@article{20848, abstract = {Genetic variation that influences complex disease susceptibility is introduced into the population by mutation and removed by natural selection and genetic drift. This mutation–selection–drift balance (MSDB) shapes the prevalence of a disease and its genetic architecture. To date, however, MSDB has been modeled only for monogenic (Mendelian) diseases. Here, we develop an MSDB model for complex disease susceptibility: we assume that genotype relates to disease risk according to the canonical liability threshold model and that the selection on variants affecting risk stems from the fitness cost of the disease. We focus on diseases that are highly polygenic, entail a substantial fitness cost, and are neither extremely common in the population nor exceedingly rare. The comparison of model predictions with genome-wide association studies and other observations in humans indicates that common genetic variation affecting complex disease susceptibility is little affected by directional selection and instead shaped by pleiotropic stabilizing selection on other traits. In turn, directional selection may exert a more substantial effect on rare, large-effect variants. Our results also suggest that current estimates of disease heritability are likely biased. The model thus provides a better understanding of the evolutionary processes that shape the architecture and prevalence of complex diseases.}, author = {Berg, Jeremy J. and Li, Xinyi and Riall, Kellen and Hayward, Laura and Sella, Guy}, issn = {1943-2631}, journal = {Genetics}, number = {4}, publisher = {Oxford University Press}, title = {{Mutation–selection–drift balance models of complex diseases}}, doi = {10.1093/genetics/iyaf220}, volume = {231}, year = {2025}, } @article{14452, abstract = {The classical infinitesimal model is a simple and robust model for the inheritance of quantitative traits. In this model, a quantitative trait is expressed as the sum of a genetic and an environmental component, and the genetic component of offspring traits within a family follows a normal distribution around the average of the parents’ trait values, and has a variance that is independent of the parental traits. In previous work, we showed that when trait values are determined by the sum of a large number of additive Mendelian factors, each of small effect, one can justify the infinitesimal model as a limit of Mendelian inheritance. In this paper, we show that this result extends to include dominance. We define the model in terms of classical quantities of quantitative genetics, before justifying it as a limit of Mendelian inheritance as the number, M, of underlying loci tends to infinity. As in the additive case, the multivariate normal distribution of trait values across the pedigree can be expressed in terms of variance components in an ancestral population and probabilities of identity by descent determined by the pedigree. Now, with just first-order dominance effects, we require two-, three-, and four-way identities. We also show that, even if we condition on parental trait values, the “shared” and “residual” components of trait values within each family will be asymptotically normally distributed as the number of loci tends to infinity, with an error of order 1/M−−√⁠. We illustrate our results with some numerical examples.}, author = {Barton, Nicholas H and Etheridge, Alison M. and Véber, Amandine}, issn = {1943-2631}, journal = {Genetics}, number = {2}, publisher = {Oxford University Press}, title = {{The infinitesimal model with dominance}}, doi = {10.1093/genetics/iyad133}, volume = {225}, year = {2023}, } @article{7400, abstract = {Suppressed recombination allows divergence between homologous sex chromosomes and the functionality of their genes. Here, we reveal patterns of the earliest stages of sex-chromosome evolution in the diploid dioecious herb Mercurialis annua on the basis of cytological analysis, de novo genome assembly and annotation, genetic mapping, exome resequencing of natural populations, and transcriptome analysis. The genome assembly contained 34,105 expressed genes, of which 10,076 were assigned to linkage groups. Genetic mapping and exome resequencing of individuals across the species range both identified the largest linkage group, LG1, as the sex chromosome. Although the sex chromosomes of M. annua are karyotypically homomorphic, we estimate that about one-third of the Y chromosome, containing 568 transcripts and spanning 22.3 cM in the corresponding female map, has ceased recombining. Nevertheless, we found limited evidence for Y-chromosome degeneration in terms of gene loss and pseudogenization, and most X- and Y-linked genes appear to have diverged in the period subsequent to speciation between M. annua and its sister species M. huetii, which shares the same sex-determining region. Taken together, our results suggest that the M. annua Y chromosome has at least two evolutionary strata: a small old stratum shared with M. huetii, and a more recent larger stratum that is probably unique to M. annua and that stopped recombining ∼1 MYA. Patterns of gene expression within the nonrecombining region are consistent with the idea that sexually antagonistic selection may have played a role in favoring suppressed recombination.