The impact of recent human demography on deleterious mutation load and the genetic architecture of disease susceptibility. G. Sella1, 2, Y. Simons1, M. C. Turchin3, J. K. Pritchard3,4 1) Department of Ecology, Evolution, and Behavior, Hebrew University of Jerusalem, Jerusalem, Israel; 2) Department of Biological Sciences, Columbia University, New York, United States of America. (as of Oct 1st); 3) Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America; 4) Howard Hughes Medical Institute.

   Human populations have undergone dramatic changes in population size in the past 100,000 years, including a severe bottleneck of non-African populations and recent explosive population growth. There is currently great interest in how these demographic events may have affected the burden of deleterious mutations in individuals and the allele frequency spectrum of disease mutations in populations. Here we use population genetic models to show that-contrary to previous conjectures-recent human demography has likely had very little impact on the average burden of deleterious mutations carried by individuals. This prediction is supported by exome sequence data showing that African American and European American individuals carry very similar burdens of damaging mutations. We next consider whether recent population growth has increased the importance of very rare mutations in complex traits. Our analysis predicts that for most classes of disease variants, rare alleles are unlikely to contribute a large fraction of the total genetic variance, and that the impact of recent growth is likely to be modest. However, for diseases that have a direct impact on fitness, strongly deleterious rare mutations likely do play important roles, and the impact of very rare mutations will be far greater as a result of recent growth. In summary, demographic history has dramatically impacted patterns of variation in different human populations, but these changes have likely had little impact on either genetic load or on the importance of rare variants for most complex traits.

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