Revisiting the evidence for long-lived balancing selection in humans

Balancing selection maintains variation in a population longer than expected under neutrality. In humans, there are dozens of tentative candidate loci for balancing selection, but only a handful of well-characterized examples, which are either evolutionarily recent alleles or ancient variants shared across species identical by descent (“trans-species polymorphisms”). Here, we look for evidence of balancing selection over a range of timescales, by taking an approach that does not rely on a demographic model or assumptions about the specific mode of balancing selection. Analyzing whole genome sequencing data from 2504 humans and 59 chimpanzees, we identify common single nucleotide polymorphisms (SNPs) that are identical in the two species. This set includes recurrent mutations, a subset of which may be maintained by balancing selection in one or both species, as well as potential trans-species polymorphisms. Using allele ages estimated from ancestral recombination graph reconstructions in humans, we show that shared SNPs are enriched for older alleles as compared to matched human SNPs that are not shared with chimpanzees. On this basis, we estimate that balancing selection has maintained over one thousand alleles in humans longer than expected by chance. Moreover, we identify over 50 trans-species polymorphisms, including an intriguing case that includes an eQTL for the gene MUC7 . However, we also estimate a minimum false discovery rate for any allele age cut-off of ∼70%; as we show, even among the trans-species polymorphisms, many may be shared between humans and chimpanzees simply by chance. Thus, while our empirical approach establishes that there are numerous loci under balancing selection yet to be found, the specific targets remain difficult to identify without independent lines of evidence.