特有の光学機器列に基づいた定量化のための励起および検出パラメータの開発を示す。
Claims (56)
- 標的核酸を含むまたは含むと推測される試料流体においてヒトゲノム二本鎖DNA標的を定量化する方法であって、
マイクロ流体チャネルにおいて(i)前記試料流体と(ii)少なくとも1つの反復ヒトAlu配列に結合することができる少なくとも1つの分子ビーコンプローブを含むプローブ流体とを組み合わせて試験液を形成するステップであって、ここに前記プローブはさらにシグナリング部分を含み、前記試料流体中の標的は増幅されていないステップと、
前記試験液を加熱して二本鎖DNAを変性させ、ついで前記試験液を冷却して分子ビーコンプローブが標的に結合するように標的核酸に対する分子ビーコンプローブの結合を容易にするステップと、
前記マイクロ流体チャネルにおける検出領域に前記試験液を配置するステップと、
前記検出領域の試験液中の前記シグナリング部分を検出するステップと、
前記試料流体と前記プローブ流体とを組み合わせてから1分以内に前記試験液における変性した増幅されていない標的核酸を定量化するステップと
を備えることを特徴とする方法。 - 前記定量化ステップは、前記試験液における前記標的核酸の濃度を究明するステップを備えることを特徴とする請求項1に記載の方法。
- 前記分子ビーコンプローブは前記ヒトAlu標的に独特の特異性を有することを特徴とする請求項1に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける前記検出領域に前記試験液を流出するステップを備えることを特徴とする請求項1に記載の方法。
- 前記配置ステップは、検出の間に前記マイクロ流体チャネルの前記検出領域を通して前記試験液を流出するステップを備えることを特徴とする請求項4に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける領域において静止した状態で試験液を保持するステップと、前記領域を前記検出領域に転換するために前記領域に1列に並ぶように検出器を移動させるステップとを備えることを特徴とする請求項1に記載の方法。
- 試料操作のための複数のマイクロ流体チャネルおよび領域を備えるバイオチップに前記マイクロ流体チャネルは配置され、前記方法は、前記定量化ステップの後に、前記バイオチップの領域に、前記試料流体の選択された量を方向づけるステップを備えるステップをさらに備え、前記選択された量は、前記定量化ステップの結果に基づいて、少なくとも部分的に究明されることを特徴とする請求項1に記載の方法。
- 前記シグナリング部分を検出するステップは、レーザーにより前記シグナリング部分を照射するステップを備えることを特徴とする請求項1に記載の方法。
- 前記マイクロ流体チャネルは、バイオチップ内に含まれ、前記レーザーは、前記マイクロ流体チャネルを備える前記バイオチップに連結されたシステムのコンポーネントであることを特徴とする請求項8に記載の方法。
- 前記シグナリング部分を検出するステップは、蛍光を検出するステップを備えることを特徴とする請求項1に記載の方法。
- 前記標的核酸は、もし存在すれば、1ナノグラム/マイクロリットル未満の濃度を有してしている、または前記試料流体中に合計量で1ナノグラム未満含まれることを特徴とする請求項1に記載の方法。
- 前記試料流体は、法医学的試料を備えることを特徴とする請求項1に記載の方法。
- 前記試料流体は、ヒト以外の非標的核酸をさらに備えることを特徴とする請求項1に記載の方法。
- 標的核酸を含むまたは含むと推測される試料流体においてヒトゲノム二本鎖DNA標的を定量化する方法であって、
マイクロ流体チャネルにおいて(i)前記試料流体と(ii)少なくとも1つの反復ヒトAlu配列に結合することができる少なくとも1つの分子ビーコンプローブを含むプローブ流体とを組み合わせて試験液を形成するステップであって、ここに前記プローブはさらにシグナリング部分を含み、前記試料流体中の標的は増幅されていないステップと、
前記試験液を加熱して二本鎖DNAを変性させ、ついで前記試験液を冷却して、分子ビーコンプローブが標的に結合するように標的に対する分子ビーコンプローブの結合を容易にするステップと、
前記マイクロ流体チャネルにおける検出領域に前記試験液を配置するステップと、
前記検出領域の試験液中の前記シグナリング部分を検出するステップと、
前記試験液における変性した増幅されていない標的核酸を試料流体と前記プローブ流体とを組合せて1分以内に定量化するステップであって、前記標的は、1ナノグラム/マイクロリットル未満の濃度を有している、または前記試料流体中に合計量で1ナノグラム未満含まれるステップと
を備えることを特徴とする方法。 - 前記定量化ステップは、前記試験液における前記標的の濃度を究明するステップを備えることを特徴とする請求項14に記載の方法。
- 前記定量化ステップは、前記試験液における前記標的の合計量を究明するステップを備えることを特徴とする請求項14に記載の方法。
- 前記分子ビーコンプローブはヒトAlu標的のための独特の特異性を有することを特徴とする請求項14に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける前記検出領域に前記試験液を流出するステップを備えることを特徴とする請求項14に記載の方法。
