JP4968498B2 - ジンクフィンガーヌクレアーゼを用いる、標的化された染色体変異誘発 - Google Patents
ジンクフィンガーヌクレアーゼを用いる、標的化された染色体変異誘発 Download PDFInfo
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
- C12N15/8201—Methods for introducing genetic material into plant cells, e.g. DNA, RNA, stable or transient incorporation, tissue culture methods adapted for transformation
- C12N15/8213—Targeted insertion of genes into the plant genome by homologous recombination
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/033—Rearing or breeding invertebrates; New breeds of invertebrates
- A01K67/0333—Genetically modified invertebrates, e.g. transgenic, polyploid
- A01K67/0337—Genetically modified Arthropods
- A01K67/0339—Genetically modified insects, e.g. Drosophila melanogaster, medfly
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
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- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
- C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
- C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
- C12N15/8257—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits for the production of primary gene products, e.g. pharmaceutical products, interferon
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/90—Stable introduction of foreign DNA into chromosome
- C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
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Description
本願は、米国仮特許出願第60/351,035号(2002年1月23日出願)およびPCT出願番号PCT/US03/02012(2003年1月22日出願)による優先権を主張する。
米国政府は、援助RO1 GM 58504による部分的支援に基づいて、本発明において、一定の権利を有する。
遺伝子標的化(相同組換えによる遺伝子置換または遺伝子変異のプロセス)は、非常に有用であるが、代表的には、宿主細胞の遺伝物質に所望の変化を導入するためには非効率的な技術である。標的化された産物についての強力な選択が適用され得る場合にのみ、所望の変化の回収が可能である。遺伝子標的化の効率を改善するための一般的方法は、より広範囲の生物へのこのツールの拡大と同様、多くの場合において有益である。
本発明は、標的化された遺伝子組換えまたは変異を実施するための組成物および方法を提供する。細胞または生物における内因性核酸の任意のセグメントは、標的領域もしくはその標的領域の一部分の配列が公知である限り、またはこの標的領域に相同な単離されたDNAが利用可能である限り、本発明の方法によって改変され得る。
本発明は、標的化された遺伝子組換えまたは標的化された変異を実行するための方法および組成物に関連する。以前に知られている標的化された遺伝子組換えの方法と対照的に、本発明は、実行が、効率的かつ安価であり、そして任意の細胞または生物に適応可能である。細胞または生物の二本鎖核酸の任意のセグメントは、本発明の方法により改変され得る。この方法は、全ての細胞に内在性である相同組換えプロセスおよび非相同組換えプロセスの両方を利用する。
