Diverse functions associate with non-coding polymorphisms shared between humans and chimpanzees

Abstract

Background Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species in the state of identity-by-descent, hereafter “trans-species polymorphisms”, can result from LTBS, often due to host–pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred candidate LTBS regions have been identified in humans and chimpanzees; however, because many are in non-protein-coding regions of the genome, the functions and potential adaptive roles for most remain unknown. Results We integrated diverse genomic annotations to explore the functions of 60 previously identified regions with multiple shared polymorphisms (SPs) between humans and chimpanzees, including 19 with strong evidence of LTBS. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS) for all the regions. We identify functional annotations for 59 regions, including 58 with evidence of gene regulatory function from GTEx or functional genomics data and 19 with evidence of trait association from GWAS or PheWAS. As expected, the SPs associate in humans with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body size, alcohol intake, cognitive performance, risk-taking behavior, and urate levels. Conclusions The diversity of traits associated with non-coding regions with multiple SPs support previous hypotheses that functions beyond the immune system are likely subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in human and chimpanzee populations, such as the importance of variation in risk sensitivity.

More evidence for widespread antagonistic pleiotropy in polymorphic disease alleles

“…In fact, multiple genomic studies now provide evidence for balancing selection at large numbers of loci but are then left to speculate on the selective factors in the absence of direct studies of the individual alleles. Typically, these are hypothesis-free studies looking for genetic patterns of balancing selection and identifying them in a large number of loci, but often without any more detail than knowing the functional classes of the loci (e.g., Andrés et al, 2009 ; Abraham et al, 2022 ; Velazquez-Arcelay et al, 2022 ; Aqil et al, 2023 ). While reliable and complete identification of the types of balancing selection revealed are unresolved, at a minimum it seems that previous suggestions that balancing selection is rare or irrelevant ( Asthana et al, 2005 ; Hedrick, 2012 ) are weakened by this increasing evidence.…”