Author:
Seplyarskiy Vladimir B.,Soldatov Ruslan A.,McGinty Ryan J.,Goldmann Jakob M.,Hernandez Ryan,Barnes Kathleen,Correa Adolfo,Burchard Esteban G.,Ellinor Patrick T.,McGarvey Stephen T.,Mitchell Braxton D.,Ramachandran Vasan S.,Redline Susan,Silverman Edwin,Weiss Scott T.,Arnett Donna K.,Blangero John,Boerwinkle Eric,He Jiang,Montgomery Courtney,Rao D.C.,Rotter Jerome I.,Brody Jennifer A,Ida Chen Yii-Der,de las Fuentes Lisa,Hwu Chii-Min,Rich Stephen S.,Manichaikul Ani W.,Mychaleckyj Josyf C.,Palmer Nicholette D.,Smith Jennifer A.,Kardia Sharon L.R.,Peyser Patricia A.,Bielak Lawrence F.,O’Connor Timothy D.,Emery Leslie S.,Gilissen Christian,Wong Wendy S.W.,Kharchenko Peter V.,Sunyaev Shamil, ,
Abstract
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.
Publisher
Cold Spring Harbor Laboratory