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研究分野生物医学と臨床科学腫瘍学とがん発生分子標的
ヒトの機能喪失による遺伝的変異による薬物標的の評価

ヒトの機能喪失による遺伝的変異による薬物標的の評価

Eric Vallabh Minikel ^{1,2,3,4,5,6,7,8}, Konrad J Karczewski ^9,10, Hilary C Martin ¹¹, Beryl B Cummings ^9,10,12, Nicola Whiffin ^9,13, Daniel Rhodes ¹⁴, Jessica Alföldi ^9,10, Richard C Trembath ¹⁵, David A van Heel ¹⁶, Mark J Daly ^9,10, , , Stuart L Schreiber ^17,18, Daniel G MacArthur ^19,20,21,22

Eric Vallabh Minikel ^{1,2,3,4,5,6,7,8}, Konrad J Karczewski ^9,10, Hilary C Martin ¹¹

¹Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eminikel@broadinstitute.org.
²Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eminikel@broadinstitute.org.
³Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eminikel@broadinstitute.org.
⁴Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. eminikel@broadinstitute.org.
⁵Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA. eminikel@broadinstitute.org.
⁶Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA. eminikel@broadinstitute.org.
⁷Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. eminikel@broadinstitute.org.
⁸Prion Alliance, Cambridge, MA, USA. eminikel@broadinstitute.org.
⁹Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹¹Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.
¹²Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
¹³National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.
¹⁴Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, UK.
¹⁵School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
¹⁶Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁷Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁸Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA.
¹⁹Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. d.macarthur@garvan.org.au.
²⁰Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. d.macarthur@garvan.org.au.
²¹Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia. d.macarthur@garvan.org.au.
²²Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia. d.macarthur@garvan.org.au.

⁰Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eminikel@broadinstitute.org.

Nature +

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2020年5月29日

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PubMedで要約を見る

まとめ

この要約は機械生成です。

ヒトの遺伝的変異は遺伝子機能や薬の開発の洞察力を提供します重要な遺伝子は薬の標的になるかもしれませんが

科学分野

遺伝学
薬理学について
人間生物学

背景

自然に発生するヒトの遺伝子変異は,遺伝子不活性化のための in vivo モデルとして機能します.
これらの変種は,細胞およびモデル生物系における伝統的なノックアウト研究を補完します.
薬剤候補の標的の評価は,人間の機能喪失の変種によって決定される.

研究の目的

薬物の標的を特定し,検証する際に,人間の機能喪失の変種の有用性を評価する.
薬の標的として機能の喪失に耐えられない遺伝子の可能性を探求するためです
ヒトの遺伝子ノックアウトの遺伝子型に基づく識別の可能性を評価する.

主な方法

自然に発生するヒトの遺伝子変異の分析はタンパク質をコードする遺伝子を不活性化すると予測されています
抑制薬の標的としての生存可能性に関する重要な遺伝子の評価
ホモジゴスまたは複合ヘテロジゴス個体の遺伝子型に基づく確認のための変種希少性の評価.
マニュアルキュレーションで補完された自動化された変数アノテーションとフィルタリングを使用します.

主要な成果

機能の喪失に対する不耐性にもかかわらず重要な遺伝子は効果的な薬の標的となり得ます
ホモジゴスまたは複合ヘテロジゴス"ノックアウト"の人間を特定するには,血縁集団に焦点を当てない限り,かなり大きなサンプルサイズ (現在の1,000倍) が必要です.
自動化された変種アノテーションは強力ですが,精度および遺伝子型によるリコール研究には手動キュレーションが不可欠です.

結論

人間の機能喪失の変種は,薬物標的の評価に価値があります.
ヒトでのノックアウト研究のためのロードマップが提供され,薬物開発の解釈を導く.
薬学研究における遺伝的多様性を活用する戦略を強調しています.

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