本発明の目的のために、以下の用語は、以下の意味を有する:
本明細書中で使用される場合、用語「標的化された遺伝子組換え」とは、宿主細胞または宿主生物に存在するDNA標的遺伝子座内で組換えが生じるプロセスを言う。組換えは、相同DNAまたは非相同DNAのいずれかを含み得る。相同標的遺伝子組換えの1つの例は、ジンクフィンガーヌクレアーゼ(ZFN)による宿主DNAの選択遺伝子座の切断後に続く、外因性起源であるか、または内因性起源のいずれかの相同DNAを用いた、切断DNAの相同組換えである。非相同標的遺伝子組換えの1つの例は、ZFNによる宿主DNAの選択遺伝子座の切断後に続く、切断DNAの非相同末端結合(NHEJ)である。
本発明のジンクフィンガーヌクレアーゼ(ZFN)は、標的遺伝子座で二本鎖切断(DSB)を引き起こすことによって、宿主細胞において標的化された遺伝子組み換えまたは標的化された変異を指向し得る、キメラタンパク質分子である。本発明のZFNは、DNA結合ドメインおよびDNA切断ドメインを含み、ここで、DNA結合ドメインは、少なくとも1つのジンクフィンガーを含み、DNA切断ドメインに作動可能に連結される。ジンクフィンガーDNA結合ドメインは、キメラタンパク質分子のN末端にあり、DNA切断ドメインは、この分子のC末端に位置される。
ZFNのDNA認識特異性および/または結合特異性は、細胞性DNAの任意の選択された部位で標的化された遺伝子組換えを達成するように変更され得る。このような改変は、公知の分子生物学的合成技術および/または化学的合成技術を使用して達成され得る。広範な種々のDNA認識特異性および/または結合特異性を有するジンクフィンガーを含むZFNは、本発明の範囲内である。
本発明の方法は、任意の細胞または生物の標的化された遺伝子組換えまたは変異のために使用され得る。最低限の必要条件は、遺伝物質を細胞または生物に導入するための方法(安定な形質転換または一過性形質転換のいずれか)、内因性標的領域に関する配列情報、ならびに標的遺伝子座を認識および切断するZFN構築物を含む。本発明のいくつかの実施形態に従って、例えば、相同組換え、ドナーDNAもまた必要とされる。
形質転換体は、各細胞または生物の特定の要件に依存する、種々の公知の技術によって実施され得る。このような技術は、多数の生物および細胞に対して研究されており、そして全ての他の細胞に対して、過度な実験なしで適合され得る。適切な形質転換は、細胞および細胞核へのDNAの進入を包含する。単細胞生物および単一細胞から再生され得る生物(全ての植物およびいくらかの哺乳動物を含む)については、形質転換が、インビトロ培養で実施され得、次いで、形質転換体の選択および形質転換体の再生が行われる。DNAまたはRNAを細胞に移入するためにしばしば使用される方法は、カチオン性の脂質、リポソーム、または他の材料と、DNAまたはRNAの複合体を形成し、微小注射、粒子銃ボンバードメント、エレクトロポレーション、およびDNAまたはRNAをウイルスベクターに形質転換するように組み込むことを包含する。他の技術は、当該分野において周知である。
(リポソーム処方物:)
本発明の特定の広範な実施形態において、オリゴヌクレオチドまたは/ポリヌクレオチドならびに/あるいはZFNおよび適切な場合にはドナーDNAを含む、発現ベクターが、リポソーム内にトラップされ得る。リポソームとは、リン脂質二重膜および内側の水性媒体によって特徴付けられる、小胞構造体である。多層リポソームは、水性媒体によって分離された、多脂質層を有する。これらの層は、リン脂質が過剰の水溶液中に懸濁されると自発的に形成される。この脂質成分は、自己再配置を起こし、その後、閉じた構造を形成し、そして水をトラップし、そして脂質二重層の間に、溶解した溶質をトラップする。カチオン性脂質−核酸複合体(例えば、リポフェクタミン−核酸複合体)もまた企図される。本発明による使用のために適切な脂質は、市販供給源により得られ得る。本発明によって使用されるリポソームは、異なる方法によって作製され得、そしてこのような方法は、当該分野において公知である。リポソームのサイズは、合成方法に依存して変動する。
ZFNをコードし、そして適切な場合は、ドナーDNAをコードするDNA構築物の宿主細胞への移入のためのいくつかの非ウイルス方法が、本発明によって企図される。この方法としては、リン酸カルシウム沈殿、リポフェクタミン−DNA複合体、およびレセプター媒介性トランスフェクションが挙げられる。これらの技術のいくつかは、インビボ使用またはエキソビボ使用のために首尾良く適合され得る。
