Biology subjects

Charlesworth, B.

Publications and source records attributed to Charlesworth, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Maintenance of quantitative genetic variation in regions of restricted recombination via associative overdominance

Mutation-selection balance is the most plausible general mechanism for the maintenance of additive genetic variance (VA) for quantitative traits in natural populations. It is well established that the genetic variants affecting traits (QTLs) are widely distributed across species' genomes. At the same time, unconditionally deleterious mutations are also expected to be common, with those with the largest fitness effects tending to be strongly recessive. Many genomes possess regions of restricted recombination that could result in tight linkage between largely recessive deleterious alleles, conditions which can lead to elevated heterozygosity via associative overdominance (AOD). Here we show that weakly selected QTLs linked to genomic regions exhibiting AOD can elevate VA above what is expected in the absence of unconditionally deleterious mutations. Selection on traits when VA is maintained by AOD, however, may expose recessive deleterious alleles as homozygotes, reducing fitness. Thus, while AOD may contribute to the maintenance of VA, variation maintained in this way may not be readily accessible by natural or artificial selection.

evolutionary biology↗

bioRxiv2026

The effect of a reduction in population size on mean fitness and inbreeding depression

A sudden reduction in population size increases the rate of genetic drift, reducing variability and increasing the mean level of homozygosity. The resulting increase in exposure of strongly deleterious, recessive or partially recessive alleles to selection against homozygotes may lead to their being purged from the population, potentially allowing mean fitness to increase after an initial decline, and accelerating the decline in inbreeding depression associated with reduced variability. However, detailed population genetic theory on the effects of population bottlenecks on mean fitness and inbreeding depression remains limited. We develop a theoretical framework for small, randomly mating populations founded from a large population at mutation-selection-drift equilibrium, using both simulations and approximate analytical results. These provide quantitative predictions for the dynamics of the population's mean fitness and level of inbreeding depression following a bottleneck. In particular, we derive an approximate expression for the time needed for mean fitness to recover after an initial decline; such a recovery requires selection to be sufficiently strong relative to drift, and mutations to be sufficiently recessive. In contrast, weakly deleterious mutations cause reductions in mean fitness and inbreeding depression that are similar in size to those predicted from increases in homozygosity for neutral alleles, over the relatively short timescales considered here.

genetics↗

bioRxiv2025

Beyond Recombination: Exploring the Impact of Meiotic Frequency on Genome-wide Genetic Diversity

An important aim of population genetics is to elucidate the processes affecting genetic diversity across regions of the genome and across species. Canonical population genetic models of sexually reproducing species define the rate of meiotic recombination in terms of the frequency of recombination events per site per sexual generation. This paper studies the interplay of several factors with respect to their effects on neutral genetic diversity in a facultatively sexual, diploid, unicellular species such as yeast. The relevant factors are the prevalence of meiosis versus mitosis, the recombination rate, and the selection and dominance coefficients at loci under positive selection. We assume that many generations of mitotic cell divisions are interspersed with episodes of sexual reproduction, in which all individuals in the population undergo meiosis, followed by random matings among the resulting gametes. Our findings reveal that a single hard selective sweep can reduce neutral nucleotide site diversity across the entire genome, provided that the frequency of meiotic events is sufficiently low, and that the effects of a selective sweep on levels of neutral diversity at sites linked to the target of selection can be markedly different from those predicted by standard models of sweeps based on obligate sexuality. Species that reproduce by facultative sex are thus likely to exhibit unusual patterns of genetic diversity. Author summaryIn this study, we explored how different sexual strategies influence genetic diversity. Specifically, we looked at how the balance between sexual reproduction (which involves meiosis) and asexual reproduction (which involves mitosis) affect genetic variation in a species like yeast. Our research focused on the effects of recombination rates and the role of selective sweeps -- when a beneficial genetic variant spreads rapidly through a population -- on genetic diversity. We found that, in species with facultative sex, a selective sweep can dramatically reduce genetic diversity across the genome, but only if sexual reproduction occurs infrequently. We compared our findings to existing models and also developed a new mathematical framework for understanding the effects of sweeps when sexual reproduction is rare. The fact that facultative sex can reduce genetic diversity over the entire genome is likely to complicate inferences about population size and evolutionary dynamics in species with mixed reproductive strategies.

genetics↗

bioRxiv2025

A gene-based model of fitness and its implications for genetic variation: Genetic and inbreeding loads

