Stabilizing Selection, Purifying Selection, and Mutational Bias in Finite Populations

Charlesworth, Brian

doi:10.1534/genetics.113.151555

Cited by 56 publications

(79 citation statements)

References 79 publications

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“…We make the assumption that the strength of selection, included in k, and the shape of the DFE remain constant as N e changes; however, this is unlikely to be the case (although there is evidence to suggest that the strength of selection can be nearly independent of N e in some evolutionary scenarios (Charlesworth, 2013)). It may be that generally there is a negative relationship between k and N e across the species in our data set: this would result in making the slope of the relationship steeper than that predicted by the shape parameter of the gamma distribution.…”

Section: Discussionmentioning

confidence: 99%

DNA sequence diversity and the efficiency of natural selection in animal mitochondrial DNA

2016

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Selection is expected to be more efficient in species that are more diverse because both the efficiency of natural selection and DNA sequence diversity are expected to depend upon the effective population size. We explore this relationship across a data set of 751 mammal species for which we have mitochondrial polymorphism data. We introduce a method by which we can examine the relationship between our measure of the efficiency of natural selection, the nonsynonymous relative to the synonymous nucleotide site diversity (π N /π S ), and synonymous nucleotide diversity (π S ), avoiding the statistical non-independence between the two quantities. We show that these two variables are strongly negatively and linearly correlated on a log scale. The slope is such that as π S doubles, π N /π S is reduced by 34%. We show that the slope of this relationship differs between the two phylogenetic groups for which we have the most data, rodents and bats, and that it also differs between species with high and low body mass, and between those with high and low mass-specific metabolic rate.

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Section: Discussionmentioning

confidence: 99%

DNA sequence diversity and the efficiency of natural selection in animal mitochondrial DNA

2016

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“…It has recently been argued that some genomic features may exhibit evolutionary behaviors that are nearly independent of population size, particularly when such features are linearly related to a phenotypic trait under stabilizing selection (53). However, a central conclusion from the preceding theory is that the evolutionary behavior of binding interfaces is strongly influenced by N e , even when the level of gene expression is under stabilizing selection.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary meandering of intermolecular interactions along the drift barrier

Lynch¹,

Hagner

2014

Proc. Natl. Acad. Sci. U.S.A.

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Many cellular functions depend on highly specific intermolecular interactions, for example transcription factors and their DNA binding sites, microRNAs and their RNA binding sites, the interfaces between heterodimeric protein molecules, the stems in RNA molecules, and kinases and their response regulators in signaltransduction systems. Despite the need for complementarity between interacting partners, such pairwise systems seem to be capable of high levels of evolutionary divergence, even when subject to strong selection. Such behavior is a consequence of the diminishing advantages of increasing binding affinity between partners, the multiplicity of evolutionary pathways between selectively equivalent alternatives, and the stochastic nature of evolutionary processes. Because mutation pressure toward reduced affinity conflicts with selective pressure for greater interaction, situations can arise in which the expected distribution of the degree of matching between interacting partners is bimodal, even in the face of constant selection. Although biomolecules with larger numbers of interacting partners are subject to increased levels of evolutionary conservation, their more numerous partners need not converge on a single sequence motif or be increasingly constrained in more complex systems. These results suggest that most phylogenetic differences in the sequences of binding interfaces are not the result of adaptive fine tuning but a simple consequence of random genetic drift. cellular evolution | molecular interaction | transcription | random genetic drift | coevolution M uch of biology relies on the specificity of intermolecular interactions-the regulation of gene expression, the transmission of information via signal transduction, the assembly of monomeric subunits into multimers, vesicle sorting in eukaryotic cells, toxin-antitoxin systems in microbes, mating-type recognition, and many other cellular features. Although the basic structural features of such fitness-related traits would seem to be under strong purifying selection, molecular specificity often seems to be highly flexible in evolutionary time. For example, transcription-factor binding-site motifs often vary dramatically among orthologous genes in different species and even among similarly regulated genes within the same species (1-3). The binding interfaces of multimeric proteins can vary substantially among species, sometimes with no overlap at all (4, 5). The key amino acid sequences involved in intermolecular cross-talk in signal-transduction systems can evolve at high rates (6, 7), and growing evidence suggests that the locations of sites involved in posttranslational modification in individual proteins are under much weaker selective constraints than their absolute numbers (8). Although it is often argued that subtle differences in the motifs involved in intermolecular interactions are molded by the demands of natural selection, seldom has any direct evidence ever been provided in support of such arguments.The theory provided below makes the case...

