Population sequencing data reveal a compendium of mutational processes in the human germ line.

Pubmed ID: 34385354

Pubmed Central ID: PMC9217108

Journal: Science (New York, N.Y.)

Publication Date: Aug. 27, 2021

MeSH Terms: Humans, Algorithms, Genome, Human, Mutagenesis, Transcription, Genetic, Genetic Variation, CpG Islands, DNA Damage, DNA Demethylation, DNA Mutational Analysis, DNA Replication, Germ Cells, Germ-Line Mutation, Long Interspersed Nucleotide Elements, Oocytes

Grants: R01 HL120393, R01 HL117626, R35 HL135818, R35 GM127131, R01 MH101244, U01 HG009088, R01 HG010372, R01 HL131768, HHSN268201800001C, U01 DK062413

Authors: McGarvey ST, Vasan RS, He J, Mitchell BD, de Las Fuentes L, Rich SS, Boerwinkle E, Taylor KD, Rotter JI, Brody JA, Correa A, Arnett DK, Smith JA, Rao DC, Chen YI, Blangero J, Mychaleckyj JC, Palmer ND, Bielak LF, Peyser PA, Redline S, Koch E, Ellinor PT, Weiss ST, Montgomery C, Seplyarskiy VB, Soldatov RA, McGinty RJ, Goldmann JM, Hernandez RD, Barnes K, Burchard EG, Silverman E, Hwu CM, Manichaikul AW, Kardia SLR, O'Connor TD, Emery LS, Gilissen C, Wong WSW, Kharchenko PV, Sunyaev S

Cite As: Seplyarskiy VB, Soldatov RA, Koch E, McGinty RJ, Goldmann JM, Hernandez RD, Barnes K, Correa A, Burchard EG, Ellinor PT, McGarvey ST, Mitchell BD, Vasan RS, Redline S, Silverman E, Weiss ST, Arnett DK, Blangero J, Boerwinkle E, He J, Montgomery C, Rao DC, Rotter JI, Taylor KD, Brody JA, Chen YI, de Las Fuentes L, Hwu CM, Rich SS, Manichaikul AW, Mychaleckyj JC, Palmer ND, Smith JA, Kardia SLR, Peyser PA, Bielak LF, O'Connor TD, Emery LS, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Population Genetics Working Group, Gilissen C, Wong WSW, Kharchenko PV, Sunyaev S. Population sequencing data reveal a compendium of mutational processes in the human germ line. Science 2021 Aug 27;373(6558):1030-1035. Epub 2021 Aug 12.

Studies:

Abstract

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.