The Maintenance of Deleterious Variation in Wild Chinese Rhesus Macaques

Abstract

Understanding how deleterious variation is shaped and maintained in natural populations is of importance for both medical research and conservation biology. Various demographic processes can influence these patterns. For example, population bottlenecks and inbreeding increase the likelihood of inheriting identical-by-descent haplotypes from a recent common ancestor, creating long tracts of homozygous genotypes called runs of homozygosity (ROH). Long ROH (e.g., those created as a result of inbreeding) have been associated with an accumulation of mildly deleterious homozygotes. Counter intuitively, positive selection can also maintain deleterious variants in a population by increasing the frequency of a damaging allele tightly linked to an advantageous mutation (i.e., via genetic hitchhiking).Here we analyze whole genomes of 79 wild Chinese rhesus macaques across five sub-species and characterize patterns of deleterious variation with respect to ROH and signals of recent positive selection. We show that the fraction of deleterious homozygotes occurring in long ROH is significantly higher for deleterious homozygotes than tolerated ones (p= 3.4×10−5) but not in short and medium ROH. This confirms that inbreeding, by generating these long tracts of homozygosity, is the main driver of the high burden of homozygous deleterious alleles in wild macaque populations. Furthermore, we show that small ROH have a lower proportion of homozygous loss-of-function variants than tolerated ones (p= 0.05), suggesting the purging of these variants through natural selection. Next, we identify regions putatively experiencing a recent or ongoing sweep and examine the presence of deleterious variants in these regions to find signals of genetic hitchhiking. We found 7 deleterious variants at high frequency in regions under selection containing genes involved with olfaction and other processes.SignificanceOur results offer insights into the relationship between demographic and evolutionary processes and the maintenance of deleterious alleles in rhesus macaques. We demonstrate how inbreeding and positive selection can contribute to the maintenance of deleterious variants in wild non-human primate populations. This work also adds to our understanding of the evolutionary history of macaques and, as rhesus macaques are the most widely used non-human primate in biomedical research, may help inform the study of human diseases.

Genomic consequences of isolation and inbreeding in an island dingo population

“…Accumulation of long ROH in the genome, indicators of inbreeding, is associated with increased presence of deleterious homozygotes and potential fitness effects (Szpiech et al 2013;Szpiech et al 2019;Stoffel et al 2021;Steux and Szpiech 2023;Swinford et al 2023).…”

“…On the other hand, small and isolated populations tend to have a higher burden of deleterious variants as a result of inbreeding (Robinson et al 2018; Hedrick et al 2019; Grossen et al 2020; Khan et al 2021; Stoffel et al 2021). Accumulation of long ROH in the genome, indicators of inbreeding, is associated with increased presence of deleterious homozygotes and potential fitness effects (Szpiech et al 2013; Szpiech et al 2019; Stoffel et al 2021; Steux and Szpiech 2023; Swinford et al 2023).…”

Pervasive selective sweeps across human gut microbiomes

“…iLDS may have power in diverse systems because it exploits a common signature associated with selective sweeps: deleterious variants hitchhiking to high frequency with a beneficial variant. To our knowledge, the tight linkage of beneficial variants with hitchhiking deleterious variants, which has been shown to be a common feature of evolution both in theory and in numerous systems [48, 49, 50, 51, 52], has not been explicitly incorporated into any selection scan statistic. By contrast, current LD-based methodology for detection of sweeps instead relies more generically on signatures of hitchhiking which are not unique to selective sweeps [18, 19, 20, 21, 22, 23].…”