形質転換された植物を、全植物を形質転換するプロセスによって、または培養物中の単細胞もしくは組織サンプルを形質転換して、この形質転換された細胞から全植物を再生するプロセスによって得る。胚細胞または種子が、形質転換される場合、全植物を再生する必要はない。なぜなら、形質転換された植物は、種子から直接成長し得るからである。トランスジェニック植物を、当該分野で公知の任意の手段(Agrobacterium tumefaciens媒介性DNA移入(好ましくは、ディスアーム型(disarmed)T−DNAベクターを用いる)、エレクトロポレーション、直接DNA移入、および粒子ボンバードメントが挙げられるが、これに限定されない)によって生成し得るからである。DNAを単子葉植物および双子葉植物に導入するための技術は、このような植物の組織を培養するための技術およびこれらの組織を再生するための技術と同様に、当該分野で公知である。形質転換された細胞または組織からの全形質転換植物の再生は、全ての農学的に重要な作物を含むほとんどの植物属(単子葉植物と双子葉植物の両方)において達成されている。
ゲノムDNAサンプル、cDNAサンプルまたはRNAサンプルにおける変異を正確に検出するための遺伝子スクリーニング方法が、特定の状況に基づいて用いられ得る。多数の異なる方法が、点変異を検出するために用いられ、この方法としては、変性勾配ゲル電気泳動(「DGGE」)、制限酵素多型分析、化学的切断方法および酵素的切断方法などが挙げられる。現在使用されているより一般的な手順としては、PCRTMにより増幅された標的領域の直接スクリーニング、および一本鎖コンフォメーション多型分析(「SSCP」)が挙げられる。SSCPは、ゲル電気泳動における異なる配列の一本鎖核酸分子の異なる移動度に依存する。SSCP分析のための技術は、当該分野で周知である。
(ジンクフィンガー設計)
一対のZFNを、Drosophilaのyellow(y)遺伝子における染色体標的遺伝子座について設計しそして構築した。ジンクフィンガーは、一般的に、DNAのGリッチ領域に優先的に結合し、そして全ての5’−GNN−3’トリプレットに結合するフィンガーの大規模な研究が、行われている。結合部位は、ZFNによる有効な切断のために、互いに対して逆方向でなければならないため、Drosophila(y)の染色体標的遺伝子座を、(NNC)3...(GNN)3の形態の逆方向認識配列について検索した。このような部位は、成分9マー認識部位の間で6bpの間隔のエキソン2において同定され、これは、付加されたリンカーもスペーサーも結合ドメインと切断ドメインとの間に有さないZFNによる特異的認識および切断のために最適なスペーサーである。2つのZFNの特異的認識配列は、Bibikovaら、2002、Genetics 161:1169−1175に記載される。DNA配列である、5’−GCGGATGCG−3’(配列番号1)および5’−GCGGTAGCG−3’(配列番号2)を認識するジンクフィンガーをコードするDNAを、Drs.David SegalとCarlos Barbas(Scripps Research Institute,La Jolla,CA)から得た。次いで、このジンクフィンガーをコードするDNAを、変異誘発性PCRプライマーを使用して改変し、そして3つのジンクフィンガーの2セット(一方を、yA(y遺伝子標的の成分9マーの1つ(5’−GTGGATGAG−3’(配列番号3))を認識する)と呼び、そして他方を、yB(y遺伝子標的の他の成分9マー(5’−GCGGTAGGC−3’(配列番号4))を認識する)と呼ぶ)の各々を作成した。2つのフィンガーが、yAにおいて改変されたが、yBにおいては1つのフィンガーしか改変されなかった。ジンクフィンガーの得られた両方の3フィンガーセットの各々をコードするDNAを、DNA認識ドメインと切断ドメインとの間に介在リンカーDNAを有さない、pET15b発現プラスミド中のFokI DNA切断ドメインとインフレームにクローニングした。両方のキメラZFNタンパク質を発現させ、Niアフィニティクロマトグラフィーで精製し、そして完全y遺伝子を保有するpS/Gプラスミドを使用して、インビトロで切断活性について試験した。2つのZFNは共に、二本鎖切断(DSB)を、y遺伝子を保有する10.7kbのプラスミドDNA中の推定部位で構成した。
