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

Science
Authors
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.

Year of Publication
2021
Journal
Science
Volume
373
Issue
6558
Pages
1030-1035
Date Published
2021 Aug 27
ISSN
1095-9203
DOI
10.1126/science.aba7408
PubMed ID
34385354
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