RT Journal Article SR Electronic T1 Population sequencing data reveal a compendium of mutational processes in human germline JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.10.893024 DO 10.1101/2020.01.10.893024 A1 Vladimir B. Seplyarskiy A1 Ruslan A. Soldatov A1 Ryan J. McGinty A1 Jakob M. Goldmann A1 Ryan Hernandez A1 Kathleen Barnes A1 Adolfo Correa A1 Esteban G. Burchard A1 Patrick T. Ellinor A1 Stephen T. McGarvey A1 Braxton D. Mitchell A1 Vasan S. Ramachandran A1 Susan Redline A1 Edwin Silverman A1 Scott T. Weiss A1 Donna K. Arnett A1 John Blangero A1 Eric Boerwinkle A1 Jiang He A1 Courtney Montgomery A1 D.C. Rao A1 Jerome I. Rotter A1 Jennifer A Brody A1 Yii-Der Ida Chen A1 Lisa de las Fuentes A1 Chii-Min Hwu A1 Stephen S. Rich A1 Ani W. Manichaikul A1 Josyf C. Mychaleckyj A1 Nicholette D. Palmer A1 Jennifer A. Smith A1 Sharon L.R. Kardia A1 Patricia A. Peyser A1 Lawrence F. Bielak A1 Timothy D. O’Connor A1 Leslie S. Emery A1 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium A1 TOPMed Population Genetics Working Group A1 Christian Gilissen A1 Wendy S.W. Wong A1 Peter V. Kharchenko A1 Shamil Sunyaev YR 2020 UL http://biorxiv.org/content/early/2020/01/11/2020.01.10.893024.abstract AB Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.