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“…It is interesting in this context to note that there is only a small difference in the mean level of codon usage bias between C. brenneri and C. remanei, despite an approximately threefold difference in synonymous site diversity (A. Cutter, personal communication). This raises the question of whether the purifying selection model used here is appropriate for codon usage or whether a model of stabilizing selection (Kimura 1981) is more realistic, since the latter means that g is insensitive to N e over a wide range of parameter values, provided that there is mutational bias (Charlesworth 2013). The behavior of this model with hyperdiversity would, therefore, be worth studying.…”

Section: Some Other Implicationsmentioning

confidence: 99%

Purifying Selection, Drift, and Reversible Mutation with Arbitrarily High Mutation Rates

Charlesworth

Jain

2014

Genetics

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Some species exhibit very high levels of DNA sequence variability; there is also evidence for the existence of heritable epigenetic variants that experience state changes at a much higher rate than sequence variants. In both cases, the resulting high diversity levels within a population (hyperdiversity) mean that standard population genetics methods are not trustworthy. We analyze a population genetics model that incorporates purifying selection, reversible mutations, and genetic drift, assuming a stationary population size. We derive analytical results for both population parameters and sample statistics and discuss their implications for studies of natural genetic and epigenetic variation. In particular, we find that (1) many more intermediate-frequency variants are expected than under standard models, even with moderately strong purifying selection, and (2) rates of evolution under purifying selection may be close to, or even exceed, neutral rates. These findings are related to empirical studies of sequence and epigenetic variation.T HE infinite sites model, originally proposed by Fisher (1922Fisher ( , 1930 and developed in detail by Kimura (1971), has been the workhorse of molecular population genetics for four decades. Its core assumption is that any nucleotide site segregates for at most two variants and that the mutation rate scaled by effective population size (N e ) is so low that new mutations arise only at sites that are fixed within the population (see also Charlesworth and Charlesworth 2010, p. 207). This assumption facilitates calculations of the theoretical values of some key observable quantities, such as the expected level of pairwise nucleotide site diversity or the expected number of segregating sites in a sample (Kimura 1971;Watterson 1975;Ewens 2004). In the framework of coalescent theory, this implies a linear relation between the genealogical distance between two sequences and the neutral sequence divergence between them, greatly simplifying methods of inference and statistical testing (Hudson 1990;Wakeley 2008).There has recently been some discussion of how to go beyond the infinite sites assumption of a low scaled mutation rate, which breaks down for species with very large effective population sizes, including some species of virus and bacteria, and even eukaryotes such as the sea squirt and outbreeding nematode worms, resulting in "hyperdiversity" of DNA sequence variability within a population . It is important to note, however, that this problem can arise even when the scaled mutation rate is relatively low, since then the proportion of neutral nucleotide sites that are currently segregating in a population (which depends on the scaled mutation rate) can be substantial when the population size is sufficiently large. For example, with a neutral mutation rate of u per site in a population of N breeding adults, the expected fraction of sites that are segregating in a randomly mating population is f s = u [ln(2N) + 0.6775], where u = 4N e u (Ewens 2004, p. 298). Thus, with u =...

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Stabilizing Selection, Purifying Selection, and Mutational Bias in Finite Populations

Cited by 56 publications

References 79 publications

DNA sequence diversity and the efficiency of natural selection in animal mitochondrial DNA

DNA sequence diversity and the efficiency of natural selection in animal mitochondrial DNA

Evolutionary meandering of intermolecular interactions along the drift barrier

Purifying Selection, Drift, and Reversible Mutation with Arbitrarily High Mutation Rates

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