Determinants of de novo mutations in extended pedigrees of 43 dog breeds

Abstract

Understanding the determinants of de novo mutation is critical for elucidating evolutionary processes and genetic disease susceptibility. But the interplay between life history, genomic architecture, and recombination remains poorly understood in non-model species. Domestic dogs, lacking the recombination regulator PRDM9 and subject to intense artificial selection, offer a unique system for dissecting factors that jointly influence mutation accumulation. Here, we leverage large-scale trio sequencing to unravel the determinants of de novo mutations across diverse dog breeds. By analyzing 390 trios from 43 breeds, we estimate a germline mutation rate of 4.89 × 10−9 per base pair per generation. Parental age, especially paternal age, strongly influences mutation rates, with a 1.5-fold greater paternal age effect in dogs compared to humans. Larger breeds exhibit elevated early-life mutations, aligning with accelerated developmental trajectories. Strikingly, CpG Islands in dogs exhibit a 2.6-fold higher mutation rate than the genomic average, unlike humans where no such increase occurs. We also find a tenfold hypermutated dog and suggest a unique maternal mechanism of MLH1-mediated germline instability during gametogenesis. The unique mutational landscape in canids is determined by paternal age, body size, and CpG Islands recombination. Despite extensive breeding, germline mutation rates in dogs remain stable across breeds. The elevated mutation rate in CpG Islands due to recombination in the absence of PRDM9 underscores a distinct evolutionary mechanism in canids. These findings enhance our understanding of mutation dynamics, with implications for canine genetic diversity, disease susceptibility, and broader genomic studies in species lacking PRDM9.