In the companion paper to this, we examined the consequences for patterns of linkage disequilibrium of the "gene" model of fitness, which postulates that the effects of recessive or partially recessive deleterious mutations located at different sites within a gene fail to complement each other. Here, we examine the consequences of the gene model for the genetic and inbreeding loads, using both analytical and simulation methods, and contrast it with the frequently used "sites" model that allows allelic complementation. We show that the gene model results in a slightly lower genetic load, but a much smaller inbreeding load, than the sites model, implying that standard predictions of mutational contributions to inbreeding depression may be overestimates. Synergistic epistasis between pairs of mutations was also modeled, and shown to considerably reduce the inbreeding load for both the gene and sites models. The theoretical results are discussed in relation to data on inbreeding load in Drosophila melanogaster. The widespread assumption that inbreeding depression is largely due to deleterious mutations should be re-examined in the light of our findings.

evolutionary biology↗

bioRxiv2024

A model of Hill-Robertson interference caused by purifying selection in a non-recombining genome

A new approach to modeling the effects of Hill-Robertson interference on levels of adaptation and patterns of variability in a non-recombining genome or genomic region is described. The model assumes a set of L diallelic sites subject to reversible mutations between beneficial and deleterious alleles, with the same selection coefficient at each site. The assumption of reversibility allows the system to reach a stable statistical equilibrium with respect to the frequencies of deleterious mutations, in contrast to many previous models that assume irreversible mutations to deleterious alleles. The model is therefore appropriate for understanding the long-term properties of non-recombining genomes such as Y chromosomes, and is applicable to haploid genomes or to diploid genomes when there is intermediate dominance with respect to the effects of mutations on fitness. Approximations are derived for the equilibrium frequencies of deleterious mutations, the effective population size that controls the fixation probabilities of mutations at sites under selection, the nucleotide site diversity at neutral sites located within the non-recombining region, and the site frequency spectrum for segregating neutral variants. The approximations take into account the effects of linkage disequilibrium on the genetic variance at sites under selection. Comparisons with published and new computer simulation results show that the approximations are sufficiently accurate to be useful, and can provide insights into a wider range of parameter sets than is accessible by simulation. The relevance of the findings to data on non-recombining genome regions is discussed.

evolutionary biology↗

bioRxiv2024

A gene-based model of fitness and its implications for genetic variation

A widely used model of the effects of mutations on fitness (the "sites" model) assumes that heterozygous recessive or partially recessive deleterious mutations at different sites in a gene complement each other, similarly to mutations in different genes. However, the general lack of complementation between major effect allelic mutations suggests an alternative possibility, which we term the "gene" model. This assumes that a pair of heterozygous deleterious mutations in trans behave effectively as homozygotes, so that the fitnesses of trans heterozygotes are lower than those of cis heterozygotes. We examine the properties of the two different models, using both analytical and simulation methods. We show that the gene model predicts positive linkage disequilibrium (LD) between deleterious variants within the coding sequence, under conditions when the sites model predicts zero or slightly negative LD. We also show that focussing on rare variants when examining patterns of LD, especially with Lewontins D measure, is likely to produce misleading results with respect to inferences concerning the causes of the sign of LD. Synergistic epistasis between pairs of mutations was also modeled; it is less likely to produce negative LD under the gene model than the sites model. The theoretical results are discussed in relation to patterns of LD in natural populations of several species.

evolutionary biology↗

bioRxiv2023

Do deleterious mutations promote the evolution ofrecombination suppression between X and Y chromosomes?

An interesting new model has recently been proposed for the evolution of suppressed recombination between newly evolving X and Y chromosomes, where males are heterozygous for a locus determining sex and females are homozygous (the same principles apply to systems with female heterogamety, with the role of the two sexes reversed). The model appeals to the selective advantage that accrues to a recombination suppressor (e.g., an inversion), which arises on a male-determining haplotype that carries a smaller number of deleterious mutations than average and remains completely associated with the sex determining locus. The underlying logic of the model rests on the idea that, because such an inversion cannot become homozygous, it is "sheltered" from selection against any deleterious recessive mutations it may carry, in contrast to an autosomal inversion. It has been claimed that computer simulations of this process show that the probability that a new inversion becomes fixed within the population of Y chromosomes is substantially higher than expected under selective neutrality, and higher than that for a comparable autosomal inversion. However, analytical population genetic models of some special cases cast doubt on the magnitude of the selective advantage claimed for Y-linked inversions under this process, demanding re-evaluation of the simulation results. The published estimates of fixation probabilities of Y-linked inversions were in fact calculated after excluding inversions that were lost in the first 20 generations. This generates a substantial bias towards high fixation probabilities and obscures comparisons with neutrality. If all simulation runs are included, most parameter sets yield estimates of fixation probabilities that are close to neutral expectation, unless deleterious mutations are close to being completely recessive. The proposed sheltering mechanism is unlikely to provide a robust selective advantage to inversions suppressing recombination between evolving X and Y (or Z and W) chromosomes.

