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PLoS Genet. 2015 Nov 12;11(11):e1005550. doi: 10.1371/journal.pgen.1005550. eCollection 2015 Nov.

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

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Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
Department of Mathematics and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America.


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.

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