X-chromosome contributes more SVs under positive selection
The population genetic theory predicts that positive Darwinian selection can drive the standing or de novo mutations to sweep through a population, to achieve diverse local adaptations and develop novel phenotypes [71]. To understand the influence of positive selection on the evolutionary fate of SVs, we inferred the regions under positive selection for the Chinese and Indian rhesus macaques. Based on population genetics, positive selection would hallmark several features along chromosomes, including but not limited to, the increased fixation index (FST ) between focal population and control population, the reduced nucleotide diversity (π) in focal population relative to control population, and the elevated expected haplotype homozygosity [72-74]. The selective sweep signals were estimated based on three complementary methods including the ratio of nucleotide diversity between Indian and Chinese populations (θ π_India/θ π_China), the fixation index (FST ), and the haplotype homozygosity (Ihh12) (Figure 5A-C).
Totally, we identified 1400 genes under selective sweep for the two subspecies, with 164 genes for the Chinese and 1236 genes for Indian rhesus macaques (Supplementary table 3). Notably, over 38% of positively selected genes were distributed in X chromosome, significantly higher than the expected average level of autosomes (the Χ² test, p < 0.00001). The strongest signal in the Chinese group was found in an autosome gene TTC28 (Figure 5B), which is related to human developmental disease based on human exome sequencing of fetal anomaly syndromes [75]. For Indian rhesus macaques, the highest signal was found in an X-chromosome gene, IL1RAPL2(Figure 5C), which is involved in diseases including mental development and autism [76, 77]. The gene function enrichment analysis revealed that the most significant pathways involve the Guanyl-nucleotide exchange factor activity and regulation of cell projection organization, for the Chinese (Figure 5D) and Indian rhesus macaques (Figure 5E), respectively.
Interesting, we found that the two genes with the strongest signals among all positively selected genes, IL1RAPL2 and TTC28 , were involved in intragenic SVs (insertions and deletions, Supplementary table 4). Thus, it is very interesting to know whether SVs could be driven by the evolutionary force of positive selection in rhesus macaques. We found that, among the 2248 congruent SVs shared by three methods, 3.20% of SVs (72/2248) showed signals of selective sweep in intergenic and intragenic DNA regions (Supplementary table 5). Moreover, 3.79% of positively selected genes (53/1400) were detected with signals of congruent SVs (Supplementary table 6). Interestingly, X chromosome exhibited a significant higher contribution (26.45%, 14/53) to the positively selected genes involved in SVs than autosomes (the Χ² test, p < 0.00001; Figure 5F). The regression analysis revealed the positively selected SVs in autosomes do not follow a simple linear model against the overall congruent SVs (p = 0.4, Figure 5F). However, the X chromosome exhibited as an obvious outlier with excess number of positively selected SVs (Figure 5G). These findings suggest that SVs could serve as an important raw material for natural selection to operate on genomic diversity.