A NHEJ1 mutator allele influencing germline mutation rates sex-specifically in humans

Germline mutations play a pivotal role in evolution and are the primary cause of hereditary diseases in humans. Although interpopulation and interspecific variations in the mutation rate and spectrum are observed, their underlying genetic basis is still unclear. In this study, we explore the genetic regulation of germline mutation rates using one of the largest publicly available datasets derived from parent-offspring whole-genome sequencing. We first showed that germline mutation rates are strongly correlated between siblings, suggesting the influence of heritable factors. We then performed a genome-wide association study (GWAS), identifying 14 loci significantly associated with mutation rates, Notably, a lead single-nucleotide polymorphism (SNP) in the NHEJ1 gene, critical for DNA repair, was linked to a 27% increase in maternal mutation rates and a significant shift toward A-to-T mutations only in females. This mutator allele is particularly prevalent in East Asian populations, where a similar shift in the A-to-T mutation spectrum has been observed. Evolutionary analysis suggests that this allele likely emerged in the common ancestor of humans and the Pan genus. Furthermore, the genotype at the lead SNP position in Pan species is also the same as the human mutator allele, supporting the potential role for this allele to explain the accelerated A-to-T mutations observed in the human- Pan lineage. Together, these results indicate that genetic variants, particularly in DNA repair pathways, contribute to variation in mutation rates and spectra across individuals and populations, with a notable sex-specific effect.