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Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis.

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Peer-reviewed

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Authors

Bernstein, Nicholas 
Spencer Chapman, Michael  ORCID logo  https://orcid.org/0000-0002-5320-8193
Chen, Zhenghao 

Abstract

Human aging is marked by the emergence of a tapestry of clonal expansions in dividing tissues, particularly evident in blood as clonal hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations in a set of established genes. However, the majority of clones lack known drivers. Here we infer gene-level positive selection in whole blood exomes from 200,618 individuals in UK Biobank. We identify 17 additional genes, ZBTB33, ZNF318, ZNF234, SPRED2, SH2B3, SRCAP, SIK3, SRSF1, CHEK2, CCDC115, CCL22, BAX, YLPM1, MYD88, MTA2, MAGEC3 and IGLL5, under positive selection at a population level, and validate this selection pattern in 10,837 whole genomes from single-cell-derived hematopoietic colonies. Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.

Description

Acknowledgements: We thank N. Rubinstein, E. Sorokin, M. Cule, C. Connelly, E. Melamud and F. Harding for their feedback and guidance. UKBB analysis was funded by Calico Life Sciences LLC and conducted under UKBB application 18448. J.N. is a Cancer Research UK (CRUK) Advanced Clinician Scientist Fellow. K.N. is supported by CRUK and the Wellcome Trust. Work in the Nangalia lab is supported by CRUK, Wellcome core funding at Wellcome Sanger Institute, Alborada Trust and Rosetrees Trust.


Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289


Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440


Funder: Calico


Funder: Alborada Trust; doi: https://doi.org/10.13039/100008288

Keywords

Humans, Mutation, Clonal Hematopoiesis, Aging, Aged, Selection, Genetic, Male, Middle Aged, Adult, Female, Exome

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

56

Publisher

Springer Science and Business Media LLC