次いで、yA ZFNコード配列およびyB ZFNコード配列の両方を、改変phsp70プラスミドのBamHI部位とSalI部位との間にZFN DNAを挿入することによって、Drosophila Hsp70熱ショックプロモーターの後ろに別々にクローニングした。熱ショックプロモーターおよびZFN DNA配列を保有するフラグメントを、部分HindIII消化および完全ApaI消化によって切除し、そして市販のクローニングベクターであるpBluescript中のこれらの同じエンドヌクレアーゼ部位の間にクローニングした。挿入物の配列の確認の後、これを、NotIで消化することにより切り出し、そしてry+PエレメントベクターpDM30に挿入した。得られたyAプラスミドおよびyBプラスミドを、P−トランスポサーゼ発現プラスミドのpπ25.lwcと共に、v ry胚中に別々に注入し、そして孵化した成体を、交配させて、ry+生殖細胞系列形質転換体についてスクリーニングした。ry+挿入を、各ZFNを有する複数の独立した形質転換体に特異的な染色体に対してマッピングした。両方の平衡化したホモ接合性のストックを、ほとんどの場合に生存率の問題を有さず、yAおよびyBを保有するいくつかの株について作製した。2つのZFNの遺伝子を、(以下の実施例に記載されるようにして)成熟ハエの適切な交雑種と合わせ、そしてその子孫に、これらのハエが入ったガラス容器を35℃の水浴に1時間漬けることによって、交配の開始後4日で熱ショックを与えた。成体が孵化すると、これらを、体細胞y変異の証拠についてスクリーニングした。各ヌクレアーゼを含む交雑種由来のコントロール容器を、別々に熱ショックに供し、そしてyA+yBハエ(これは熱ショックを受けていない)もまたスクリーニングした。
熱ショックプロトコルから現れ、かつyAヌクレアーゼおよびyBヌクレアーゼの両方を保有する全てのハエを、交配して、潜在的生殖細胞系列変異を評価した。雄を、2または3匹の固定したX[C(1)DX]雌と交配し、そして得られた雄性子孫を、黄色の体色についてスクリーニングした。雌を、2または3匹のy(FM6)雄と交配し、そして両方の性の得られた子孫をスクリーニングした。変異種を同定し、そしてこれら全ては、雄性親に由来する雄であった。これらの同定された変異種の雄性子孫を、次いで、C(1)DX雌と交配して、同じ変異を保有するさらなる子孫を生成した。
標的DNAの存在または非存在を、DNA分析によって同定した。個々のハエを、フェノールとグリンド(grind)緩衝液(7Mの尿素、2%のSDS、10mMのTris、pH8.0、1mMのEDTA、0.35MのNaCl)の予め60℃に加熱した1:1混合物(100μl)中でホモジナイズした。各サンプルを、50μlのクロロホルムで抽出し、有機相を、100μlのグリンド緩衝液で逆抽出し、そして合わせた水相を、50μlのクロロホルムで再抽出した。DNAを、エタノールで沈殿させ、そして20μlの10mM Tris(pH8.5)中に再溶解した。600bpのDNAフラグメントを、yA+yB認識部位に隣接するプライマーを用いるPCRによって増幅させた。これらのプライマーを、YF2(5’ATTCCTTGTGTCCAAAATAATGAC−3’(配列番号5))およびYR3(5’−AAAATAGGCATATGCATCATCGC3’(配列番号6))と呼んだ。より大きな欠失について、YR3を、より遠い配列であるYF1(5’ATTTTGTACATATGTTCTTAAGCAG−3’(配列番号7))と共に使用した。増幅されたフラグメントを、ゲル電気泳動の後に回収し、そしてDNA配列を、ABI3700キャピラリーシーケンサーおよびYR3プライマーを用いて、University of Utah DNA Sequencing Core Facilityで決定した。
37℃で誘導されたyAの発現のレベルは、いくつかの独立した形質転換体において、幼虫期および胚期に適用された場合に致死性であることが見出された。熱ショックを35℃に調整することにより、かなりのyA保有ハエが生存できた。yB ZFNは、試験したいかなる温度でも生存度に影響しなかった。
生殖系列y変異を単離するために、いくつかの熱ショック実験からの全てのyA+yB雄を、固定したX染色体を保有する雌に交雑し[C(1)DX/Y]、父親のX染色体のみを受け取ることが知られる雄性子孫を生成させた。全体において、228の雄性父親が5,870の息子を生じ;13の異なる父親からの雄性子孫のうち26が、明らかに、全身を通してyであった。従って、yA+yB雄の父親の5.7%が、少なくとも1つの生殖系列変異体を生じた。13の父親のうち6が、y体斑を有するとして同定されたが、他の7は、診断的特徴において全体的にy+であるようであった。y雄に交雑した125の熱ショックyA+yB雌の7050の子孫間では、yハエは単離されなかった。ZFNは、雄性生殖系列において最も効率的にNHEJを介して変異を誘導する際に有効であるようである。
本実施例は、永久的な遺伝子変化を生じるために、例示のゲノム中の標的染色体遺伝子座においてDSBを生じるZFNが、設計され得ることを実証した。観察された身体変異の頻度は非常に高かったので、身体モザイクの実数はずっと高いものであり得る。なぜなら、y変異は、多くの可視的な特徴に対して影響を有しないからである。このことは、表現系的にy+の親からの生殖系列変異の回収によって確証され得る。
