A scan for human-specific relaxation of negative selection reveals unexpected polymorphism in proteasome genes

Abstract

Environmental or genomic changes during evolution can relax negative selection pressure on specific loci, permitting high frequency polymorphisms at previously conserved sites. Here, we jointly analyze population genomic and comparative genomic data to search for functional processes showing relaxed negative selection specifically in the human lineage, whereas remaining evolutionarily conserved in other mammals. Consistent with previous studies, we find that olfactory receptor genes display such a signature of relaxation in humans. Intriguingly, proteasome genes also show a prominent signal of human-specific relaxation: multiple proteasome subunits, including four members of the catalytic core particle, contain high frequency nonsynonymous polymorphisms at sites conserved across mammals. Chimpanzee proteasome genes do not display a similar trend. Human proteasome genes also bear no evidence of recent positive or balancing selection. These results suggest human-specific relaxation of negative selection in proteasome subunits; the exact biological causes, however, remain unknown.

Keywords: human evolution; negative selection; olfactory transduction; proteasome; relaxation of constraints.

Fig. 1.

(A) Representation depicting the tests for human-specific relaxed selection. Genes in a gene set are ranked according to functional human diversity (nsMAF), mammalian divergence (dN/dS), or chimpanzee diversity (nsMAF). The ranks are compared using a Wilcoxon signed rank test (supplementary material, Supplementary Material online). (B) Median human nsMAF and mouse–rhesus macaque dN/dS values among 181 KEGG pathways, each containing minimum five genes. Each dot represents one KEGG gene set. Groups that have significantly higher human diversity ranks relative to mammalian divergence ranks (as in A, Wilcoxon signed rank test), and also have significantly higher human diversity in member genes compared with the genome average (Wilcoxon rank sum test), are indicated in red. (C) Genes (n = 12,405) were ranked according to their relative mouse–rhesus macaque dN/dS (right) or human nsMAF (left) values, with higher ranks indicating weaker negative selection. Each line represents a gene and connects its dN/dS and nsMAF-based ranks. The red lines show proteasome and green lines show selenoamino acid metabolism genes. The two groups were chosen as examples representing significant shifts or no shifts toward human–specific relaxation, respectively. (D) nsMAF values at common proteasome nsSNPs (world-wide MAF > 0.05) in Africans and non-Africans. nsMAF in the non-African sample is higher, but not significantly (Wilcoxon signed rank test P = 0.2). (E) Median human nsMAF and chimpanzee nsMAF values among 182 KEGG pathways with minimum give genes, shown as in (A).

Fig. 2.

Distribution of median MAF for nsSNPs and sSNPs in human (left panels) and chimpanzee (right panels), across genes in three KEGG pathways: olfactory transduction (n = 323), proteasome (n = 18), and Wnt signaling (n = 87), compared with the all genes annotated in KEGG and with nsSNPs in human and chimpanzee data sets (n = 3,741). Wnt signaling was chosen here as an example category that is expected to be under strong negative selection in both human and chimpanzee. The left and right y axes show the percentage of genes falling in a MAF quantile across all genes or genes in a KEGG pathway, respectively. We use the same subset of genes with SNPs detected in both human and chimpanzee. Note that the chimpanzee site frequency spectrum is less skewed to the left than that of human, due to the fact that we use 12 chimpanzee and 54 human subjects. The asterisks show significance measured in a two-sided Wilcoxon rank sum test. °P < 0.10; **P < 0.01; ***P < 0.001.

Fig. 3.

(A) Schematic representation of the proteasome 20S core and 19S regulatory particles based on (Tanaka 2009). Peptides are colored with respect to their polymorphism characteristics. Note that the β1 subunit coded by PSMB6 contains a SNP that is close to fixation in humans, with derived allele frequency (DAF) = 0.98. (B) Representation of bovine 20S core complex, with nsSNP containing chains shown in orange. (C) Box plot showing the percentage of number of nonsynonymous mutations per nonsynonymous site among proteasome genes compared with all genes with at least one mutation (n = 17,294) in the Complete Genomics data set. We assign zero to any gene where only synonymous SNPs are detected (n = 2,191). Note that among 33 proteasome genes, 15 contain only sSNPs but no nsSNP. Outliers are not shown. ***P < 0.001.