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The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.


ABSTRACT: Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

SUBMITTER: Weinstock JS 

PROVIDER: S-EPMC10132750 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.

Weinstock Joshua S JS   Laurie Cecelia A CA   Broome Jai G JG   Taylor Kent D KD   Guo Xiuqing X   Shuldiner Alan R AR   O'Connell Jeffrey R JR   Lewis Joshua P JP   Boerwinkle Eric E   Barnes Kathleen C KC   Chami Nathalie N   Kenny Eimear E EE   Loos Ruth J F RJF   Fornage Myriam M   Redline Susan S   Cade Brian E BE   Gilliland Frank D FD   Chen Zhanghua Z   Gauderman W James WJ   Kumar Rajesh R   Grammer Leslie L   Schleimer Robert P RP   Psaty Bruce M BM   Bis Joshua C JC   Brody Jennifer A JA   Silverman Edwin K EK   Yun Jeong H JH   Qiao Dandi D   Weiss Scott T ST   Lasky-Su Jessica J   DeMeo Dawn L DL   Palmer Nicholette D ND   Freedman Barry I BI   Bowden Donald W DW   Cho Michael H MH   Vasan Ramachandran S RS   Johnson Andrew D AD   Yanek Lisa R LR   Becker Lewis C LC   Kardia Sharon S   He Jiang J   Kaplan Robert R   Heckbert Susan R SR   Smith Nicholas L NL   Wiggins Kerri L KL   Arnett Donna K DK   Irvin Marguerite R MR   Tiwari Hemant H   Correa Adolfo A   Raffield Laura M LM   Gao Yan Y   de Andrade Mariza M   Rotter Jerome I JI   Rich Stephen S SS   Manichaikul Ani W AW   Konkle Barbara A BA   Johnsen Jill M JM   Wheeler Marsha M MM   Custer Brian S BS   Duggirala Ravindranath R   Curran Joanne E JE   Blangero John J   Gui Hongsheng H   Xiao Shujie S   Williams L Keoki LK   Meyers Deborah A DA   Li Xingnan X   Ortega Victor V   McGarvey Stephen S   Gu C Charles CC   Chen Yii-Der Ida YI   Lee Wen-Jane WJ   Shoemaker M Benjamin MB   Darbar Dawood D   Roden Dan D   Albert Christine C   Kooperberg Charles C   Desai Pinkal P   Blackwell Thomas W TW   Abecasis Goncalo R GR   Smith Albert V AV   Kang Hyun M HM   Mathias Rasika R   Natarajan Pradeep P   Jaiswal Siddhartha S   Reiner Alexander P AP   Bick Alexander G AG  

Science advances 20230426 17


Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased wit  ...[more]

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