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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-D I, 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 08 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
Grant ListR35 GM127131 / GM / NIGMS NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
R01 HG010372 / HG / NHGRI NIH HHS / United States
R01 HL131768 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States