No effect of recombination on the efficacy of natural selection in primates

Bullaughey, Kevin; Przeworski, Molly; Coop, Graham

doi:10.1101/gr.071548.107

Cited by 54 publications

(65 citation statements)

References 77 publications

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“…Since b-values are typically between 0.1 and 0.3 in most species (Table S2), changes in N e tend to cause small changes in the proportion of effectively neutral mutations; for example, a 10-fold increase in effective population size will reduce the proportion of effectively neutral mutations by only 37% if b = 0.2. We find no evidence of a significant negative correlation between c and either u S or N e in humans, in agreement with the work of Bullaughey et al (2008). They found no evidence that the ratio of the nonsynonymous (d N ) to the synonymous (d S ) substitution rate between human, chimpanzee, and macaque was correlated to the rate of recombination.…”

supporting

confidence: 81%

“…Furthermore, for our mouse species we are using an F 2 genetic linkage map constructed from intercrosses between M. m. domesticus and M. m. castaneus to infer recombination rates for M. m. castaneus. In humans it has previously been shown that diversity over divergence is correlated positively to recombination rate (Hellmann et al 2005) and that d n /d s is correlated to gene density (Bullaughey et al 2008). In contrast to Hellmann et al (2005), we do not find a significant correlation between N e and recombination rate, but they used long noncoding sequences to investigate diversity over divergence; their estimates were therefore subject to much less error than ours.…”

contrasting

confidence: 50%

“…Likewise it has been shown that d N /d S is higher on the Y or W chromosome than on the other chromosomes in humans (Wyckoff et al 2002) and birds (Berlin and Ellegren 2006) and on the fourth chromosome of Drosophila species (Arguello et al 2010). In contrast, Bullaughey et al (2008) found no correlation between d N /d S and the rate of recombination in primates.It is thought that the correlation between d N /d S or P n /P s and the rate of recombination is due to regions of the genome with little or no recombination having low effective population size and hence reduced effectiveness of natural selection (Betancourt et al 2009). P n /P s is negatively correlated to the rate of recombination because regions with low effective population size allow more slightly deleterious mutations to segregate for a longer time.…”

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confidence: 40%

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Quantifying the Variation in the Effective Population Size Within a Genome

2011

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The effective population size (N e ) is one of the most fundamental parameters in population genetics. It is thought to vary across the genome as a consequence of differences in the rate of recombination and the density of selected sites due to the processes of genetic hitchhiking and background selection. Although it is known that there is intragenomic variation in the effective population size in some species, it is not known whether this is widespread or how much variation in the effective population size there is. Here, we test whether the effective population size varies across the genome, between protein-coding genes, in 10 eukaryotic species by considering whether there is significant variation in neutral diversity, taking into account differences in the mutation rate between loci by using the divergence between species. In most species we find significant evidence of variation. We investigate whether the variation in N e is correlated to recombination rate and the density of selected sites in four species, for which these data are available. We find that N e is positively correlated to recombination rate in one species, Drosophila melanogaster, and negatively correlated to a measure of the density of selected sites in two others, humans and Arabidopsis thaliana. However, much of the variation remains unexplained. We use a hierarchical Bayesian analysis to quantify the amount of variation in the effective population size and show that it is quite modest in all species-most genes have an N e that is within a few fold of all other genes. Nonetheless we show that this modest variation in N e is sufficient to cause significant differences in the efficiency of natural selection across the genome, by demonstrating that the ratio of the number of nonsynonymous to synonymous polymorphisms is significantly correlated to synonymous diversity and estimates of N e , even taking into account the obvious nonindependence between these measures.T HE effective population size (N e ) is one of the most fundamental quantities in population genetics, evolutionary biology, and molecular ecology, since it determines the effectiveness of natural selection and the level of neutral genetic diversity that a population contains (Charlesworth 2009). Populations and regions of the genome with small N e tend to have low levels of genetic diversity, to be susceptible to the accumulation of deleterious mutations through genetic drift, and to have potentially low rates of adaptive evolution (Charlesworth 2009).The effective population size is expected to vary across the genome as a consequence of genetic hitchhiking (Smith and Haigh 1974) and background selection (Charlesworth et al. 1993). The action of both positive and negative natural selection, particularly in regions of the genome with low rates of recombination, is expected to reduce the effective population size leading to lower levels of genetic diversity and reduced effectiveness of selection. Hence variation in the rate of recombination and the density of selected sit...