- 前記配置ステップは、検出の間に前記マイクロ流体チャネルの前記検出領域を通して前記試験液を流出するステップを備えることを特徴とする請求項18に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける領域で静止した状態で試験液を保持するステップと、前記領域を前記検出領域に転換するために前記領域に1列に並ぶように検出器を移動させるステップとを備えることを特徴とする請求項14に記載の方法。
- 試料操作のための複数のマイクロ流体チャネルおよび領域を備えるバイオチップに前記マイクロ流体チャネルは配置され、前記方法は、前記定量化ステップの後に、前記バイオチップの領域に、前記試料流体の選択された量を方向づけるステップを備えるステップをさらに備え、前記選択された量は、前記定量化ステップの結果に基づいて、少なくとも部分的に究明されることを特徴とする請求項14に記載の方法。
- 前記シグナリング部分を検出するステップは、レーザーにより前記シグナリング部分を照射するステップを備えることを特徴とする請求項14に記載の方法。
- 前記マイクロ流体チャネルは、バイオチップ内に含まれ、前記レーザーは、前記マイクロ流体チャネルを備える前記バイオチップに連結されたシステムのコンポーネントであることを特徴とする請求項22に記載の方法。
- 前記シグナリング部分を検出するステップは、蛍光を検出するステップを備えることを特徴とする請求項14に記載の方法。
- 前記試料流体は、法医学的試料を備えることを特徴とする請求項14に記載の方法。
- 前記試料流体は、ヒト以外の非標的核酸をさらに備えることを特徴とする請求項25に記載の方法。
- 前記定量化ステップは、前記試験液における前記標的核酸の濃度を究明するステップを備えることを特徴とする請求項1または14に記載の方法。
- 前記定量化ステップは、前記試験液における前記標的核酸の合計量を究明するステップを備えることを特徴とする請求項1または14に記載の方法。
- 標的を含むまたは含むと推測される試料流体においてヒトゲノム二本鎖DNA標的を定量化する方法であって、
レーザーを備える検出器を備える電子装置に連結されたマイクロ流体デバイスを準備するステップであって、前記レーザーはマイクロ流体デバイスに集積されているステップと、
前記マイクロ流体デバイスのマイクロ流体チャネルにおいて(i)前記試料流体と(ii)少なくとも1つの反復ヒトAlu配列に結合することができる少なくとも1つの分子ビーコンプローブを含むプローブ流体とを組み合わせるステップであって、前記分子ビーコンプローブがさらにシグナリング部分を含んで試験液を形成し、前記試料流体中の標的が増幅されていないステップと、
前記試験液を加熱して二本鎖DNAを変性させ、ついで前記試験液を冷却して、分子ビーコンプローブが標的に結合するように標的に対する分子ビーコンプローブの結合を容易にするステップと、
前記電子装置の前記検出器に作用する近接に配置された前記マイクロ流体チャネルの検出領域に前記試験液を配置するステップと、
前記集積レーザーを用いて、前記シグナリング部分を照射するステップと、
前記試験液における変性した増幅されていない標的核酸を試料流体と前記プローブ流体とを組合せて1分以内に定量化するステップと
を備えることを特徴とする方法。 - 前記定量化ステップは、前記試験液における前記標的の濃度を究明するステップを備えることを特徴とする請求項29に記載の方法。
- 前記定量化ステップは、前記試験液における前記標的の合計量を究明するステップを備えることを特徴とする請求項29に記載の方法。
- 前記分子ビーコンプローブは前記ヒトAlu標的のための独特の特異性を有することを特徴とする請求項29に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける前記検出領域に前記試験液を流出するステップを備えることを特徴とする請求項29に記載の方法。
- 前記配置ステップは、検出の間に前記マイクロ流体チャネルの前記検出領域を通して前記試験液を流出するステップを備えることを特徴とする請求項33に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける領域で静止した状態で前記試験液を保持するステップと、前記領域を前記検出領域に転換するために前記領域に1列に並ぶように検出器を移動させるステップとを備えることを特徴とする請求項29に記載の方法。
- 試料操作のための複数のマイクロ流体チャネルおよび領域を備えるバイオチップに前記マイクロ流体チャネルは配置され、前記方法は、前記定量化ステップの後に、前記バイオチップの領域に、前記試料流体の選択された量を方向づけるステップを備えるステップをさらに備え、前記選択された量は、前記定量化ステップの結果に基づいて、少なくとも部分的に究明されることを特徴とする請求項29に記載の方法。
- 前記標的は、もし存在すれば、1ナノグラム/マイクロリットル未満の濃度を有している、または前記試料流体中に合計量で1ナノグラム未満含まれることを特徴とする請求項29に記載の方法。
