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

Science. 2021 Aug 27;373(6558):1030-1035. doi: 10.1126/science.aba7408. Epub 2021 Aug 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • CpG Islands
  • DNA Damage
  • DNA Demethylation
  • DNA Mutational Analysis
  • DNA Replication
  • Genetic Variation
  • Genome, Human*
  • Germ Cells
  • Germ-Line Mutation*
  • Humans
  • Long Interspersed Nucleotide Elements
  • Mutagenesis
  • Oocytes / physiology
  • Transcription, Genetic