単一分子解像度での体質変異の風景

Federico Abascal¹, Luke M R Harvey¹, Emily Mitchell^1,2

¹Wellcome Sanger Institute, Hinxton, UK.

Nature

|April 29, 2021

まとめ

体内の変異つまり細胞のDNAの変化は癌や老化の鍵となります新しいナノレートシーケンシング (NanoSeq) は,単細胞でのこれらの変異の検出を可能にし,組織変異の洞察を明らかにします.

科学分野:

遺伝学
分子生物学
癌研究

背景:

体内の突然変異は癌や老化や病気の発生に重要な役割を果たします
単細胞での低頻度の体内変異の検出は,特定の組織への研究を制限する重要な課題でした.
多様な細胞タイプと状態における体内変異の理解は不可欠である.

研究の目的:

低頻度の体変異を検出するための非常に敏感なシーケンシング方法を開発する.
非分裂細胞を含む様々な組織における体変異負荷とシグネチャーを調査する.
分裂する vs 分裂しない細胞と分化した vs 幹細胞の変異を比較する.

主な方法:

ナノレートシーケンシング (NanoSeq) の開発,二重シーケンシングプロトコル.
単一分子レベルで超低誤差率 (<5誤差/億塩基対) を達成する.
NanoSeqの適用は,幹細胞,分化細胞,ニューロン,および滑らかな筋肉の体内の変異を研究する.

主要な成果:

NanoSeqは,クローナリティとは関係なく,どんな組織でも体内の変異を研究することができます.
分化された血液と結腸細胞は,細胞分裂歴に関係なく,幹細胞と似た変異負荷とシグネチャを示している.
転移後の神経細胞と滑らかな筋肉細胞は,転移後活性組織と比べて,生涯を通じて一定の速度で体内の変異を蓄積する.

結論:

細胞分裂は体変異の唯一の要因ではなく,分裂に依存しない過程が重要な要因である.
体の変異は神経細胞のように分裂しない細胞に絶えず蓄積されます
単一分子DNA変異を検出する能力は,体内の変異性の研究に革命をもたらし,大規模な非侵襲的なコホート研究を可能にします.

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