Relationships between germline mutation rates and reproductive success in the collaborative cross mice
Authors: Alexis Garretson 1,2; Beth Dumont 1,2
Affiliations: 1) The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME; 2) Graduate School of Biomedical Sciences, Tufts University, Boston, MA
Keywords: Complex traits
The mutation rate is a critical genomic parameter, as germline mutations are the cause of heritable genetic disorders and the ultimate source of evolutionary novelty. The germline mutation rate is a complex trait, but we know little about how it is modified by heritable genetic features. In humans, elevated mutational burdens have been tentatively linked to reproductive capacity, with higher mutation rates associated with lower reproductive success and earlier age at last birth. However, the phenotypic effects of natural variation in mutation rates are incompletely understood. We expect elevated mutation rates in mice will be associated with lower breeding success and more rapid decline in reproductive capacity during aging, and we hypothesize shared genetic mechanisms related to DNA damage repair. Here we harness the breeding funnel design of the Collaborative Cross (CC) mouse population, analogous to a mutation accumulation experiment, to study the accumulation of mutations over ~30 generations of organized inbreeding and evaluate associations between mutation rate and phenotypic diversity. Using a powerful pan-genome, graph-based variant caller applied to publicly available whole-genome sequences for 69 completed CC strains, we comprehensively identify de novo mutations specific to each CC line and absent from the eight founder strains. Overall, we identify ~11,000 DNMs, including many with projected functional effects. The per generation rate of mutation accumulation varies 11-fold among strains, above simulated expectations. These findings suggest the presence of mutation rate modifiers segregating among the 8 CC founder strains. To explore the broader phenotypic consequences of this diversity, we assessed correlations between strain-level mutation rates and trait values, focusing on phenotypes related to reproduction and fertility. We find a negative relationship between reproductive capacity metrics, including the average litter size, the interbirth interval, and the age at the first litter. We also find a negative relationship between mutation rates and reproductive capacity, with higher mutation rates associated with a more rapid increase in the interbirth interval and a more rapid decrease in the litter size as the mice age. Overall, we demonstrate that germline mutation rates in healthy mice are related to reproductive aging and may suggest shared genetic mechanisms underpin variation in mutation rate and fertility.