Δ-d_N/d_S: A New Criteria to Distinguish among Different Selection Modes in Gene Evolution

Abstract

One of the most widely-used measures for protein evolution is the ratio of nonsynonymous distance (dN) to synonymous distance (dS). Under the assumption that synonymous substitutions in the coding region are selectively neutral, the dN/dS ratio can be used to test the adaptive evolution if dN/dS>1 statistically significantly.However, due to selective constraints imposed on amino acid sites, most encoding genes demonstrate dN/dS<1. As a result, dN/dS of a gene is less than 1, even some sites may have experienced positive selections. In this paper, we develop a new criterion, called Δ-dN/dS, for positive selection testing by introducing an index H, which is a relative measure of rate variation among sites. Under the context of strong purifying selection at some amino acid sites, our model predicts dN/dS=1-H for the neutral evolution, dN/dS<1-H for the nearly-neutral selection, and dN/dS>1-H for the adaptive evolution. The potential of this new method for resolving the neutral-adaptive debates has been illustrated by case studies. For over 4000 vertebrate genes, virtually all of them showed dN/dS<1-H, indicating the dominant role of the nearly-neutral selection in molecular evolution. Moreover, we calculated the dN/dS ratio for cancer somatic mutations of a human gene, specifically denoted by CN/CS. For over 4000 human genes in cancer genomics, about 55% of genes showed 1-H<CN/CS<1, about 45% of genes showed CN/CS<1, whereas less than 1% of genes showed CN/CS<1-H. Together our analysis suggested driver mutations, i.e., those initiate and facilitate carcinogenesis, confer a selective advantage on cancer cells, leading to CN/CS>1 (strong positive selection) or 1-H<CN/CS<1 (weak positive selection, combined with strong purifying selection), whereas nearly neutral selection due to reduced effective clonal size is highly unlikely in cancer evolution.