When ancestry runs deep: Trans-species polymorphisms in apes. L. Segurel1,2, E. Leffler1, Z. Gao1, S. Pfeifer3, A. Auton4, O. Venn4, L. Stevison5, A. Venkat1,2, J. L. Kelley6, J. Kidd6, C. Bustamante6, R. Bontrop7, M. Hammer8, J. Wall5, P. Donnelly3,4, G. McVean3,4, M. Przeworski1,2,9 1) Department of Human Genetics, University of Chicago, Chicago, IL, USA; 2) Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA; 3) Department of Statistics, University of Oxford, Oxford, UK; 4) Wellcome Trust Centre for Human Genetics, Oxford, UK; 5) UCSF, San Francisco, CA, USA; 6) Stanford University, Stanford, CA, USA; 7) Biomedical Primate Research Centre, Rijswijk, the Netherlands; 8) University of Arizona, Tucson, AZ, USA; 9) Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA.

   Balancing selection refers to the maintenance of more than one allele in the population for a longer time than would be expected from genetic drift alone. In cases where balancing selection pressures have existed for millions of years, different species can share the same polymorphism identical by descent, resulting in a trans-species polymorphism. This mode of selection is thought to be extremely rare, with only MHC and ABO known in humans. However, modeling work suggests that it leaves a small footprint in genetic variation, so additional cases may have gone undetected. With these considerations in mind, we searched for trans-species polymorphisms between humans and chimpanzees using genome-wide resequencing data for 10 western chimpanzees from the PanMap project and 179 humans from the 1000 Genomes Pilot 1 data. We considered all orthologous sites polymorphic for the same alleles in both species, and found them to be in excess of what would be expected by chance after controlling for local variation in mutation rates. We then focused on shared haplotypes, i.e. cases of two or more close shared SNPs with the same linkage disequilibrium patterns in both species, in order to minimize the contribution of recurrent mutation to allele sharing between species. In addition to the MHC region, we identified over 100 cases, a set significantly enriched for transmembrane glycoproteins, which are often involved in interactions with pathogens. To further rule out the possibility of deep coalescent events by chance, we examined patterns of variation in seven samples of Gorilla gorilla. We discovered 25 cases shared among all three species, which we verified by Sanger sequencing. In a subset, within species diversity levels were unusually high and the tree of haplotypes clustered by allelic type rather than by species, providing definitive evidence for trans-species polymorphisms. Interestingly, when we considered non-synonymous polymorphisms shared between the three species, transmembrane glycoproteins again emerged as enriched. Thus, our scan revealed numerous targets of long-lived balancing selection in apes, narrowed down to only a couple of possible causal SNPs, and revealed a common theme to targets of balancing selection, likely related to immune response. Given our conservative criteria, our findings indicate that ancient balancing selection may be more common than previously believed.

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