Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes

The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 ± 0.13 × 10−8 mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes.Author Summary: The rate at which new heritable mutations occur in the human genome is a fundamental parameter in population and evolutionary genetics. However, recent direct family-based estimates of the mutation rate have consistently been much lower than previous results from comparisons with other great ape species. Because split times of species and populations estimated from genetic data are often inversely proportional to the mutation rate, resolving the disagreement would have important implications for understanding human evolution. In our work, we apply a new technique that uses mutations that have accumulated over many generations on either copy of a chromosome in an individual’s genome. Instead of an external reference point, we rely on fine-scale knowledge of the human recombination rate to calibrate the long-term mutation rate. Our procedure accounts for possible errors found in real data, and we also show that it is robust to a range of model violations. Using eight diploid genomes from non-African individuals, we infer a rate of 1.61 ± 0.13 × 10−8 single-nucleotide changes per base per generation, which is intermediate between most phylogenetic and pedigree-based estimates. Thus, our estimate implies reasonable, intermediate-age population split times across a range of time scales.