Pathogen pressure and molecular evolutionary genetics of innate immunity genes in humans

Abstract

We report results of an extensive and comprehensive study of genetic diversity in 12 genes of the innate immune system in a population of eastern India. Almost half of the 548 DNA variants discovered was novel. DNA sequence comparisons with human and chimpanzee reference sequences revealed evolutionary features indicative of natural selection operating among individuals, who are residents of an area with a high load of microbial and other pathogens. The haplotype structures in India are significantly different from those of European-American and African-American populations, indicating local adaptation to pathogens. 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. We have tested the opposing views concerning evolution of genes of the innate immune system that (a) being evolutionary ancient, the system may have been highly optimized by natural selection and therefore should be under purifying selection and (b) the system may be plastic and continuing to evolve under balancing selection. We have found that in these genes, there is (a) generally an excess of rare variants (b) high, but variable, degrees of extended haplotype homozygosity, (c) low tolerance to non-synonymous changes and (d) 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 abroad range of pathogens. Hence, functional constraints are imposed on mutations that diminish the ability of these proteins to detect pathogens.