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

TitlePopulation sequencing data reveal a compendium of mutational processes in the human germ line.
Publication TypeJournal Article
Year of Publication2021
AuthorsSeplyarskiy, 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, Y-DIda, Fuentes, Lde Las, Hwu, C-M, Rich, SS, Manichaikul, AW, Mychaleckyj, JC, Palmer, ND, Smith, JA, Kardia, SLR, Peyser, PA, Bielak, LF, O'Connor, TD, Emery, LS, Gilissen, C, Wong, WSW, Kharchenko, PV, Sunyaev, S
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Population Genetics Working Group
Date Published2021 Aug 27
KeywordsAlgorithms, CpG Islands, DNA Damage, DNA Demethylation, DNA Mutational Analysis, DNA Replication, Genetic Variation, Genome, Human, Germ Cells, Germ-Line Mutation, Humans, Long Interspersed Nucleotide Elements, Mutagenesis, Oocytes, Transcription, Genetic

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.

Alternate JournalScience
PubMed ID34385354
PubMed Central IDPMC9217108
Grant ListR01 HL120393 / HL / NHLBI NIH HHS / United States
U01 DK062413 / DK / NIDDK NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
R01 HL131768 / HL / NHLBI NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
R35 GM127131 / GM / NIGMS NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 HG010372 / HG / NHGRI NIH HHS / United States

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