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

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.

Automated summary

The study utilized nonnegative matrix factorization to uncover the biological mechanisms of human germline mutations. Analysis of a sequencing dataset revealed nine processes explaining the variation in mutation properties between loci, including bulky DNA lesions, replication direction and timing, among others. This research identified mutagenic effects of active demethylation, long interspersed nuclear elements, and a specific mutagenic process in oocytes.