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Germline Mutagenesis Traced Back to Meiotic Breaks, Error-Prone Repair

NEW YORK – New research has highlighted the extent to which double-strand DNA breaks (DSBs) that arise during meiosis — and the processes used to repair them — contribute to mutagenesis in the human germline.

"Despite the central role of meiotic DSBs in generating eggs and sperm, their impact on de novo mutation is not well understood," senior and corresponding author Anjali Hinch, a group leader and Sir Henry Dale and Wellcome-Beit fellow at the University of Oxford's Wellcome Centre for Human Genetics, and her colleagues wrote in a paper appearing in Science on Thursday, noting that "much remains unknown about the range of repair pathways used."

Building on prior studies centered on the consequences of specific crossover events in egg and sperm cells undergoing meiotic cell division, Hinch and colleagues from the University of Oxford's Wellcome Centre for Human Genetics, the Big Data Institute, and Genomics plc set out to map mutations in relation to meiotic recombination hotspots, recognizing that meiotic DSBs tend to turn up at recombination hotspots in the genome.

"Previous work looked only at the particular outcome of crossovers, which represent a small minority of breaks, on single-base changes," Hinch said in an email. "We show that those are only the tip of the iceberg with the full impact of meiotic breaks being almost an order of magnitude higher."

For their analyses, investigators brought together data from population genomic datasets — including genetic variant profiles from version 3.0 of the gnomAD database and de novo mutation and crossover data for nearly 3,000 parent-child trios from Iceland — to map 341 million SNPs, 64 million small insertions or deletions, and half a million structural variants at the base-pair level, setting them against almost 28,300 human recombination hotspots.

"These high-resolution maps enable us to characterize sequence properties of mutations and compare their footprints with the localization of distinct molecular processes taking place within hotspots," the authors explained. "They reveal the scale of mutagenesis and link it with particular DNA repair processes, thereby providing new insights on the nature, impacts, and mechanisms of these errors in the human germ line."

In particular, the investigators estimated that meiotic break repair-related mutations lead to de novo single-based substitutions in roughly one quarter of sperm cells and in around one in a dozen egg cells. They also described a boost in small insertions and deletions or structural variants around meiotic DSB sites on autosomal chromosomes — an effect that was more pronounced and produced specific mutation patterns on X chromosomes, where they saw an overrepresentation of deletions.

In contrast, short insertions and structural variant insertions tended to turn up near recombination hotspots. By bringing in data from gnomAD and ClinVar, the team narrowed in on 77 indels and 206 structural variants suspected of stemming from meiotic breaks that are classified as predicted loss-of-function changes in genes implicated in autosomal or X-linked conditions.

"One implication is that making eggs and sperm is an inherently dangerous process, which can lead to mutations in the DNA that our children inherit from us," Hinch explained. "These mutations increase their risk of many diseases including inborn developmental disorders, therefore it is important to understand what causes them."

"Many of the processes that underlie these mutations also cause mutations in cancers," Hinch added, "and our work provides a novel and detailed window of how errors are introduced in DNA in general."

Together with findings from chromatin immunoprecipitation sequencing experiments on mouse testes tissue, the team's mutation map pointed to activity by error-prone DNA repair mechanisms in response to DNA breaks occurring in meiosis.

"Repair of meiotic breaks is a significant, direct, and underappreciated source of human de novo mutation," the authors wrote. "We provide evidence that these mutations are generated through a compendium of error-prone repair mechanisms that have hitherto been thought to be unused or suppressed in meiosis."