Footprints of ancient-balanced polymorphisms in genetic variation data from closely related species

Abstract

When long-lasting, balancing selection can lead to "trans-species" polymorphisms that are shared by two or more species identical by descent. In such cases, the gene genealogy at the selected site clusters by allele instead of by species, and nearby neutral sites also have unusual genealogies because of linkage. While this scenario is expected to leave discernible footprints in genetic variation data, the specific patterns remain poorly characterized. Motivated by recent findings in primates, we focus on the case of a biallelic polymorphism under ancient balancing selection and derive approximations for summaries of the polymorphism data from two species. Specifically, we characterize the length of the segment that carries most of the footprints, the expected number of shared neutral single nucleotide polymorphisms (SNPs), and the patterns of allelic associations among them. We confirm the accuracy of our approximations by coalescent simulations. We further show that for humans and chimpanzees-more generally, for pairs of species with low genetic diversity levels-these patterns are highly unlikely to be generated by neutral recurrent mutations. We discuss the implications for the design and interpretation of genome scans for ancient balanced polymorphisms in primates and other taxa.

Keywords: Ancient genetic variation; balancing selection; genome scan for selection; trans-species polymorphism.

Figure 1

Sites linked to a balanced trans-species polymorphism have unusual genealogies. (A) The trees are ordered by the distance from the selected site. Blue and red lines represent lineages from the two allelic classes, respectively. (B) The state of each segment in ten simulation replicates. Each bar represents a 10 kb region centered on a trans-species balanced polymorphism (red dotted line). The color of the bar indicates the genealogical state of each segment (same as in A). Parameters were chosen to be plausible for humans and chimpanzees: N = 10,000, N_a = 50,000, T = 160,000, p = 0.5, and r = 1.25 cM/Mb (see Supporting Information). (C) Summary of the coalescent time for a single realization of a segment carrying a balanced trans-species polymorphism. The sample consists of 20 lineages in total, five from each allelic class in each species. Each plot shows the time to the MRCA for a specific subset of the 20 lineages indicated on the top and left. The selected site is located in the center of the segment.

Figure 2

The genealogy of the contiguous ancestral segment. The proportion of each stage has been distorted for illustration purpose (e.g., stage I should be much shorter compared to stage II). See main text and Table1 for the meaning of symbols.

Figure 3

Expected coalescent time between two lineages carrying different alleles. Parameters are chosen to be plausible for the ancestral population for humans and chimpanzees: N_a = 50,000, p = 0.5, and T_S = 600,000 generations (see Supporting Information). The mean and standard deviation of the simulation results were obtained from 10,000 replicates.

Figure 4

Expected number of shared SNPs in the contiguous ancestral segment. The upper panel is a schematic diagram of the demographic history of humans and chimpanzees, which merged into an ancestral species five million years ago (Mya). The star indicates the age of the balanced polymorphism. The lower panel shows the expected number of shared SNPs (including the selected one) in the two-sided contiguous ancestral segment. Note that the age of the balanced polymorphism here is measured from present, which is the sum of T_S and the lengths of stages I and II.

Figure 5

LD between shared SNPs generated by balancing selection or by recurrent mutations. Fifty chromosomes were sampled from each species in both scenarios. We assumed an allele frequency of 0.5 for the scenario of balancing selection and sampled an equal number of chromosomes from each allelic class (see Supporting Information for details of the simulations). Panels (A) and (B) show the distribution of r² in the two species, respectively.