}, author = {Veltsos, Paris and Ridout, Kate E. and Toups, Melissa A and González-Martínez, Santiago C. and Muyle, Aline and Emery, Olivier and Rastas, Pasi and Hudzieczek, Vojtech and Hobza, Roman and Vyskot, Boris and Marais, Gabriel A. B. and Filatov, Dmitry A. and Pannell, John R.}, issn = {1943-2631}, journal = {Genetics}, number = {3}, pages = {815--835}, publisher = {Genetics Society of America}, title = {{Early sex-chromosome evolution in the diploid dioecious plant Mercurialis annua}}, doi = {10.1534/genetics.119.302045}, volume = {212}, year = {2019}, } @article{7723, abstract = {Genome-wide association studies (GWAS) have identified thousands of loci that are robustly associated with complex diseases. The use of linear mixed model (LMM) methodology for GWAS is becoming more prevalent due to its ability to control for population structure and cryptic relatedness and to increase power. The odds ratio (OR) is a common measure of the association of a disease with an exposure (e.g., a genetic variant) and is readably available from logistic regression. However, when the LMM is applied to all-or-none traits it provides estimates of genetic effects on the observed 0–1 scale, a different scale to that in logistic regression. This limits the comparability of results across studies, for example in a meta-analysis, and makes the interpretation of the magnitude of an effect from an LMM GWAS difficult. In this study, we derived transformations from the genetic effects estimated under the LMM to the OR that only rely on summary statistics. To test the proposed transformations, we used real genotypes from two large, publicly available data sets to simulate all-or-none phenotypes for a set of scenarios that differ in underlying model, disease prevalence, and heritability. Furthermore, we applied these transformations to GWAS summary statistics for type 2 diabetes generated from 108,042 individuals in the UK Biobank. In both simulation and real-data application, we observed very high concordance between the transformed OR from the LMM and either the simulated truth or estimates from logistic regression. The transformations derived and validated in this study improve the comparability of results from prospective and already performed LMM GWAS on complex diseases by providing a reliable transformation to a common comparative scale for the genetic effects.}, author = {Lloyd-Jones, Luke R. and Robinson, Matthew Richard and Yang, Jian and Visscher, Peter M.}, issn = {0016-6731}, journal = {Genetics}, number = {4}, pages = {1397--1408}, publisher = {Genetics Society of America}, title = {{Transformation of summary statistics from linear mixed model association on all-or-none traits to odds ratio}}, doi = {10.1534/genetics.117.300360}, volume = {208}, year = {2018}, } @article{39, abstract = {We study how a block of genome with a large number of weakly selected loci introgresses under directional selection into a genetically homogeneous population. We derive exact expressions for the expected rate of growth of any fragment of the introduced block during the initial phase of introgression, and show that the growth rate of a single-locus variant is largely insensitive to its own additive effect, but depends instead on the combined effect of all loci within a characteristic linkage scale. The expected growth rate of a fragment is highly correlated with its long-term introgression probability in populations of moderate size, and can hence identify variants that are likely to introgress across replicate populations. We clarify how the introgression probability of an individual variant is determined by the interplay between hitchhiking with relatively large fragments during the early phase of introgression and selection on fine-scale variation within these, which at longer times results in differential introgression probabilities for beneficial and deleterious loci within successful fragments. By simulating individuals, we also investigate how introgression probabilities at individual loci depend on the variance of fitness effects, the net fitness of the introduced block, and the size of the recipient population, and how this shapes the net advance under selection. Our work suggests that even highly replicable substitutions may be associated with a range of selective effects, which makes it challenging to fine map the causal loci that underlie polygenic adaptation.