RELAX: Detecting Relaxed Selection in a Phylogenetic Framework

Abstract

Relaxation of selective strength, manifested as a reduction in the efficiency or intensity of natural selection, can drive evolutionary innovation and presage lineage extinction or loss of function. Mechanisms through which selection can be relaxed range from the removal of an existing selective constraint to a reduction in effective population size. Standard methods for estimating the strength and extent of purifying or positive selection from molecular sequence data are not suitable for detecting relaxed selection, because they lack power and can mistake an increase in the intensity of positive selection for relaxation of both purifying and positive selection. Here, we present a general hypothesis testing framework (RELAX) for detecting relaxed selection in a codon-based phylogenetic framework. Given two subsets of branches in a phylogeny, RELAX can determine whether selective strength was relaxed or intensified in one of these subsets relative to the other. We establish the validity of our test via simulations and show that it can distinguish between increased positive selection and a relaxation of selective strength. We also demonstrate the power of RELAX in a variety of biological scenarios where relaxation of selection has been hypothesized or demonstrated previously. We find that obligate and facultative γ-proteobacteria endosymbionts of insects are under relaxed selection compared with their free-living relatives and obligate endosymbionts are under relaxed selection compared with facultative endosymbionts. Selective strength is also relaxed in asexual Daphnia pulex lineages, compared with sexual lineages. Endogenous, nonfunctional, bornavirus-like elements are found to be under relaxed selection compared with exogenous Borna viruses. Finally, selection on the short-wavelength sensitive, SWS1, opsin genes in echolocating and nonecholocating bats is relaxed only in lineages in which this gene underwent pseudogenization; however, selection on the functional medium/long-wavelength sensitive opsin, M/LWS1, is found to be relaxed in all echolocating bats compared with nonecholocating bats.

Do relaxed selection and habitat temperature facilitate biased mitogenomic introgression in a narrowly endemic fish?

“…The relaxation parameter ( K ) and the significance ( P ) of relaxed selection along the branch leading to H. minckleyi for mtDNA proteins as inferred from RELAX (Wertheim et al. 2015) are shown. The number of amino acid sites examined for each protein (AA sites) as well as the number of divergent amino acids between the “ H. minckleyi ” and “ H. cyanoguttatus ” proteins is given in parentheses.…”

“…2015; Wertheim et al. 2015). The small range of H. minckleyi and the spatial population structure of the springs of Cuatro Ciénegas (Fig.…”

“…The smaller effective population size could have translated into the enhanced accumulation of mutations in the H. minckleyi mitochondrial genome due to the more pronounced effects of genetic drift (Wertheim et al. 2015). …”

“…2006; Wertheim et al. 2015). Because the mitochondrial genome contains numerous genes that are physically linked and do not recombine (Lynch 2007; Burton et al.…”

Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

“…MEME relaxes the assumption of equal rates among different branches, and FUBAR assumes that each site can belong to a broad distribution of rate-categories. To determine whether elevated rates were due to relaxation of functional constraints or to positive selection, we employed relaxation analysis using the RELAX method [57]. RELAX assigns the significance using a Kparameter to the two cases, relaxation of functional constraints (K < 1) and intensification of selection (K > 1).…”