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supporting

confidence: 81%

contrasting

confidence: 50%

contrasting

confidence: 40%

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Quantifying the Variation in the Effective Population Size Within a Genome

2011

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“…It is, therefore, possible that a greater number of true PSGs exist in regions of high recombination for this reason. However, a recent study found no evidence that recombination affects the efficacy of selection in the human genome (Bullaughey et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Detecting positive selection within genomes: the problem of biased gene conversion

Ratnakumar

Mousset

Glémin

et al. 2010

Phil. Trans. R. Soc. B

137

160

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The identification of loci influenced by positive selection is a major goal of evolutionary genetics. A popular approach is to perform scans of alignments on a genome-wide scale in order to find regions evolving at accelerated rates on a particular branch of a phylogenetic tree. However, positive selection is not the only process that can lead to accelerated evolution. Notably, GC-biased gene conversion (gBGC) is a recombination-associated process that results in the biased fixation of G and C nucleotides. This process can potentially generate bursts of nucleotide substitutions within hotspots of meiotic recombination. Here, we analyse the results of a scan for positive selection on genes on branches across the primate phylogeny. We show that genes identified as targets of positive selection have a significant tendency to exhibit the genomic signature of gBGC. Using a maximumlikelihood framework, we estimate that more than 20 per cent of cases of significantly elevated non-synonymous to synonymous substitution rates ratio (d N /d S ), particularly in shorter branches, could be due to gBGC. We demonstrate that in some cases, gBGC can lead to very high d N /d S (more than 2). Our results indicate that gBGC significantly affects the evolution of coding sequences in primates, often leading to patterns of evolution that can be mistaken for positive selection.

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“…Such differences may be related to the functional categories of genes that reside in regions of low recombination and/or to their expression level. Interestingly, in Drosophila, subsets of loci such as male-biased genes ( (Bullaughey et al 2008), but relationships between local recombination rates and DNA diversity in the human genome are weak (Hellmann et al 2005).…”

Section: Population Size and Rates Of Evolutionmentioning

confidence: 99%

Weak Selection and Protein Evolution

2012

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The "nearly neutral" theory of molecular evolution proposes that many features of genomes arise from the interaction of three weak evolutionary forces: mutation, genetic drift, and natural selection acting at its limit of efficacy. Such forces generally have little impact on allele frequencies within populations from generation to generation but can have substantial effects on long-term evolution. The evolutionary dynamics of weakly selected mutations are highly sensitive to population size, and near neutrality was initially proposed as an adjustment to the neutral theory to account for general patterns in available protein and DNA variation data. Here, we review the motivation for the nearly neutral theory, discuss the structure of the model and its predictions, and evaluate current empirical support for interactions among weak evolutionary forces in protein evolution. Near neutrality may be a prevalent mode of evolution across a range of functional categories of mutations and taxa. However, multiple evolutionary mechanisms (including adaptive evolution, linked selection, changes in fitness-effect distributions, and weak selection) can often explain the same patterns of genome variation. Strong parameter sensitivity remains a limitation of the nearly neutral model, and we discuss concave fitness functions as a plausible underlying basis for weak selection.U NDER the neutral model, newly arising mutations fall into two major fitness classes: strongly deleterious and selectively neutral (Kimura 1968;King and Jukes 1969). The first class is well supported by mutation accumulation experiments (reviewed in Simmons and Crow 1977;Halligan and Keightley 2009) and early DNA sequence comparisons (Grunstein et al. 1976;Kafatos et al. 1977) and is shared among competing evolutionary models. The novel and controversial aspect of the neutral theory was the proposition that, among mutations that go to fixation, the vast majority are selectively neutral. Advantageous substitutions, although important in phenotypic evolution, are sufficiently rare at the molecular level that they need not be considered to adequately model the process. Under the neutral theory, within-and between-species variation sample two aspects of a process of origination by mutation and changes in gene frequency dominated by drift and, for some mutations, negative selection (Kimura and Ohta 1971a). In contrast, polymorphism and divergence may be "uncoupled" under selection models (Gillespie 1987). Protein polymorphism and the neutral model: invariance of heterozygosityClear predictions for levels of polymorphism within populations and divergence among species are appealing aspects of the neutral model. However, within a few years of its proposal, the notion of drift-dominated evolution was challenged by overall patterns of allozyme polymorphism and contrasts between DNA and protein divergence.Although evolutionary geneticists were generally surprised by the extent of naturally occurring variation revealed by allozyme gel electrophoresis in the 197...

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No effect of recombination on the efficacy of natural selection in primates

Cited by 54 publications

References 77 publications

Quantifying the Variation in the Effective Population Size Within a Genome

Quantifying the Variation in the Effective Population Size Within a Genome

Detecting positive selection within genomes: the problem of biased gene conversion

Weak Selection and Protein Evolution

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