evolutionary biology↗

bioRxiv2023

The fitness consequences of genetic divergence between polymorphic gene arrangements

Inversions restrict recombination when heterozygous with standard arrangements, but often have few noticeable phenotypic effects. Nevertheless, there are several examples of inversions that can be maintained polymorphic by strong selection under laboratory conditions. A long-standing model for the source of such selection is divergence between arrangements with respect to recessive or partially recessive deleterious mutations, resulting in a selective advantage to heterokaryotypic individuals over homokaryotypes. This paper uses a combination of analytical and numerical methods to investigate this model, for the simple case of an autosomal inversion with multiple independent nucleotide sites subject to deleterious mutations. A complete lack of recombination in heterokaryotypes is assumed, as well as constancy of the frequency of the inversion over space and time. It is shown that a significantly higher mutational load will develop for the less frequent arrangement. A selective advantage to heterokaryotypes is only expected when the two alternative arrangements are nearly equal in frequency, so that their mutational loads are very similar in size. The effects of some Drosophila pseudoobscura polymorphic inversions on fitness traits seem to be too large to be explained by this process, although it may contribute to some of the observed effects. Several population genomic statistics can provide evidence for signatures of a reduced efficacy of selection associated with the rarer of two arrangements, but there is currently little published data that are relevant to the theoretical predictions.

genetics↗

bioRxiv2023

The effects of inversion polymorphisms on patterns of neutral genetic diversity

The strong reduction in the frequency of recombination in heterozygotes for an inversion and a standard gene arrangement causes the arrangements to become partially isolated genetically, resulting in sequence divergence between them and changes in the levels of neutral variability at nucleotide sites within each arrangement class. Previous theoretical studies on the effects of inversions on neutral variability have either assumed that the population is panmictic or that it is divided into two populations subject to divergent selection. Here, the theory is extended to a model of an arbitrary number of demes connected by migration, using a finite island model with the inversion present at the same frequency in all demes. Recursion relations for mean pairwise coalescent times are used to obtain simple approximate expressions for diversity and divergence statistics for an inversion polymorphism at equilibrium under recombination and drift, and for the approach to equilibrium following the sweep of an inversion to a stable intermediate frequency. The effects of an inversion polymorphism on patterns of linkage disequilibrium are also examined. The reduction in effective recombination rate caused by population subdivision can have significant effects on these statistics. The theoretical results are discussed in relation to population genomic data on inversion polymorphisms, with an emphasis on Drosophila melanogaster. Methods are proposed for testing whether or not inversions are close to recombination-drift equilibrium, and for estimating the rate of recombinational exchange in heterozygotes for inversions; difficulties involved in estimating the ages of inversions are also discussed.

genetics↗

bioRxiv2021

The effects of weak selection on neutral diversity at linked sites

The effects of selection on variability at linked sites have an important influence on levels and patterns of within-population variation across the genome. Most theoretical models of these effects have assumed that selection is sufficiently strong that allele frequency changes at the loci concerned are largely deterministic. These models have led to the conclusion that directional selection for selectively favorable mutations, or against recurrent deleterious mutations, reduces nucleotide site diversity at linked neutral sites. Recent work has shown, however, that fixations of weakly selected mutations, accompanied by significant stochastic changes in allele frequencies, can sometimes cause higher diversity at linked sites when compared with the effects of fixations of neutral mutations. The present paper extends this work by deriving approximate expressions for the mean conditional times to fixation and loss of mutations subject to selection, and analysing the conditions under which selection increases rather than reduces these times. Simulations are used to examine the relations between diversity at a neutral site and the fixation and loss times of mutations at a linked site that is subject to selection. It is shown that the long-term level of neutral diversity can be increased over the purely neutral value by recurrent fixations and losses of linked, weakly selected dominant or partially dominant favorable mutations, or linked recessive or partially recessive deleterious mutations. The results are used to examine the conditions under which associative overdominance, as opposed to background selection, is likely to operate.

