Abstract Background Regions of the genome that are under evolutionary constraint across multiple species have previously been used to identify functional sequences in the human genome. Furthermore, it is known that there is an inverse relationship between evolutionary constraint and the allele frequency of a mutation segregating in human populations, implying a direct relationship between interspecies divergence and fitness in humans. Here we utilise this relationship to test differences in the accumulation of putatively deleterious mutations both between populations and on the individual level. Results Using whole genome and exome sequencing data from Phase 1 of the 1000 Genome Project for 1,092 individuals from 14 worldwide populations we show that minor allele frequency (MAF) varies as a function of constraint around both coding regions and non-coding sites genome-wide, implying that negative, rather than positive, selection primarily drives the distribution of alleles among individuals via background selection. We find a strong relationship between effective population size and the depth of depression in MAF around the most conserved genes, suggesting that populations with smaller effective size are carrying more deleterious mutations, which also translates into higher genetic load when considering the number of putatively deleterious alleles segregating within each population. Finally, given the extreme richness of the data, we are now able to classify individual genomes by the accumulation of mutations at functional sites using high coverage 1000 Genomes data. Using this approach we detect differences between ‘healthy’ individuals within populations for the distributions of putatively deleterious rare alleles they are carrying. Conclusions These findings demonstrate the extent of background selection in the human genome and highlight the role of population history in shaping patterns of diversity between human individuals. Furthermore, we provide a framework for the utility of personal genomic data for the study of genetic fitness and diseases.

The unique inheritance pattern of the X chromosome exposes it to natural selection in a way that is different from that of the autosomes, potentially resulting in accelerated evolution. We perform a comparative analysis of X chromosome polymorphism in 10 great ape species, including humans. In most species, we identify striking megabase-wide regions, where nucleotide diversity is less than 20% of the chromosomal average. Such regions are found exclusively on the X chromosome. The regions overlap partially among species, suggesting that the underlying targets are partly shared among species. The regions have higher proportions of singleton SNPs, higher levels of population differentiation, and a higher nonsynonymous-to-synonymous substitution ratio than the rest of the X chromosome. We show that the extent to which diversity is reduced is incompatible with direct selection or the action of background selection and soft selective sweeps alone, and therefore, we suggest that very strong selective sweeps have independently targeted these specific regions in several species. The only genomic feature that we can identify as strongly associated with loss of diversity is the location of testis-expressed ampliconic genes, which also have reduced diversity around them. We hypothesize that these genes may be responsible for selective sweeps in the form of meiotic drive caused by an intragenomic conflict in male meiosis.

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.