}, author = {Sachdeva, Himani and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {4}, pages = {1411--1427}, publisher = {Genetics Society of America}, title = {{Replicability of introgression under linked, polygenic selection}}, doi = {10.1534/genetics.118.301429}, volume = {210}, year = {2018}, } @article{1169, abstract = {Dispersal is a crucial factor in natural evolution, since it determines the habitat experienced by any population and defines the spatial scale of interactions between individuals. There is compelling evidence for systematic differences in dispersal characteristics within the same population, i.e., genotype-dependent dispersal. The consequences of genotype-dependent dispersal on other evolutionary phenomena, however, are poorly understood. In this article we investigate the effect of genotype-dependent dispersal on spatial gene frequency patterns, using a generalization of the classical diffusion model of selection and dispersal. Dispersal is characterized by the variance of dispersal (diffusion coefficient) and the mean displacement (directional advection term). We demonstrate that genotype-dependent dispersal may change the qualitative behavior of Fisher waves, which change from being “pulled” to being “pushed” wave fronts as the discrepancy in dispersal between genotypes increases. The speed of any wave is partitioned into components due to selection, genotype-dependent variance of dispersal, and genotype-dependent mean displacement. We apply our findings to wave fronts maintained by selection against heterozygotes. Furthermore, we identify a benefit of increased variance of dispersal, quantify its effect on the speed of the wave, and discuss the implications for the evolution of dispersal strategies.}, author = {Novak, Sebastian and Kollár, Richard}, issn = {0016-6731}, journal = {Genetics}, number = {1}, pages = {367 -- 374}, publisher = {Genetics Society of America}, title = {{Spatial gene frequency waves under genotype dependent dispersal}}, doi = {10.1534/genetics.116.193946}, volume = {205}, year = {2017}, } @article{1111, abstract = {Adaptation depends critically on the effects of new mutations and their dependency on the genetic background in which they occur. These two factors can be summarized by the fitness landscape. However, it would require testing all mutations in all backgrounds, making the definition and analysis of fitness landscapes mostly inaccessible. Instead of postulating a particular fitness landscape, we address this problem by considering general classes of landscapes and calculating an upper limit for the time it takes for a population to reach a fitness peak, circumventing the need to have full knowledge about the fitness landscape. We analyze populations in the weak-mutation regime and characterize the conditions that enable them to quickly reach the fitness peak as a function of the number of sites under selection. We show that for additive landscapes there is a critical selection strength enabling populations to reach high-fitness genotypes, regardless of the distribution of effects. This threshold scales with the number of sites under selection, effectively setting a limit to adaptation, and results from the inevitable increase in deleterious mutational pressure as the population adapts in a space of discrete genotypes. Furthermore, we show that for the class of all unimodal landscapes this condition is sufficient but not necessary for rapid adaptation, as in some highly epistatic landscapes the critical strength does not depend on the number of sites under selection; effectively removing this barrier to adaptation.}, author = {Heredia, Jorge and Trubenova, Barbora and Sudholt, Dirk and Paixao, Tiago}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {803 -- 825}, publisher = {Genetics Society of America}, title = {{Selection limits to adaptive walks on correlated landscapes}}, doi = {10.1534/genetics.116.189340}, volume = {205}, year = {2017}, } @article{7731, abstract = {Genetic association studies in admixed populations are underrepresented in the genomics literature, with a key concern for researchers being the adequate control of spurious associations due to population structure. Linear mixed models (LMMs) are well suited for genome-wide association studies (GWAS) because they account for both population stratification and cryptic relatedness and achieve increased statistical power by jointly modeling all genotyped markers. Additionally, Bayesian LMMs allow for more flexible assumptions about the underlying distribution of genetic effects, and can concurrently estimate the proportion of phenotypic variance explained by genetic markers. Using three recently published Bayesian LMMs, Bayes R, BSLMM, and BOLT-LMM, we investigate an existing data set on eye (n = 625) and skin (n = 684) color from Cape Verde, an island nation off West Africa that is home to individuals with a broad range of phenotypic values for eye and skin color due to the mix of West African and European ancestry. We use simulations to demonstrate the utility of Bayesian LMMs for mapping loci and studying the genetic architecture of quantitative traits in admixed populations. The Bayesian LMMs provide evidence for two new pigmentation loci: one for eye color (AHRR) and one for skin color (DDB1).}, author = {Lloyd-Jones, Luke R. and Robinson, Matthew Richard and Moser, Gerhard and Zeng, Jian and Beleza, Sandra and Barsh, Gregory S. and Tang, Hua and Visscher, Peter M.