JP5133898B2 - シトシンメチル化の検出方法 - Google Patents
シトシンメチル化の検出方法 Download PDFInfo
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- JP5133898B2 JP5133898B2 JP2008549021A JP2008549021A JP5133898B2 JP 5133898 B2 JP5133898 B2 JP 5133898B2 JP 2008549021 A JP2008549021 A JP 2008549021A JP 2008549021 A JP2008549021 A JP 2008549021A JP 5133898 B2 JP5133898 B2 JP 5133898B2
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- butyl
- dna sample
- hydroxyphenyl
- dna
- naphthoquinone
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- 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
- C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
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Description
a)ゲノムDNAサンプルを、テトラヒドロフルフリルアルコールの存在下、0.1〜6mol/lの濃度範囲内の重亜硫酸塩(=亜硫酸水素塩、二硫酸塩)溶液とインキュベートする;
b)得られた反応混合物を、工程a)で添加された反応物質を除去するために精製または除去工程に付すか、または、処理されたDNAサンプルを、工程a)で添加された試薬が以下の反応を妨げないように、水または水溶液で希釈する;
e)ゲノムDNAサンプルと比較して、工程a)の処理によって配列が変化した程度の検出を実施し、ゲノムDNAサンプルの少なくとも1つの遺伝子座でのメチル化状態に関する結果を出す。
a)少なくとも1つのラジカル捕捉剤およびテトラヒドロフルフリルアルコールに加えて、任意にさらなる変性試薬および/または溶媒の存在下、ゲノムDNAサンプルを、0.1〜6mol/lの濃度範囲内の重亜硫酸塩(=亜硫酸水素塩、二硫酸塩)溶液とインキュベートする;
b)得られた反応混合物を、工程a)で添加された反応物質を除去するために精製または除去工程に付すか、または、処理されたDNAサンプルを、工程a)で添加された試薬が以下の反応を妨げないように、水または水溶液で希釈する;
c)DNAサンプルを、精製または除去工程の間、任意に脱スルホン化工程に付すか、または、DNAサンプルをその後の反応において脱スルホン化工程に付す;
d)DNAサンプルを、ポリメラーゼ反応において任意に増幅する;
e)ゲノムDNAサンプルと比較して、工程a)の処理によって配列が変化した程度の検出を実施し、ゲノムDNAサンプルの少なくとも1つの遺伝子座でのメチル化状態に関する結果を出す。
ジ−、トリヒドロキシベンゼン、緑茶抽出物、松樹皮抽出物(ピクノジェノール)、イチョウ葉抽出物(EGb761)、種々の果物および野菜抽出物のフラボノイド混合物(GNLD)、バイオノーマライザー(Bio-Normalizer)(サンオー社(Sun-O Corp))、DPPH(1,1-ジフェニル-2-ピクリルヒドラジル)、NDGA(ノルジヒドログアファレチン酸(nordihydroguajaretic acid))、トロロックス(Trolox)(6-ヒドロキシ-2,5,7,8-テトラメチルクロマン-2-カルボン酸)、2,6-ジ-t-ブチルフェノール、4-メチル-ジ-t-ブチルフェノール、4-メトキシ-ジ-t-ブチルフェノール、2,6-ジ-t-ブチル-p-クレゾール、3,4-ジヒドロキシ安息香酸、ビタミンC、ビタミンE、ビタミンQ、ヒドロキノン、ユビキノン、リグナン、ヒドロキシテルペン、フラボノイド、クルクミン、タンニン、レチノイン酸化合物、Ge-132 ビス-β-カルボキシエチルゲルマニウムセスキオキサイド、スーパーオキシドジスムターゼ(SOD)、スーパーオキシドカタラーゼ、α-ナフトフラボン、イチョウ葉抽出物(EGb761)、ジ(2-メチル-5-クロロフェニル)ジチオナートおよびCu(ll)-誘導体、メベンダゾール、CS(クロロホルム可溶性)アルカロイド抽出物、4-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-1,2-ナフトキノン、4-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-1,2-ナフトキノン、4-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-1,2-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ブロモ-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-クロロ-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-1,4-ナフトキノン、4-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,2-アントラキノン、4-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,2-アントラキノン、4-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,2-アントラキノン、3-ブロモ-4-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,2-アントラキノン、2-(3,5-ジ-t-ブチル-4-オキソシクロヘキサ-2,5-ジエニリデン)-インダン-1,3-ジオン、2-(3,5-ジ-t-ブチル-4-オキソシクロヘキサ-2,5-ジエニリデン)-3,4-エポキシ-3-ヒドロキシ-4-メトキシ-3,4-