Evaluation of Methods to Detect Shifts in Directional Selection at the Genome Scale.

Identifying the footprints of selection in coding sequences can inform about the importance and function of individual sites. Analyses of the ratio of nonsynonymous to synonymous substitutions (dN/dS) have been widely used to pinpoint changes in the intensity of selection, but cannot distinguish them from changes in the direction of selection, that is, changes in the fitness of specific amino acids at a given position. A few methods that rely on amino-acid profiles to detect changes in directional selection have been designed, but their performances have not been well characterized. In this paper, we investigate the performance of six of these methods. We evaluate them on simulations along empirical phylogenies in which transition events have been annotated and compare their ability to detect sites that have undergone changes in the direction or intensity of selection to that of a widely used dN/dS approach, codeml's branch-site model A. We show that all methods have reduced performance in the presence of biased gene conversion but not CpG hypermutability. The best profile method, Pelican, a new implementation of Tamuri AU, Hay AJ, Goldstein RA. (2009. Identifying changes in selective constraints: host shifts in influenza. PLoS Comput Biol. 5(11):e1000564), performs as well as codeml in a range of conditions except for detecting relaxations of selection, and performs better when tree length increases, or in the presence of persistent positive selection. It is fast, enabling genome-scale searches for site-wise changes in the direction of selection associated with phenotypic changes.

Inferring Long-Term Effective Population Size with Mutation-Selection Models.

Mutation-selection phylogenetic codon models are grounded on population genetics first principles and represent a principled approach for investigating the intricate interplay between mutation, selection, and drift. In their current form, mutation-selection codon models are entirely characterized by the collection of site-specific amino-acid fitness profiles. However, thus far, they have relied on the assumption of a constant genetic drift, translating into a unique effective population size (Ne) across the phylogeny, clearly an unrealistic assumption. This assumption can be alleviated by introducing variation in Ne between lineages. In addition to Ne, the mutation rate (µ) is susceptible to vary between lineages, and both should covary with life-history traits (LHTs). This suggests that the model should more globally account for the joint evolutionary process followed by all of these lineage-specific variables (Ne, µ, and LHTs). In this direction, we introduce an extended mutation-selection model jointly reconstructing in a Bayesian Monte Carlo framework the fitness landscape across sites and long-term trends in Ne, µ, and LHTs along the phylogeny, from an alignment of DNA coding sequences and a matrix of observed LHTs in extant species. The model was tested against simulated data and applied to empirical data in mammals, isopods, and primates. The reconstructed history of Ne in these groups appears to correlate with LHTs or ecological variables in a way that suggests that the reconstruction is reasonable, at least in its global trends. On the other hand, the range of variation in Ne inferred across species is surprisingly narrow. This last point suggests that some of the assumptions of the model, in particular concerning the assumed absence of epistatic interactions between sites, are potentially problematic.

Detecting adaptive convergent amino acid evolution.

In evolutionary genomics, researchers have taken an interest in identifying substitutions that subtend convergent phenotypic adaptations. This is a difficult question that requires distinguishing foreground convergent substitutions that are involved in the convergent phenotype from background convergent substitutions. Those may be linked to other adaptations, may be neutral or may be the consequence of mutational biases. Furthermore, there is no generally accepted definition of convergent substitutions. Various methods that use different definitions have been proposed in the literature, resulting in different sets of candidate foreground convergent substitutions. In this article, we first describe the processes that can generate foreground convergent substitutions in coding sequences, separating adaptive from non-adaptive processes. Second, we review methods that have been proposed to detect foreground convergent substitutions in coding sequences and expose the assumptions that underlie them. Finally, we examine their power on simulations of convergent changes-including in the presence of a change in the efficacy of selection-and on empirical alignments. This article is part of the theme issue 'Convergent evolution in the genomics era: new insights and directions'.