Distância da África-Subsaariana prediz carga mutacional em diversos genomas humanos

quarta-feira, janeiro 20, 2016

Distance from sub-Saharan Africa predicts mutational load in diverse human genomes

Brenn  M. Henn a,1,2, Laura R. Botigué a,1, Stephan Peischl b,c,d,1, Isabelle Dupanloup b, Mikhail Lipatov a, Brian K. Maples e, Alicia R. Martine, Shaila Musharoff e, Howard Cann f,3, Michael P. Snyder e, Laurent Excoffier b,c,4, Jeffrey M. Kidd g,4, and Carlos D. Bustamante e,2,4

aDepartment of Ecology and Evolution, Stony Brook University, The State University of New York, Stony Brook, NY 11794;

bInstitute of Ecology and Evolution, University of Berne, 3012 Berne, Switzerland;

cSwiss Institute of Bioinformatics, 1015 Lausanne, Switzerland;

dInterfaculty Bioinformatics Unit, University of Berne, 3012 Berne, Switzerland;

eDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305;

fCentre d’Etude du Polymorphisme Humain, Foundation Jean Dausset, 75010 Paris, France;

gDepartment of Human Genetics and Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109

Edited by Charles F. Aquadro, Cornell University, Ithaca, NY, and accepted by the Editorial Board November 13, 2015 (received for review June 9, 2015)


Human genomes carry hundreds of mutations that are predicted to be deleterious in some environments, potentially affecting the health or fitness of an individual. We characterize the distribution of deleterious mutations among diverse human populations, modeled under different selection coefficients and dominance parameters. Using a new dataset of diverse human genomes from seven different populations, we use spatially explicit simulations to reveal that classes of deleterious alleles have very different patterns across populations, reflecting the interaction between genetic drift and purifying selection. We show that there is a strong signal of purifying selection at conserved genomic positions within African populations, but most predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa.


The Out-of-Africa (OOA) dispersal ∼50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive.

mutation founder effect range expansion expansion load purifying selection


1B.M.H., L.R.B., and S.P. contributed equally to this work.

2To whom correspondence may be addressed. Email: brenna.henn{at}stonybrook.edu or cdbustam{at}stanford.edu.

3Deceased May 3, 2014.

4L.E., J.M.K., and C.D.B. contributed equally to this work.

Author contributions: B.M.H., M.P.S., L.E., J.M.K., and C.D.B. designed research; B.M.H., L.R.B., S.P., and J.M.K. performed research; S.P., H.C., and L.E. contributed new reagents/analytic tools; B.M.H., L.R.B., S.P., I.D., M.L., B.K.M., A.R.M., S.M., and J.M.K. analyzed data; and B.M.H., L.R.B., S.P., L.E., J.M.K., and C.D.B. wrote the paper.

Conflict of interest statement: C.D.B. is the founder of IdentifyGenomics, LLC, and is on the scientific advisory boards of Personalis, Inc. and Ancestry.com as well as the medical advisory board InVitae. None of this played a role in the design, execution, or interpretation of experiments and results presented here.

This article is a PNAS Direct Submission. C.F.A. is a guest editor invited by the Editorial Board.

Data deposition: The sequence reported in this paper has been deposited in the NCBI Sequence Read Archive (accession no. SRP036155).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1510805112/-/DCSupplemental.