Rapid Detection of Positive Selection in Genes and Genomes Through Variation Clusters

Abstract

Positive selection in genes and genomes can point to the evolutionary basis for differences among species and among races within a species. The detection of positive selection can also help identify functionally important protein regions and thus guide protein engineering. Many existing tests for positive selection are excessively conservative, vulnerable to artifacts caused by demographic population history, or computationally very intensive. I here propose a simple and rapid test that is complementary to existing tests and that overcomes some of these problems. It relies on the null hypothesis that neutrally evolving DNA regions should show a Poisson distribution of nucleotide substitutions. The test detects significant deviations from this expectation in the form of variation clusters, highly localized groups of amino acid changes in a coding region. In applying this test to several thousand human-chimpanzee gene orthologs, I show that such variation clusters are not generally caused by relaxed selection. They occur in well-defined domains of a protein's tertiary structure and show a large excess of amino acid replacement over silent substitutions. I also identify multiple new human-chimpanzee orthologs subject to positive selection, among them genes that are involved in reproductive functions, immune defense, and the nervous system.

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

“…These values are greater than the genome-wide average (K A /K S B0.2) for human-chimpanzee gene pairs. 12 They are, however, much lower than the K A /K S estimates for intrinsic defense genes investigated in the context of human immunodeficiency virus pathogenesis, such as TRIM5a and APOBEC3G (K A /K S ¼ 1.1 for both genes). 13 Comparative analysis of the genes that encode APO-BEC3G and TRIM5a has revealed the intensity of the selective pressures resulting from the long-standing conflict between retroviruses and their hosts.…”

Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition

“…Genes undergoing positive selection based on the ratio of nonsynonymous:synonymous mutations are overrepresented for immunity and host defense, diet, and brain (85). Moreover, genes associated with immunity and brain have variation clusters of highly localized groups of changes in coding regions (86).…”

Bioinformatical Analysis of Point Mutations in Human Genome

“…There is of course a long way to go to attain an in-depth view as to how the human specific traits are coded. One could combine the results of studies of nucleotide replacement densities with the studies of positive or accelerated evolution (Wagner 2007) of protein coding regions. Under normal circumstances the mutabilities of the protein coding regions is an oscillatory function with period 3 -what is the codon length.…”