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

Mark Lipson, Po-Ru Loh, Sriram Sankararaman, Nick Patterson, Bonnie Berger, David Reich
doi: https://doi.org/10.1101/015560
Mark Lipson
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: mlipson@genetics.med.harvard.edu reich@genetics.med.harvard.edu
Po-Ru Loh
2Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA
3Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Sriram Sankararaman
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
3Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Nick Patterson
3Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Bonnie Berger
3Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Department of Mathematics and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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David Reich
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
3Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
5Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: mlipson@genetics.med.harvard.edu reich@genetics.med.harvard.edu
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Abstract

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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 13, 2015.
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Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes
Mark Lipson, Po-Ru Loh, Sriram Sankararaman, Nick Patterson, Bonnie Berger, David Reich
bioRxiv 015560; doi: https://doi.org/10.1101/015560
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Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes
Mark Lipson, Po-Ru Loh, Sriram Sankararaman, Nick Patterson, Bonnie Berger, David Reich
bioRxiv 015560; doi: https://doi.org/10.1101/015560

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