}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {1113--1126}, publisher = {Genetics Society of America}, title = {{Inference on the genetic basis of eye and skin color in an admixed population via Bayesian linear mixed models}}, doi = {10.1534/genetics.116.193383}, volume = {206}, year = {2017}, } @article{1074, abstract = {Recently it has become feasible to detect long blocks of nearly identical sequence shared between pairs of genomes. These IBD blocks are direct traces of recent coalescence events and, as such, contain ample signal to infer recent demography. Here, we examine sharing of such blocks in two-dimensional populations with local migration. Using a diffusion approximation to trace genetic ancestry, we derive analytical formulae for patterns of isolation by distance of IBD blocks, which can also incorporate recent population density changes. We introduce an inference scheme that uses a composite likelihood approach to fit these formulae. We then extensively evaluate our theory and inference method on a range of scenarios using simulated data. We first validate the diffusion approximation by showing that the theoretical results closely match the simulated block sharing patterns. We then demonstrate that our inference scheme can accurately and robustly infer dispersal rate and effective density, as well as bounds on recent dynamics of population density. To demonstrate an application, we use our estimation scheme to explore the fit of a diffusion model to Eastern European samples in the POPRES data set. We show that ancestry diffusing with a rate of σ ≈ 50–100 km/√gen during the last centuries, combined with accelerating population growth, can explain the observed exponential decay of block sharing with increasing pairwise sample distance.}, author = {Ringbauer, Harald and Coop, Graham and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {3}, pages = {1335 -- 1351}, publisher = {Genetics Society of America}, title = {{Inferring recent demography from isolation by distance of long shared sequence blocks}}, doi = {10.1534/genetics.116.196220}, volume = {205}, year = {2017}, } @article{7751, abstract = {This work demonstrates that environmental conditions experienced by individuals can shape their development and affect the stability of genetic associations. The implication of this observation is that the environmental response may influence the evolution of traits in the wild. Here, we examined how the genetic architecture of a suite of sexually dimorphic traits changed as a function of environmental conditions in an unmanaged population of Soay sheep (Ovis aries) on the island of Hirta, St. Kilda, northwest Scotland. We examined the stability of phenotypic, genetic, and environmental (residual) covariance in males during the first year of life between horn length, body weight, and parasite load in environments of different quality. We then examined the same covariance structures across environments within and between the adult sexes. We found significant genotype-by-environment interactions for lamb male body weight and parasite load, leading to a change in the genetic correlation among environments. Horn length was genetically correlated with body weight in males but not females and the genetic correlation among traits within and between the sexes was dependent upon the environmental conditions experienced during adulthood. Genetic correlations were smaller in more favorable environmental conditions, suggesting that in good environments, loci are expressed that have sex-specific effects. The reduction in genetic correlation between the sexes may allow independent evolutionary trajectories for each sex. This study demonstrates that the genetic architecture of traits is not stable under temporally varying environments and highlights the fact that evolutionary processes may depend largely upon ecological conditions. ENVIRONMENTAL heterogeneity has long been recognized as an important factor influencing the evolution of fitness-related traits in the wild (Roff 2002). The evolution of a trait depends upon the selection upon it, underlying genetic variation, and to a large degree the genetic relationships with other traits (Lynch and Walsh 1998). There is evidence that selection can vary considerably from year to year (Price et al. 1984; Robinson et al. 2008) and genetic variability in quantitative traits can change in response to environmental conditions (Hoffmann and Merilä 1999; Charmantier and Garant 2005). However, we know surprisingly little about the influence of environmental conditions on genetic correlations between traits in wild populations. Laboratory evidence suggests that the environment may influence genetic relationships between traits (Sgrò and Hoffmann 2004), but estimates obtained in a controlled or in an arbitrary range of conditions show a lack of concordance with those obtained in wild habitats (Conner et al. 2003). As a result, laboratory and environment-specific estimates of genetic correlations can make predictions for a trait's evolution, but these are valid only for the environment in which they were measured. Therefore, at