Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Abstract

We tested the opposing views concerning evolution of genes of the innate immune system that (i) being evolutionary ancient, the system may have been highly optimized by natural selection and therefore should be under purifying selection, and (ii) the system may be plastic and continuing to evolve under balancing selection. We have resequenced 12 important innate-immunity genes (CAMP, DEFA4, DEFA5, DEFA6, DEFB1, MBL2, and TLRs 1, 2, 4, 5, 6, and 9) in healthy volunteers (n ‫؍‬ 171) recruited from a region of India with high microbial load. We have compared these data with those of European-Americans (EUR) and African-Americans (AFR). We have found that most of the human haplotypes are many mutational steps away from the ancestral (chimpanzee) haplotypes, indicating that humans may have had to adapt to new pathogens. The haplotype structures in India are significantly different from those of EUR and AFR populations, indicating local adaptation to pathogens. In these genes, there is (i) generally an excess of rare variants, (ii) high, but variable, degrees of extended haplotype homozygosity, (iii) low tolerance to nonsynonymous changes, (iv) essentially one or a few high-frequency haplotypes, with star-like phylogenies of other infrequent haplotypes radiating from the modal haplotypes. Purifying selection is the most parsimonious explanation operating on these innate immunity genes. This genetic surveillance system recognizes motifs in pathogens that are perhaps conserved across a broad range of pathogens. Hence, functional constraints are imposed on mutations that diminish the ablility of these proteins to detect pathogens. extended haplotype homozygosity ͉ haplotype networks ͉ neutrality tests ͉ resequencing

Survey of Global Genetic Diversity Within theDrosophilaImmune System

“…In a laboratory-based study with the insect Tribolium castaneum, Berenos et al (2011) demonstrated that evolution in the presence of parasites counteracted the effects of drift, leading to higher levels of allelic diversity within populations and lower levels of differentiation between populations. Although more diverged and in possession of an adaptive immune response, humans also show patterns in their innate immune genes that are similar to what we find here: while numerous single genes show signs of directional selection, innate immune genes have globally experienced stronger purifying selection than nonimmune genes (Mukherjee et al 2009;Deschamps et al 2016). Together, these results highlight that immune evolution is more complex than the outlier scenarios that garner the greatest attention in the literature.…”

Naturally occurring Toll-like receptor 11 (TLR11) and Toll-like receptor 12 (TLR12) polymorphisms are not associated with Toxoplasma gondii infection in wild wood mice

“…Furthermore, in a bottlenecked population of New Zealand robin (Petroica australis rakiura), seven out of nine analysed TLRs were polymorphic, with two to five amino acid variants each (Grueber et al, 2012). This relatively high genetic diversity observed in wildlife is in agreement with human studies (Mukherjee et al, 2009;Wlasiuk and Nachman, 2010), and shows that there is the potential for parasite-mediated selection to act on…”

Diversity and evolution of 11 innate immune genes in Bos taurus taurus and Bos taurus indicus cattle

“…One plausible explanation for this is that strong purifying selection has constrained TLR10 within the B. t. taurus lineage. This explanation is supported by evidence that the vertebrate TLRs evolved under purifying selection (52,53), thereby preserving host ability to recognize specific PAMPs. Interestingly, TLR10 is the only functional member of the human TLR gene family for which a specific ligand has not been identified (16).…”