(ジンクフィンガーおよびドナーDNA設計)
実施例1に記載のようにDrosophilaの黄色(yellow)(y)遺伝子における染色体標的遺伝子座のために、一対のZFNを設計し、そして構築した。
標的化された遺伝子組み換え実験の設計は、以下の通りである:y+標的は、X染色体上にある。yA ZFNおよびyB ZFNのための導入遺伝子は、一方の第2染色体上にあり、FLPおよび/またはI−SceI(存在する場合)の導入遺伝子は、他方の第2染色体上にある。ドナーDNA(yM)は、白色(white)遺伝子(W+)もまた有するPエレメントベクター中の第3染色体上に位置する。これらの挿入された遺伝子の各々は、Drosophila HSP70プロモーターの制御下にある。熱ショック誘導の際に、ZFNは、yでそれらの標的を切断する。この破壊された染色体が野生型に回復され得るか、またはそれが、NHEJによるか、または相同組換えによるかのいずれかでy変異を獲得し得る。FLPもI−SceIも存在しない場合、ドナーは、組み込まれたままである。FLPが発現される場合、ドナーは、染色体外環として切り出される。I−SceIがまた発現される場合、それは、ドナーを末端のない線状分子(ends−out linear molecule)に変換し、これは、切断された標的遺伝子座と組み換え得る。yAおよびyBの存在しない場合にのみ(従って、標的を切断することなく)線状ドナーを用いた実験もまた行った。
ND、ドナーなし:yA+yBのみ;
ID、組み込まれたドナー:yA+yB+ドナー、FLPもI−SceIもなし;
CD、環状染色体外ドナー:yA+yB+FLP+ドナー;
LD、線状染色体外ドナー:yA+yB+FLP+I−SceI+ドナー;
DO、線状ドナーのみ:FLP+I−SceI+ドナー、但しZFNなし。
(標的化された変異の導入を刺激するためのArabidopsisにおけるキメラZFNの発現)
実験設計:本発明の方法は、Arabidopsis TRANSPARENT TESTA GLABRA1遺伝子(TTG1、遺伝子番号AT5G24520(GenBank番号AJ133743)を標的化し、そしてノックアウトするのに用いられる。この遺伝子のESTは配列決定されている(GenBank番号F20055,F20056)。この遺伝子は、WD40反復を含むタンパク質をコードする。
TTG1遺伝子を、以下の形状の配列について走査した:
NNY NNY NNY NNNNNN RNN RNN RNN
ここで、YはTまたはCのいずれかであり、RはAまたはGであり、そして、Nは任意の塩基である。この同定された配列は、AまたはGから対向する方向(すなわち対向する鎖に)で開始され、正確に6bp離れるトリプレットからなった。このことは、ジンクフィンガーヌクレアーゼの認識および切断のための好ましい構造であることが示されている。
5’−TCC GGT CAC AGA ATC GCC GTC GGA−3’(配列番号8)および5’−ACT TCC TTC GAT TGG AAC GAT GTA3’(配列番号9)(TTG1配列のヌクレオチド406)。
HS::ZnTTG1A遺伝子およびHS::ZnTTG1B遺伝子を、Agrobacterium媒介性形質転換を使用してArabidopsisのゲノムに導入する。こうするために、HS::ZnTTG1AおよびB遺伝子を、ハイグロマイシン耐性選択マーカーを有するAgrobacterium T−DNA形質転換ベクター(pCAMBIA1380)に挿入する。次いで、pCAMBIA HS::ZnTTG1クローンを、標準のAgrobacterium形質転換手順を用いてAgrobacterium細胞に導入し、次いで、HS::ZnTTG1AおよびHS::ZnTTG1B遺伝子を、標準の花浸漬方法を用いてArabidopsis植物に導入する。
T1世代からの種子を浸漬した植物から回収する。形質転換された実生を選択するために、T1種子を抗生物質(ハイグロマイシン)を含む寒天プレートに発芽させる。発芽の約4日後、発芽した実生を含むプレートをプラスチック製のラップで覆い、40℃の水に2時間浸し、ZFN遺伝子の発現を誘導する。発芽の約2週間後、ハイグロマイシン耐性の形質転換実生を土に移す。
(スクリーニング方法1:)
HS::ZnTTG1遺伝子を、野生型のArabidopsis植物に導入し、T1植物を上記のように加熱する。熱処理の1〜2週間後、組織サンプルを熱処理植物から回収し、この組織からDNAを抽出する。ジンクフィンガー標的部位に隣接する20bpのプライマー(標的部位の両側の25bp)を用いるPCR増幅を使用し、HS::ZnTTG1遺伝子が存在するかどうかを決定する。熱処理をしないコントロール植物からのPCRのバンドは、約90bpの大きさであるべきである。熱処理した植物からのPCRのバンドは、ジンクフィンガー標的部位の周囲の欠失の存在による90bpよりも小さい産物を含むべきである。小さい欠失の存在を検証するために、本発明者らは、より小さいPCR産物をクローニングし、そのDNA配列を決定する。