present, it is difficult to generalize about the evolution of a trait that is expressed in populations that experience variable environmental conditions (Steppan et al. 2002). The influence of changing environmental conditions on the G matrix (the matrix of additive genetic variance and covariances corresponding to a set of traits) has been the focus of theoretical quantitative genetic studies (e.g., Jones et al. 2003). There is evidence of genotype-by-environment interaction for many traits expressed in wild populations (Charmantier and Garant 2005) and thus we may also expect that associations between traits may depend upon the environmental conditions encountered by an individual. Genetic correlations among traits may arise from pleiotropy, where a given locus affects more than one trait (Cheverud 1988; Lynch and Walsh 1998), which may limit the potential for those traits to evolve independently. There has recently been much interest in assessing genetic correlations between the sexes (Rice and Chippindale 2001; Foerster et al. 2007; Poissant et al. 2008), but all of these predictions have also been made in average environmental conditions. For sexually dimorphic traits, expectations of between-sex genetic correlations are unclear (Lande 1980; Badyaev 2002). We might expect that the genetic determination of a trait and the patterns of genetic covariance between traits may differ both within and between the sexes, producing the differences in trait growth that are commonly observed (Lande 1980; Badyaev 2002; Roff 2002), but so far evidence suggests that genetic expression in both sexes is influenced by the same developmental pathway (Roff 2002; Jensen et al. 2003; Parker and Garant 2005). However, to our knowledge, no study has yet determined whether genetic correlations, both within and between the sexes, vary across gradients of the environmental conditions encountered by individuals in the wild (Garant et al. 2008). This study aims to assess the stability of phenotypic, genetic, and environmental (residual) associations between traits, within and between the sexes, across a range of environmental conditions experienced by a wild population. We focus on the traits of horn length, body weight, and parasite load in a feral population of Soay sheep (Ovis aries) from the island of Hirta, St. Kilda, United Kingdom. Weather conditions, population density, and consequently resource availability fluctuate from year to year, providing substantial differences between individuals in the environments they experience and thus their survival rates (Clutton-Brock and Pemberton 2004). These varying conditions, combined with a large pedigree and extensive repeated morphological measures, provide an excellent opportunity to assess the potential effects of environmental heterogeneity on genetic architecture of traits. Previous studies on this population have shown additive genetic variance for many morphological traits (Milner et al. 2000; Coltman et al. 2001; Wilson et al. 2005), genetic correlations between traits (Coltman et al. 2001), and genotype-by-environment interactions for birth weight (Wilson et al. 2006). Here we apply a random regression animal model approach to assess the extent to which quantitative genetic parameters of a range of morphological traits measured during life vary as a function of environmental conditions. We then extend this methodology to the multivariate case, testing whether the phenotypic covariance structure, and the underlying G matrix, depends on the environmental conditions experienced. Since the traits considered here are known to be sexually dimorphic and there are differences in trait growth and survival across ages, we look at sex-specific traits in lambs and then across all ages.}, author = {Robinson, Matthew Richard and Wilson, Alastair J. and Pilkington, Jill G. and Clutton-Brock, Tim H. and Pemberton, Josephine M. and Kruuk, Loeske E. B.}, issn = {0016-6731}, journal = {Genetics}, number = {4}, pages = {1639--1648}, publisher = {Genetics Society of America}, title = {{The impact of environmental heterogeneity on genetic architecture in a wild population of soay sheep}}, doi = {10.1534/genetics.108.086801}, volume = {181}, year = {2009}, } @article{3621, abstract = {In 1991, Barton and Turelli developed recursions to describe the evolution of multilocus systems under arbitrary forms of selection. This article generalizes their approach to allow for arbitrary modes of inheritance, including diploidy, polyploidy, sex linkage, cytoplasmic inheritance, and genomic imprinting. The framework is also extended to allow for other deterministic evolutionary forces, including migration and mutation. Exact recursions that fully describe the state of the population are presented; these are implemented in a computer algebra package (available on the Web at http://helios.bto.ed.ac.uk/evolgen). Despite the generality of our framework, it can describe evolutionary dynamics exactly by just two equations. These recursions can be further simplified using a "quasi-linkage equilibrium" (QLE) approximation. We illustrate the methods by finding the effect of natural selection, sexual selection, mutation, and migration on the genetic composition of a population.}, author = {Kirkpatrick, Mark and Johnson, Toby and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {4}, pages = {1727 -- 1750}, publisher = {Genetics Society of America}, title = {{General models of multilocus evolution}}, doi = {10.1093/genetics/161.4.1727}, volume = {161}, year = {2002}, } @article{4258, abstract = {We studied the effect of multilocus balancing selection on neutral nucleotide variability at linked sites by simulating a model where diallelic polymorphisms are maintained at an arbitrary number of selected loci by means of symmetric overdominance. Different combinations of alleles define different genetic backgrounds that subdivide the population and strongly affect variability. Several multilocus fitness regimes with different degrees of epistasis and gametic disequilibrium are allowed. Analytical results based on a multilocus extension of the structured coalescent predict that the expected linked neutral diversity increases exponentially with the number of selected loci and can become extremely large. Our simulation results show that although variability increases with the number of genetic backgrounds that are maintained in the population, it is reduced by random fluctuations in the frequencies of those backgrounds and does not reach high levels even in very large populations. We also show that previous results on balancing selection in single-locus systems do not extend to the multilocus scenario in a straightforward way. Different patterns of linkage disequilibrium and of the frequency spectrum of neutral mutations are expected under different degrees of epistasis. Interestingly, the power to detect balancing selection using deviations from a neutral distribution of allele frequencies seems to be diminished under the fitness regime that leads to the largest increase of variability over the neutral case. This and other results are discussed in the light of data from the Mhc.}, author = {Navarro, Arcadio and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {849 -- 863}, publisher = {Genetics Society of America}, title = {{The effects of multilocus balancing selection on neutral variability}}, doi = {10.1093/genetics/161.2.849}, volume = {161}, year = {2002}, } @article{4259, abstract = {We extend current multilocus models to describe the effects of migration, recombination, selection, and nonrandom mating on sets of genes in diploids with varied modes of inheritance, allowing us to consider the patterns of nuclear and cytonuclear associations (disequilibria) under various models of migration. We show the relationship between the multilocus notation recently presented by Kirkpatrick, Johnson, and Barton (developed from previous work by Barton and Turelli) and the cytonuclear parameterization of Asmussen, Arnold, and Avise and extend this notation to describe associations between cytoplasmic elements and multiple nuclear genes. Under models with sexual symmetry, both nuclear-nuclear and cytonuclear disequilibria are equivalent. They differ, however, in cases involving some type of sexual asymmetry, which is then reflected in the asymmetric inheritance of cytoplasmic markers. An example given is the case of different migration rates in males and females; simulations using 2, 3, 4, or 5 unlinked autosomal markers with a maternally inherited cytoplasmic marker illustrate how nuclear-nuclear and cytonuclear associations can be used to separately estimate female and male migration rates. The general framework developed here allows us to investigate conditions where associations between loci with different modes of inheritance are not equivalent and to use this nonequivalence to test for deviations from simple models of admixture. }, author = {Orive, Maria and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {3}, pages = {1469 -- 1485}, publisher = {Genetics Society of America}, title = {{Associations between cytoplasmic and nuclear loci in hybridizing populations}}, doi = {10.1093/genetics/162.3.1469}, volume = {162}, year = {2002}, } @article{4260, abstract = {We calculate the fixation probability of a beneficial allele that arises as the result of a unique mutation in an asexual population that is subject to recurrent deleterious mutation at rate U. Our analysis is an extension of previous works, which make a biologically restrictive assumption that selection against deleterious alleles is stronger than that on the beneficial allele of interest. We show that when selection against deleterious alleles is weak, beneficial alleles that confer a selective advantage that is small relative to U have greatly reduced probabilities of fixation. We discuss the consequences of this effect for the distribution of effects of alleles fixed during adaptation. We show that a selective sweep will increase the fixation probabilities of other beneficial mutations arising during some short interval afterward. We use