Inferring long-term effective population size with Mutation-Selection models

Abstract

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 unreasonable hypothesis. 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 co-vary 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.

Genes and sites under adaptation at the phylogenetic scale also exhibit adaptation at the population-genetic scale

“…Mutation-selection codon models assume a constant effective population size while it has been established that its fluctuations has a major effect on selection dynamics[27, 28]. Estimating changes in effective population size in a mutation-selection framework is possible[29], although too computational intensive in its current implementation to be performed genome-wide. Second, epistasis is not modeled while it can have a large effect on the response of the rate of evolution with change in population size[30].…”

Traditional phylogenetic models fail to account for variations in the effective population size

“…While these studies have been able to quite successfully estimate mutation and selection bias [e.g., Lartillot (2013); Latrille and Lartillot (2022)], inferring variations in the population size has been more challenging. To circumvent this limitation, proxies for population size, such as life history traits (Romiguier et al, 2014; Ellegren and Galtier, 2016) or polymorphic data are incorporated (Brevet and Lartillot, 2021), or further assumptions about the demographic history along the phylogeny are made (e.g., Latrille et al (2021) assumes an autocorrelated geometric Brownian process to model variations in the effective population size). These studies show that the patterns of nucleotide substitution are not per se enough to estimate the effective population.…”