Detecting individual sites subject to episodic diversifying selection

Abstract

The imprint of natural selection on protein coding genes is often difficult to identify because selection is frequently transient or episodic, i.e. it affects only a subset of lineages. Existing computational techniques, which are designed to identify sites subject to pervasive selection, may fail to recognize sites where selection is episodic: a large proportion of positively selected sites. We present a mixed effects model of evolution (MEME) that is capable of identifying instances of both episodic and pervasive positive selection at the level of an individual site. Using empirical and simulated data, we demonstrate the superior performance of MEME over older models under a broad range of scenarios. We find that episodic selection is widespread and conclude that the number of sites experiencing positive selection may have been vastly underestimated.

Figure 1. The standard random effects approach and samples.

A) The standard random effects approach, in which the rates vary randomly over sites but are constant over branches. Different values of are showed in different colors. B) Samples from our new random effects approach , used by MEME, in which the rate on each branch is drawn independently of the rate on any other branch. All possible assignments of rates to sites are considered.

Figure 2. Individual sites of the vertebrate rhodopsin alignment used to illustrate similarities and differences between FEL and MEME.

Branches that have experienced substitutions, based on most likely joint maximum likelihood ancestral reconstructions at a given site, are labeled as count of synonymous substitutions:count of non-synonymous substitutions. The thickness of each branch is proportional to the minimal number of single nucleotide substitutions mapped to the branch. Branches are colored according to the magnitude of the empirical Bayes factor (EBF) for the event of positive selection: red – evidence for positive selection, teal – evidence for neutral evolution or negative selection, black –Ê no information. See Methods for more detail. All three sites were identified as experiencing positive diversifying selection by MEME. FEL reported site 54 as positively selected, site 273 as neutral, and site 210 as negatively selected.