evolutionary biology↗

bioRxiv2021

Statistical inference in population genomics

The field of population genomics has grown rapidly in response to the recent advent of affordable, large-scale sequencing technologies. As opposed to the situation during the majority of the 20th century, in which the development of theoretical and statistical population-genetic insights out-paced the generation of data to which they could be applied, genomic data are now being produced at a far greater rate than they can be meaningfully analyzed and interpreted. With this wealth of data has come a tendency to focus on fitting specific (and often rather idiosyncratic) models to data, at the expense of a careful exploration of the range of possible underlying evolutionary processes. For example, the approach of directly investigating models of adaptive evolution in each newly sequenced population or species often neglects the fact that a thorough characterization of ubiquitous non-adaptive processes is a prerequisite for accurate inference. We here describe the perils of these tendencies, present our consensus views on current best practices in population genomic data analysis, and highlight areas of statistical inference and theory that are in need of further attention. Thereby, we argue for the importance of defining a biologically relevant baseline model tuned to the details of each new analysis, of skepticism and scrutiny in interpreting model-fitting results, and of carefully defining addressable hypotheses and underlying uncertainties.

evolutionary biology↗

bioRxiv2021

Selective sweeps influence diversity over large regions of the mouse genome

To what extent do substitutions in protein-coding versus gene-regulatory regions contribute to fitness change over time? Answering this question requires estimates of the extent of selection acting on beneficial mutations in the two classes of sites. New mutations that have advantageous or deleterious fitness effects can induce selective sweeps and background selection, respectively, causing variation in the level of neutral genetic diversity along the genome. In this study, we analyse the profiles of genetic variability around protein-coding and regulatory elements in the genomes of wild mice to estimate the parameters of positive selection. We find patterns of diversity consistent with the effects of selection at linked sites, which are similar across mouse taxa, despite differences in effective population size and demographic history. By fitting a model that combines the effects of selective sweeps and background selection, we estimate the strength of positive selection and the frequency of advantageous mutations. We find that strong positive selection is required to explain variation in genetic diversity across the murid genome. In particular, we estimate that beneficial mutations in protein-coding regions have stronger effects on fitness than do mutations in gene-regulatory regions, but that mutations in gene-regulatory regions are more common. Overall though, our parameter estimates suggest that the cumulative fitness changes brought about by beneficial mutations in protein-coding may be greater than those in gene-regulatory elements.

evolutionary biology↗

bioRxiv2021

Evidence for a force favouring GC over AT at short intronic sites in Drosophila simulans and D. melanogaster

Population genetics studies often make use of a class of nucleotide site free from selective pressures in order to make inferences about population size changes or natural selection at other sites. If such neutral sites can be identified, they offer the opportunity to avoid any confounding effects of selection. Here we investigate evolution at putatively neutrally evolving short intronic sites in natural populations of Drosophila melanogaster and D. simulans, in order to understand the properties of spontaneous mutations and the extent of GC-biased gene conversion in these species. Use of data on the genetics of natural populations is advantageous because it integrates information from large numbers of individuals over long timescales. In agreement with direct evidence from observations of spontaneous mutations in Drosophila, we find a bias in the spectrum of mutations towards AT basepairs. In addition, we find that this bias is stronger in the D. melanogaster lineage than the D. simulans lineage. The evidence for GC-biased gene conversion in Drosophila has been equivocal. Here we provide evidence for a weak force favouring GC in both species, which is stronger in D. simulans. Some homologous short intronic sites have diverged in GC content between the two species, which may have been caused by lineage-specific changes in the extent to which different regions of the genome are subject to a GC (or AT)-favouring force.

genetics↗

bioRxiv2020

Revisiting the notion of deleterious sweeps

It has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations could generate selective sweep-like effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites - both in the presence and absence of interference amongst deleterious mutations - and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious fixations are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of FST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration.

evolutionary biology↗

bioRxiv2020

Studying models of balancing selection usingphase-type theory

Balancing selection (BLS) is the evolutionary force that maintains high levels of genetic variability in many important genes. To further our understanding of its evolutionary significance, we analyse models with BLS acting on a biallelic locus: an equilibrium model with long-term BLS, a model with long-term BLS and recent changes in population size, and a model of recent BLS. Using phase-type theory, a mathematical tool for analysing continuous time Markov chains with an absorbing state, we examine how BLS affects polymorphism patterns in linked neutral regions, as summarised by nucleotide diversity, the expected number of segregating sites, the site frequency spectrum, and the level of linkage disequilibrium (LD). Long-term BLS affects polymorphism patterns in a relatively small genomic neighbourhood, and such selection targets are easier to detect when the equilibrium frequencies of the selected variants are close to 50%, or when there has been a population size reduction. For a new mutation subject to BLS, its initial increase in frequency in the population causes linked neutral regions to have reduced diversity, an excess of both high and low frequency derived variants, and elevated LD with the selected locus. These patterns are similar to those produced by selective sweeps, but the effects of recent BLS are weaker. Nonetheless, compared to selective sweeps, non-equilibrium polymorphism and LD patterns persist for a much longer period under recent BLS, which may increase the chance of detecting such selection targets. An R package for analysing these models, among others (e.g., isolation with migration), is available.