HS::ZnTTG1A遺伝子およびHS::ZnTTG1B遺伝を、野生型のArabidopsis植物に導入し、T1植物を上記のように熱処理する。T1植物を成熟まで成長させ、自家受粉を可能にし、T2種子を回収する。T2種子を寒天プレートで成長させ、これらを、以下に挙げる実生表現型についてスコア化する:無毛葉(無毛表現型)、より明るい葉(アントシアニンマイナス表現型)および上記のような根毛。変異体植物を、土に移してさらに成長させる。変異植物から組織を回収し、上記のようにPCRスクリーニングのための調製物にDNAを抽出する。簡単には、ジンクフィンガー標的部位に隣接するプライマーを用いてPCRを行う。約90bpの産物を示すサンプルは形質転換されていないが、90bp未満の産物を示すサンプルは形質転換されている。このことは、ジンクフィンガー標的部位の周囲の欠失の存在に起因する。さらに。小さな挿入またはより大きな欠失がまた、ジンクフィンガー標的部位の周囲に存在し得る。これらの発生の存在を検証するために、本発明者らは、より小さなPCR産物をクローニングし、そのDNA配列を決定する。
HS::ZnTTG1A遺伝子およびHS::ZnTTG1B遺伝子を、ヘテロ接合性のttg1変異体(すなわち、遺伝型ttg1/TTG1)に導入する。雄性不妊1(ms1)植物を、Agrobacterium溶液に導入する(注釈:ms1座とttg1座は連結しており、第5染色体上で6cM離れている)。次いで、浸漬した植物を、ホモ接合性のttg1−1植物由来の花粉で受粉させる。交雑した植物を成熟させ、得られたT1/F1種子を回収し、そして、T1/F1種子をハイグロマイシンの存在下で発芽させる。生き残ったT1/F1実生は、HS::ZnTTG1トランスジーンを有し、ttg1座でヘテロ接合性(すなわち、遺伝型MS1−−ttg1−1/ms1−−TTG1)である。T1/F1植物は、上記のように熱処理される。細胞のサブセットにおいて、野生型の対立遺伝子がノックアウトされ、ホモ接合性のttg1(すなわち、遺伝型ttg1−1/ttg1−ko)細胞のセクターが生じる。これらの変異体セクターは、いくつかの表現型(例えば、無毛の葉(無毛表現型)、明るい葉(アントシアニンマイナス表現型)および黄色種子(透明殻表現型))を可視化することにより検出可能(従って、標的化遺伝組換え事象)である。変異体セクターから組織を回収し、上で議論したPCR−クローニング−配列決定ストラテジーを使用して標的化を検証する。変異体セクターから、T2種子を回収し、T2植物に成長させる。T2世代において、表現型を検証する:ノックアウト対立遺伝子(すなわちttg1−ko)についてホモ接合性の植物はまた、ms1変異体についてもホモ接合性であり、従って、雄性不妊(すなわち、遺伝型ms1−−ttg1−ko/ms1−−ttg1−ko)である。二重変異体(表現型的にttg1およびms1)由来の組織を回収し、上で議論したPCR−クローニング−配列決定ストラテジーを使用して標的化について検証する。
Claims (21)
- 宿主の植物細胞または昆虫細胞における標的化された遺伝子組換え方法であって、該方法は、以下:
該宿主の植物細胞または昆虫細胞に、選択された宿主内因性標的遺伝子座に結合するように設計されたジンクフィンガーヌクレアーゼ(ZFN)をコードする核酸分子を導入する工程;
該宿主細胞内での該ZFNの発現を誘導する工程;および、
該選択された宿主内因性標的遺伝子座にて変異を示す、宿主細胞を同定する工程、
を包含する、方法。 - 前記変異は、遺伝物質の欠失、遺伝物質の挿入、ならびに遺伝物質の欠失および挿入からなる群より選択される、請求項1に記載の方法。
- ドナーDNAが標的化された遺伝子組換えにより前記宿主細胞のゲノム中に組み込まれるように該宿主細胞に該ドナーDNAを挿入する工程をさらに包含する、請求項1に記載の方法。
- 前記ドナーDNAは、前記宿主細胞中で産生される産物をコードする遺伝子配列を提供する、請求項3に記載の方法。
- 前記ドナーDNAは、タンパク質産物をコードする遺伝子配列を提供する、請求項4に記載の方法。
- 前記宿主細胞は、昆虫細胞である、請求項1に記載の方法。
- 前記宿主細胞は、植物細胞である、請求項1に記載の方法。
- 宿主の植物細胞または昆虫細胞における標的化された遺伝子組換え方法であって、該方法は、以下:
変異されるべき特定の宿主標的遺伝子座に優先的に結合し得るジンクフィンガーDNA結合ドメインを選択する工程;