- 前記シグナリング部分を検出するステップは、レーザーにより前記シグナリング部分を照射するステップを備えることを特徴とする請求項29に記載の方法。
- 前記マイクロ流体チャネルは、バイオチップ内に含まれ、前記レーザーは、前記マイクロ流体チャネルを備える前記バイオチップに連結されたシステムのコンポーネントであることを特徴とする請求項38に記載の方法。
- 前記シグナリング部分を検出するステップは、蛍光を検出するステップを備えることを特徴とする請求項29に記載の方法。
- 前記試料流体は、ヒト以外の非標的核酸をさらに備えることを特徴とする請求項29に記載の方法。
- 前記試料は、法医学的試料であることを特徴とする請求項29に記載の方法。
- 標的を含む試料流体においてヒトゲノム二本鎖DNA標的を操作する方法であって、
検出器を備える電子装置に連結された、試料操作のための複数のマイクロ流体チャネルおよび領域を備えるマイクロ流体デバイスを準備をするステップと、
前記マイクロ流体デバイスのマイクロ流体チャネルにおいて(i)試料流体と(ii)少なくとも1つの反復ヒトAlu配列に結合することができる少なくとも1つの分子ビーコンプローブを含むプローブ流体とを組み合わせるステップであって、ここに前記分子ビーコンプローブはシグナリング部分をさらに含んで試験液を形成し、ここに試料流体中の標的は増幅されていないステップと、
前記試験液を加熱して二本鎖DNAを変性させ、ついで前記試験液を冷却して、分子ビーコンプローブが標的に結合するように標的に対する分子ビーコンプローブの結合を容易にするステップと、
前記電子装置の前記検出器に作用する近接に配置された前記マイクロ流体チャネルの検出領域に前記試験液を配置するステップと、
前記試験液における変性した増幅されていない標的核酸を試料流体と前記プローブ流体とを組合せて1分以内に定量化するステップと
バイオチップの領域に、前記試料流体の選択された量を方向づけるステップであって、ここに前記選択された量は、前記定量化ステップの結果に基づいて、少なくとも部分的に究明されるステップと
を備えることを特徴とする方法。 - 前記定量化ステップは、前記試験液における前記標的核酸の濃度を究明するステップを備えることを特徴とする請求項43に記載の方法。
- 前記定量化ステップは、前記試験液における前記標的核酸の合計量を究明するステップを備えることを特徴とする請求項43に記載の方法。
- 前記分子ビーコンプローブは前記ヒトAlu標的のための独特の特異性を有することを特徴とする請求項43に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける前記検出領域に前記組み合わされた流体を流出するステップを備えることを特徴とする請求項43に記載の方法。
- 前記配置ステップは、検出の間に前記マイクロ流体チャネルの前記検出領域を通して前記組み合わされた流体を流出するステップを備えることを特徴とする請求項47に記載の方法。
- 前記配置ステップは、前記マイクロ流体チャネルにおける領域で静止した状態で前記組み合わされた流体を保持するステップと、前記領域を前記検出領域に転換するために前記領域に1列に並ぶように検出器を移動させるステップとを備えることを特徴とする請求項43に記載の方法。
- 前記標的は、もし存在すれば、1ナノグラム/マイクロリットル未満の濃度を有してしている、または前記試料流体中に合計量で1ナノグラム未満含まれることを特徴とする請求項43に記載の方法。
- 前記シグナリング部分を検出するステップは、レーザーにより前記シグナリング部分を照射するステップを備えることを特徴とする請求項43に記載の方法。
- 前記マイクロ流体チャネルは、バイオチップ内に含まれ、前記レーザーは、前記マイクロ流体チャネルを備える前記バイオチップに連結されたシステムのコンポーネントであることを特徴とする請求項51に記載の方法。
- 前記シグナリング部分を検出するステップは、蛍光を検出するステップを備えることを特徴とする請求項43に記載の方法。
- 前記試料流体は、ヒト以外の非標的核酸をさらに備えることを特徴とする請求項43に記載の方法。
- 前記試料は、法医学的試料であることを特徴とする請求項43に記載の方法。
- 前記分子ビーコンプローブは、配列番号:5または配列番号:6に記載の配列を有することを特徴とする請求項1、14、29または43のいずれかに記載の方法。
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EP2443254A2 (en) | 2012-04-25 |
JP2016039819A (ja) | 2016-03-24 |
WO2010147654A3 (en) | 2011-02-17 |
US20110008785A1 (en) | 2011-01-13 |
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US20220315996A1 (en) | 2022-10-06 |
US9550985B2 (en) | 2017-01-24 |
US11441173B2 (en) | 2022-09-13 |
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