Population sequencing data reveal a compendium of mutational processes in the human germ line
Vladimir B. Seplyarskiy, Ruslan Soldatov, Evan Koch, Ryan J. McGinty, Jakob M. Goldmann, Ryan D. Hernandez, Kathleen C. Barnes, Adolfo Correa, Esteban G. Burchard, Patrick T. Ellinor, Stephen T. McGarvey, Braxton D. Mitchell, Ramachandran S. Vasan, Susan Redline, Edwin K. Silverman, Scott T. Weiss, Donna K. Arnett, John Blangero, Eric Boerwinkle, Jiang He, Courtney G. Montgomery, D. C. Rao, Jerome I. Rotter, Kent D. Taylor, Jennifer A. Brody, Yii‐Der Ida Chen, Lisa de las Fuentes, Chii‐Min Hwu, Stephen S. Rich, Ani Manichaikul, Josyf C. Mychaleckyj, Nicholette D. Palmer, Jennifer A. Smith, Sharon L. R. Kardia, Patricia A. Peyser, Lawrence F. Bielak, Timothy D. O’Connor, Leslie S. Emery, TOPMed Population Genetics Working Group, Christian Gilissen, Wendy S.W. Wong, Peter V. Kharchenko, Shamil Sunyaev
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.