該結合ドメインに作動可能に連結されて該宿主の植物細胞または昆虫細胞に導入された場合、二本鎖DNAを切断し得る、非特異的なDNA切断ドメインを選択する工程;
該宿主細胞における発現を誘導し得る誘導性制御エレメントを選択する工程;
該結合ドメインおよび該切断ドメインをコードするDNAと、該誘導性制御エレメントとを作動可能に連結して、DNA構築物を作製する工程;
該DNA構築物を標的宿主細胞に導入する工程;ならびに、
該宿主DNA中の該標的遺伝子座において組換えを示す少なくとも1つの宿主細胞を同定する工程、
を包含する、方法。 - ドナーDNAが標的化された遺伝子組換えにより前記宿主細胞のゲノム中に組み込まれるように該ドナーDNAを該宿主細胞に導入する工程をさらに包含する、請求項8に記載の方法。
- 前記ドナーDNAは、前記宿主細胞中で産生される産物をコードする遺伝子配列を提供する、請求項9に記載の方法。
- 前記ドナーDNAは、タンパク質産物をコードする遺伝子配列を提供する、請求項10に記載の方法。
- 前記DNA結合ドメインは、3つのジンクフィンガーから構成される、請求項8に記載の方法。
- 前記ジンクフィンガーは、Cys2His2ジンクフィンガーからなる群より選択される、請求項8に記載の方法。
- 前記切断ドメインは、II型制限エンドヌクレアーゼからなる群より選択される、請求項8に記載の方法。
- 前記II型制限エンドヌクレアーゼは、FokIである、請求項8に記載の方法。
- 前記制御エレメントは、熱ショック誘導性制御エレメントからなる群より選択される、請求項8に記載の方法。
- 前記宿主細胞は、昆虫細胞である、請求項9に記載の方法。
- 前記宿主細胞は、植物細胞である、請求項9に記載の方法。
- 前記DNA結合ドメインは、3つのジンクフィンガーから構成される、請求項9に記載の方法。
- 前記切断ドメインは、II型制限エンドヌクレアーゼからなる群より選択される、請求項9に記載の方法。
- 前記制御エレメントは、熱ショック誘導性制御エレメントからなる群より選択される、請求項9に記載の方法。
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WO2020026979A1 (ja) | 2018-07-31 | 2020-02-06 | 国立大学法人東京大学 | 膜タンパク質活性測定法 |
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WO2023038020A1 (ja) | 2021-09-07 | 2023-03-16 | 国立大学法人千葉大学 | 核酸配列改変用組成物および核酸配列の標的部位を改変する方法 |
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CN100575485C (zh) | 2009-12-30 |
JP2009195256A (ja) | 2009-09-03 |
US20120219959A1 (en) | 2012-08-30 |
US20110014601A2 (en) | 2011-01-20 |
BRPI0307383B1 (pt) | 2019-12-31 |
US20200231979A1 (en) | 2020-07-23 |
US9145565B2 (en) | 2015-09-29 |
ATE347593T1 (de) | 2006-12-15 |
AU2003251286A1 (en) | 2003-10-27 |
DE60310202T2 (de) | 2007-11-22 |
US20160076045A1 (en) | 2016-03-17 |
AU2003251286B2 (en) | 2007-08-16 |
JP2005519631A (ja) | 2005-07-07 |
DE60310202D1 (de) | 2007-01-18 |
EP1476547A4 (en) | 2005-08-17 |
WO2003087341A2 (en) | 2003-10-23 |
CA2474486C (en) | 2013-05-14 |
US8106255B2 (en) | 2012-01-31 |
WO2003087341A3 (en) | 2004-04-29 |
CA2474486A1 (en) | 2003-10-23 |
CN1622993A (zh) | 2005-06-01 |
US20050208489A1 (en) | 2005-09-22 |
EP1476547A2 (en) | 2004-11-17 |
EP1476547B1 (en) | 2006-12-06 |
BR0307383A (pt) | 2005-04-26 |
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