evolutionary biology↗

bioRxiv2020

How good are predictions of the effects of selective sweeps on levels of neutral diversity?

Selective sweeps are thought to play a significant role in shaping patterns of variability across genomes; accurate predictions of their effects are, therefore, important for understanding these patterns. A commonly used model of selective sweeps assumes that alleles sampled at the end of a sweep, and that fail to recombine with wild-type haplotypes during the sweep, coalesce instantaneously, leading to a simple expression for sweep effects on diversity. It is shown here that there can be a significant probability that a pair of alleles sampled at the end of a sweep coalesce during the sweep before a recombination event can occur, reducing their expected coalescent time below that given by the simple approximation. Expressions are derived for the expected reductions in pairwise neutral diversities caused by both single and recurrent sweeps in the presence of such within-sweep coalescence, although the effects of multiple recombination events during a sweep are only treated heuristically. The accuracies of the resulting expressions were checked against the results of simulations. For even moderate ratios of the recombination rate to the selection coefficient, the simple approximation can be substantially inaccurate. The selection model used here can be applied to favorable mutations with arbitrary dominance coefficients, to sex-linked loci with sex-specific selection coefficients, and to inbreeding populations. Using the results from this model, the expected differences between the levels of variability on X chromosomes and autosomes with selection at linked sites are discussed, and compared with data on a population of Drosophila melanogaster.

evolutionary biology↗

bioRxiv2019

Towards an evolutionarily appropriate null model: jointly inferring demography and purifying selection

The question of the relative evolutionary roles of adaptive and non-adaptive processes has been a central debate in population genetics for nearly a century. While advances have been made in the theoretical development of the underlying models, and statistical methods for estimating their parameters from large-scale genomic data, a framework for an appropriate null model remains elusive. A model incorporating evolutionary processes known to be in constant operation - genetic drift (as modulated by the demographic history of the population) and purifying selection - is lacking. Without such a null model, the role of adaptive processes in shaping within- and between-population variation may not be accurately assessed. Here, we investigate how population size changes and the strength of purifying selection affect patterns of variation at neutral sites near functional genomic components. We propose a novel statistical framework for jointly inferring the contribution of the relevant selective and demographic parameters. By means of extensive performance analyses, we quantify the utility of the approach, identify the most important statistics for parameter estimation, and compare the results with existing methods. Finally, we re-analyze genome-wide population-level data from a Zambian population of Drosophila melanogaster, and find that it has experienced a much slower rate of population growth than was inferred when the effects of purifying selection were neglected. Our approach represents an appropriate null model, against which the effects of positive selection can be assessed.

evolutionary biology↗

bioRxiv2019

Patterns of genetic variability in genomic regions with low rates of recombination

Surveys of DNA sequence variation have shown that the level of genetic variability in a genomic region is often strongly positively correlated with its rate of crossing over (CO) [1-3]. This pattern is caused by selection acting on linked sites, which reduces genetic variability and can also cause the frequency distribution of segregating variants to contain more rare variants than expected without selection (skew). These effects of selection may involve the spread of beneficial mutations (selective sweeps, SSWs), the elimination of deleterious mutations (background selection, BGS) or both together, and are expected to be stronger with lower rates of crossing over [1-3]. However, in a recent study of human populations, the skew was reduced in the lowest CO regions compared with regions with somewhat higher CO rates [4]. A similar pattern is seen in the population genomic studies of Drosophila simulans described here. We propose an explanation for this paradoxical observation, and validate it using computer simulations. This explanation is based on the finding that partially recessive, linked deleterious mutations can increase rather than reduce neutral variability when the product of the effective population size (Ne) and the selection coefficient against homozygous carriers of mutations (s) is [≤] 1, i.e. there is associative overdominance (AOD) rather than BGS [5]. We show that AOD can operate in a genomic region with a low rate of CO, opening up a new perspective on how selection affects patterns of variability at linked sites.

evolutionary biology↗