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

Vladimir B. Seplyarskiy, Ruslan A. Soldatov, Evan Koch, Ryan J. McGinty, Jakob M. Goldmann, Ryan D. Hernandez, Kathleen Barnes, Adolfo Correa, Esteban G. Burchard, Patrick T. Ellinor, Stephen T. McGarvey, Braxton D. Mitchell, Ramachandran S. Vasan, Susan Redline, Edwin Silverman, Scott T. Weiss, Donna K. Arnett, John Blangero, Eric Boerwinkle, Jiang HeCourtney 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 W. 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, Christian Gilissen, Wendy S.W. Wong, Peter V. Kharchenko, Shamil Sunyaev

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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.

Original languageEnglish
Pages (from-to)1030-1035
Number of pages6
Issue number6558
StatePublished - Aug 27 2021


Dive into the research topics of 'Population sequencing data reveal a compendium of mutational processes in the human germ line'. Together they form a unique fingerprint.

Cite this