Distinct Mutational Processes Influence Germline DNA Mutations

Although the processes of DNA replication and repair and the errors in these processes that lead to mutagenesis have been extensively studied, this research has not addressed the mechanisms by which germline DNA mutations are acquired. Mutational processes are not constant throughout the genome, with some loci being more susceptible than others and some also exhibiting DNA strand bias. Using nonnegative matrix factorization analysis of the TOPMed sequencing dataset, containing 292 million rare single nucleotide variants from 42,813 individuals, Seplyarskiy, Soldatov, and colleagues described 14 components associated with 9 distinct processes which are responsible for the variation of mutational spectra and rate between loci. Five processes were identified to be DNA strand–dependent and 4 were strand-independent, and plausible biological explanations could be provided for 7 of 9 processes. Process 1/2 featured bulky DNA lesions affecting DNA asymmetrically and was almost absent in early development. Process 3/4 was described to capture asymmetric replication errors, process 5/6 had an increased intensity on nontranscribed strands with LINE repeats, and process 7 was correlated with chromatin structuring and replication timing and was more active in early development. Process 8/9 featured C>G transversion mutations and was linked to transcription-associated mutagenesis in oocytes. Process 10 was characterized by CpG transitions to TpG and was contingent on methylation level, and process 11 was characterized by CpG transversions likely caused by enzymatic demethylation and was most active in CpG islands and during very early zygotic development. The mechanism underlying the remaining two processes, which were responsible for only a tiny fraction of mutations in the dataset, could not be determined. These findings provide new insight into the mechanisms underlying germline mutation acquisition in the human genome.

Seplyarskiy VB, Soldatov RA, Koch E, McGinty RJ, Goldmann JM, Hernandez RD, et al. Population sequencing data reveal a compendium of mutational processes in the human germ line. Science 2021; 373:1030–5.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.