ジヒドロ-2H-ナフタレン-1-オン、2-(3,5-ジ-t-ブチル-4-オキソシクロヘキサ-2,5-ジエニリデン)-3,4-エポキシ-3,4-ジメトキシ-3,4-ジヒドロ-2H-ナフタレン-1-オン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-インダン-1-オン、3,3-ジ[2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-インデン-1-オン]-3-イル、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ブロモ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-クロロ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、2-ブロモ-3-(3-ブロモ-5-t-ブチル-4-ヒドロキシフェニル)-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、2-ブロモ-3-(3,5-ジブロモ-4-ヒドロキシフェニル)-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、2-ブロモ-3-(3-ブロモ-5-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロ-1,4-アントラキノン、3-ブロモ-2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-1,4-アントラキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-1,4-アントラキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-1,4-アントラキノン、5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロナフタレン-1,3-ジオール、3-メトキシ-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロナフタレン-1-オール、4-(3-クロロ-5,5,8,8-テトラメチル-1,4-ジオキソ-1,4,5,6,7,8-ヘキサヒドロアントラセン-2-イル)安息香酸、メチル-4-(3-クロロ-5,5,8,8-テトラメチル-1,4-ジオキソ-1,4,5,6,7,8-ヘキサヒドロアントラセン-2-イル)ベンゾエート、4-(3-ヒドロキシ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)安息香酸、メチル-(3-メトキシ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)安息香酸、(3-メチル-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)安息香酸メチル、4-(3-ヒドロキシ-5,5,8,8-テトラメチル-1,4-ジオキソ-1,4,5,6,7,8-ヘキサヒドロアントラセン-2-イル)安息香酸、メチル-4-(3-ヒドロキシ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル-アゾ)ベンゾエート、4-(3-ヒドロキシ-5,5,8,8-テトラメチル-1,4-ジオキソ-1,4,5,6,7,8-ヘキサヒドロアントラセン-2-イル-アゾ)安息香酸、3-(3,5-ジ-t-ブチル-4-オキソシクロヘキサ-2,5-ジエニリデン)-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロシクロペンタ[b]ナフタレン-1,2-ジオン、3-(3,5-ジ-t-ブチル-4-オキソシクロヘキサ-2,5-ジエニリデン)-5,5,8,8-テトラメチル-5,6,7,8-テトラヒドロアントラセン-3H-1,2,4-トリオン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-5,8-ジメチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-6,7-ジメチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-5-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-メトキシ-5-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-6-メチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-メトキシ-6-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-5,6-ジメチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-メトキシ-6-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-5,6-ジメチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-メトキシ-5,6-ジメチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-メトキシ-5,7-ジメチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-メトキシ-5,7-ジメチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-エチルチオ-5-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-エチルチオ-6-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5,8-ジメチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-6,7-ジメチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5-メチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-ヒドロキシ-5-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-6-メチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-ヒドロキシ-6-メチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5,6-ジメチル-1,4-ナフトキノン、2-(3-ブロモ-5-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5,6-ジメチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-ヒドロキシ-5,6-ジメチル-1,4-ナフトキノン、2-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-3-ヒドロキシ-5,7-ジメチル-1,4-ナフトキノン、3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)-2-ヒドロキシ-5,7-ジメチル-1,4-ナフトキノン。
d1)請求項1の前処理したDNAサンプルに非特異的にハイブリッド形成する異なる配列の少なくとも1組のプライマー対でPCRプレ増幅を実施し;
d2)プレ増幅において形成された産物のPCR増幅を、請求項1の前処理したDNAサンプル[(+)-ストランドまたは(-)-ストランド]の断片に毎回同一であるかまたは逆に補完的であり、かつ、増幅されるDNAに特異的にハイブリッド形成する、異なる配列のプライマー対で実施する。
a)増幅されたゲノムDNAを、二本鎖を形成しながら、少なくとも1つのオリゴヌクレオチドにハイブリッド形成するが、ハイブリッド形成したオリゴヌクレオチドは、その3'-末端と直接隣接するか、ゲノムDNAサンプルにおいてメチル化を調査する位置に最大10塩基離れて隣接する;
b)配列が分かっているn個のヌクレオチドのオリゴヌクレオチドを、ポリメラーゼによって少なくとも1つのヌクレオチドで延長するが、ヌクレオチドは検出可能なタグを有し、延長は、ゲノムDNAサンプル中の各シトシンのメチル化状態に依存する。
(a)一組のオリゴヌクレオチドを、二本鎖を形成しながら、増幅されたゲノムDNAにハイブリッド形成するが、この一組のオリゴヌクレオチドは、2つの異なる種から成り、第一の種のハイブリッド形成したオリゴヌクレオチドは、その3'-末端と直接隣接するか、ゲノムDNAサンプルにおいてメチル化を調査する位置に最大10塩基離れて隣接し、第二の種の第二のオリゴヌクレオチドは、第二の種のオリゴヌクレオチドの5'-末端が、選択された位置の部位において、第一の種のハイブリッド形成されたオリゴヌクレオチドの3'-末端から1個のヌクレオチドまたは最大10個のヌクレオチド離れて、標的分子の第二の領域にハイブリッド形成する;
(b)配列が分かっているn個のヌクレオチドの第一の種のオリゴヌクレオチドを、最大で第一の種のオリゴヌクレオチドの3'-末端と第二の種のオリゴヌクレオチドの5'-末端との間にあるヌクレオチド数のポリメラーゼによって延長するが、延長は、ゲノムDNA種中の各シトシンのメチル化状態に依存する;
(c)オリゴヌクレオチドをリガーゼの存在下でインキュベートするが、ポリメラーゼ反応において延長された第一の種の隣接するオリゴヌクレオチドと、第二の種のオリゴヌクレオチドは連結し、以下の場合、そのような方法で連結反応産物が得られる:前工程で、第一の種のオリゴヌクレオチドの延長が、利用可能な3'-ヒドロキシ基を有する延長されたオリゴヌクレオチドの3'-末端が第二の種のオリゴヌクレオチドの5'-末端に直接隣接するように起きる場合。
(a)増幅されたゲノムDNAを、二本鎖を形成しながら、配列が分かっているn個のヌクレオチドの少なくとも1つのオリゴヌクレオチドにハイブリッド形成するが、その3'-末端でハイブリッド形成されたオリゴヌクレオチドは、ゲノムDNAサンプルにおいてメチル化を調査する位置に部分的または完全にハイブリッド形成し;
(b)オリゴヌクレオチドは、塩基の誤対合なく、事前に調査下の位置にその3'-末端でハイブリッド形成するならば、ポリメラーゼによって少なくとも1個のヌクレオチドで延長されるが、少なくとも1個のヌクレオチドは、検出可能なタグを有し、延長は、ゲノムDNAサンプル中の各シトシンのメチル化状態に依存する。
Claims (6)
- DNAにおけるシトシンメチル化の検出方法であって、以下の工程が実施されることを特徴とする、方法:
a)ゲノムDNAサンプルを、テトラヒドロフルフリルアルコールの存在下、0.1〜6mol/lの濃度範囲の重亜硫酸塩(=亜硫酸水素塩、二硫酸塩)溶液とインキュベートする工程;
b)得られた反応混合物を、工程a)で添加された試薬を除去するために精製または除去工程に付すか、または、処理されたDNAサンプルを、工程a)で添加された試薬がその後の反応を妨げないように、水または水溶液で希釈する工程;
e)ゲノムDNAサンプルと比較して、工程a)の処理によって配列が変化した程度の検出を実施し、ゲノムDNAサンプルの少なくとも1つの遺伝子座でのメチル化状態に関する結果を出す工程。 - 請求項1に記載の方法であって、工程a)において少なくとも1つのラジカル捕捉剤が存在する、方法。
- 前項のうちの1つに記載の方法であって、DNAサンプルを精製または除去工程の間に脱スルホン化工程に付すか、または、DNAサンプルをその後の反応において脱スルホン化工程に付す、方法。
- 前項のうちの1つに記載の方法であって、DNAサンプルを、工程e)における検出の前にポリメラーゼ反応において増幅する、方法。
- 請求項1に記載のアッセイを実施するためのキットであって、重亜硫酸塩およびテトラヒドロフルフリルアルコールを含む少なくとも1つの試薬を含む、キット。
- 請求項5に記載のキットであって、少なくとも1つのラジカル捕捉剤をさらに含む、キット。
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