The Effects of Deleterious Mutations on Evolution at Linked Sites

Abstract

The process of evolution at a given site in the genome can be influenced by the action of selection at other sites, especially when these are closely linked to it. Such selection reduces the effective population size experienced by the site in question (the HillRobertson effect), reducing the level of variability and the efficacy of selection. In particular, deleterious variants are continually being produced by mutation and then eliminated by selection at sites throughout the genome. The resulting reduction in variability at linked neutral or nearly neutral sites can be predicted from the theory of background selection, which assumes that deleterious mutations have such large effects that their behavior in the population is effectively deterministic. More weakly selected mutations can accumulate by Muller's ratchet after a shutdown of recombination, as in an evolving Y chromosome. Many functionally significant sites are probably so weakly selected that Hill-Robertson interference undermines the effective strength of selection upon them, when recombination is rare or absent. This leads to large departures from deterministic equilibrium and smaller effects on linked neutral sites than under background selection or Muller's ratchet. Evidence is discussed that is consistent with the action of these processes in shaping genome-wide patterns of variation and evolution. MUTATIONS that increase the fitness of their carriers are, of course, the basis of adaptive evolution. For this reason, the literature on evolutionary genetics is full of studies that document "positive" selection on genetic variants in natural populations-with the advent of data on the resequencing of numerous whole genomes from the same species, we can expect a tidal wave of such examples. But, as was pointed out long ago by geneticists such as TimofeeffRessovsky (1940) and Muller (1949Muller ( , 1950, most mutations that affect the phenotype must be deleterious, because biological machinery has been subject to billions of years of selection to improve its performance. Because the nucleotide sites at which deleterious mutations can arise are numerous and distributed throughout the genome, the constant mutational production of deleterious variants and their elimination by "purifying" selection have major effects on the mean fitness of a population, its level of inbreeding depression, and its genetic variability with respect to fitness components.These properties of populations have important consequences for the evolution of such fundamental features of organisms as sex and genetic recombination, diploidy vs. haploidy, outbreeding vs. inbreeding, mate choice, and aging. Jim Crow, a great admirer of Muller (Crow 2005), has devoted much of his career both to improving our theoretical understanding of the population consequences of deleterious mutations and to documenting their rates of occurrence and their effects on fitness, summed up in several masterly reviews (Crow 1970(Crow , 1993(Crow , 2000Simmons and Crow 1977;Crow and Simmons 1983). T...

A coalescent model of background selection with recombination, demography and variation in selection coefficients

“…Such a relationship has been found in many organisms such as Drosophila (Begun and Aquadro, 1992), humans (Cai et al, 2009) and Caenorhabditis (Cutter and Choi, 2010). Two population genetic models, selective sweeps and background selection, have been widely perceived as potential explanations for this correlation Charlesworth, 2012a). The selective sweeps model postulates that neutral mutations linked to a nearby favourable mutation, which is on its way to fixation, will 'hitchhike' to high frequencies or even fixation, causing a substantial loss in diversity (Maynard Smith and Haigh, 1974).…”

“…Intuitively, the association between selected and neutral variants loosens with increasing local recombination rates. Thus, both models predict a positive correlation between nucleotide diversity and recombination rates (reviewed by Sella et al, 2009;Stephan, 2010;Charlesworth, 2012a).…”

Heterogeneity in effective population size and its implications in conservation genetics and animal breeding

“…Positive and background selection affect diversity across the genome (Sella et al 2009), but distinguishing their relative importance is challenging (Elyashiv et al 2014). Some analytical results-holding when selection is strong-show that local N e at a site experiencing background selection is scaled by the fraction of individuals free from deleterious mutations (Charlesworth et al 1993;Charlesworth 2012). We thus have a neutral site that is apparently neutrally evolving, albeit with a N e lower than the one in absence of background selection.…”

“…N e , the number of individuals effectively contributing to future generations, is affected by the fact that, due to selection, some individuals contribute disproportionately to future generations because they are carrying more beneficial and/ or less deleterious mutations around the site of interest. There is a wealth of population genetics theory that has accumulated since the mid-60s (see recent exhaustive review by Charlesworth 2012;Cutter and Payseur 2013) showing that selection can locally reduce the N e experienced by a genomic site reducing both the level of genetic variability and the efficacy of selection at that site. We hereafter talk about this ''local N e '' to describe the potential heterogeneity in N e in the genome.…”

The genomics of adaptation

“…(b) Genomics of adaptive change: hard and soft sweeps The effectiveness of selection depends greatly on effective population size and recombination rate [26,27]; thus it is very probable that the process of adaptation will differ fundamentally in taxonomic groups differing in these parameters. Models of adaptive evolution have traditionally assumed adaptation from de novo mutations [13,28].…”