JC:Weighing the evidence for adaptation at the molecular level

The abundance of genome polymorphism and divergence data has provided unprecedented insight into how mutation, drift and natural selection shape genome evolution. Application of the McDonald-Kreitman (MK) test to such data indicates a pervasive influence of positive selection, particularly in Drosophila species. However, evidence for positive selection in other species ranging from yeast to humans is often weak or absent. Although evidence for positive selection could be obscured in some species, there is also reason to believe that the frequency of adaptive substitutions could be overestimated as a result of epistatic fitness effects or hitchhiking of deleterious mutations. Based on these considerations it is argued that the common assumption of independence among sites must be relaxed before abandoning the neutral theory of molecular evolution. Estimating the frequency of positive selection using the MK test The extent to which molecular evolution is driven by positive selection has long been debated. The neutral theory (see Glossary) holds that the vast majority of DNA sequence differences between species are neutral [1] or nearly neutral [2] with respect to fitness. However, models assuming that natural selection plays a dominant role in driving molecular evolution can also explain many features of DNA polymorphism and divergence data One test for positive selection that has been extensively applied to genome-wide polymorphism and divergence data is the MK test Evidence for positive selection based on the MK test Of 38 species for which polymorphism has been compared to divergence across multiple genes, 47% show evidence that positive selection has significantly increased the nonsynonymous substitution rate based on the MK test or related tests Evidence for positive selection varies among taxonomic groups. The strongest evidence comes from Drosophila, where all six species that have been examined show Opinion Corresponding author: Fay, J.C. (jfay@genetics.wustl.edu). Glossary Neutral theory: a theory that the vast majority of DNA substitutions between species is the result of neutral mutations and random drift rather than selectively driven substitutions. The neutral theory does not assert that all mutations are neutral or that there is no adaptive evolution, but instead that deleterious mutations are eliminated from a population and that positively selected mutations make only a small contribution to divergence between species. Effective population size: the size of a randomly mating population of constant size that would effectively recapitulate patterns and levels of variation observed in a real population. The effective (rather than actual) size of a population is used to account for the fact that most real populations are not constant in size and mating is not entirely random. The effective population size of a species is relevant to estimates of a because weakly deleterious and advantageous mutations are effectively neutral when their fitness effects are less than the reciprocal of the effective size of a population. Alpha (a): the estimated fraction of substitutions that were driven by positive selection, and for nonsynonymous substitutions can be estimated by 1-( pN/ pS)/(dN/dS). Selective constraint: the selective constraint on a site, or the average constraint across multiple sites, is a function of the degree to which fitness is reduced when mutated. In the absence of positive selection, pN/pS and dN/dS provide measures of the selective constraint on a site because they measure the extent to which the rate of nonsynonymous variation is reduced by negative selection relative to synonymous variation (assuming synonymous variation is neutral). Epistasis: although epistasis is used in many different contexts, here it is used to refer to mutations with effects that depend on genotypes at other loci. Hitchhiking: the process by which the frequency of mutations linked to an advantageous mutation are influenced by the spread of the advantageous mutation through a population. TIGS-898; No. of Pages 7 0168-9525/$ -see front matter