the calculated fixation probabilities to estimate the expected rate of fitness improvement in an asexual population when beneficial alleles arise continually at some low rate proportional to U. We estimate the rate of mutation that is optimal in the sense that it maximizes this rate of fitness improvement. Again, this analysis relaxes the assumption made previously that selection against deleterious alleles is stronger than on beneficial alleles. }, author = {Johnson, Toby and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {1}, pages = {395 -- 411}, publisher = {Genetics Society of America}, title = {{The effect of deleterious alleles on adaptation in asexual populations}}, doi = {10.1093/genetics/162.1.395}, volume = {162}, year = {2002}, } @article{4270, abstract = {A coalescence-based maximum-likelihood method is presented that aims to (i) detect diversity-reducing events in the recent history of a population and (ii) distinguish between demographic (e.g., bottlenecks) and selective causes (selective sweep) of a recent reduction of genetic variability. The former goal is achieved by taking account of the distortion in the shape of gene genealogies generated by diversity-reducing events: gene trees tend to be more star-like than under the standard coalescent. The latter issue is addressed by comparing patterns between loci: demographic events apply to the whole genome whereas selective events affect distinct regions of the genome to a varying extent. The maximum-likelihood approach allows one to estimate the time and strength of diversity-reducing events and to choose among competing hypotheses. An application to sequence data from an African population of Drosophila melanogaster shows that the bottleneck hypothesis is unlikely and that one or several selective sweeps probably occurred in the recent history of this population.}, author = {Galtier, Nicolas and Depaulis, Frantz and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {981 -- 987}, publisher = {Genetics Society of America}, title = {{Detecting bottlenecks and selective sweeps from DNA sequence polymorphism}}, doi = {10.1093/genetics/155.2.981}, volume = {155}, year = {2000}, } @article{3626, abstract = {There has recently been considerable debate over the relative importance of selection against hybrids ("endogenous" selection) vs. adaptation to different environments ("exogenous") in maintaining stable hybrid zones and hence in speciation. Single-locus models of endogenous and exogenous viability selection generate clines of similar shape, but the comparison has not been extended to multilocus systems, which are both quantitatively and qualitatively very different from the single-locus case. Here we develop an analytical multilocus model of differential adaptation across an environmental transition and compare it to previous heterozygote disadvantage models. We show that the shape of clines generated by exogenous selection is indistinguishable from that generated by endogenous selection. A stochastic simulation model is used to test the robustness of the analytical description to the effects of drift and strong selection, and confirms the prediction that pairwise linkage disequilibria are predominantly generated by migration. However, although analytical predictions for the width of clines maintained by heterozygote disadvantage fit well with the simulation results, those for environmental adaptation are consistently too narrow; reasons for the discrepancy are discussed. There is a smooth transition between a system in which a set of loci effectively act independently of each other and one in which they act as a single nonrecombining unit.}, author = {Kruuk, Loeske and Baird, Stuart and Gale, Katherine and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {4}, pages = {1959 -- 1971}, publisher = {Genetics Society of America}, title = {{A comparison of multilocus clines maintained by environmental adaptation or by selection against hybrids}}, doi = {10.1093/genetics/153.4.1959}, volume = {153}, year = {1999}, } @article{4279, abstract = {In this article we describe the structure of a hybrid zone in Argyll, Scotland, between native red deer (Cervus elaphus) and introduced Japanese sika deer (Cervus nippon), on the basis of a genetic analysis using 11 microsatellite markers and mitochondrial DNA. In contrast to the findings of a previous study of the same population, we conclude that the deer fall into two distinct genetic classes, corresponding to either a sika-like or red- like phenotype. Introgression is rare at any one locus, but where the taxa overlap up to 40% of deer carry apparently introgressed alleles. While most putative hybrids are heterozygous at only one locus, there are rare multiple heterozygotes, reflecting significant linkage disequilibrium within both sika- and red-like populations. The rate of backcrossing into the sika population is estimated as H = 0.002 per generation and into red, H = 0.001 per generation. On the basis of historical evidence that red deer entered Kintyre only recently, a diffusion model evaluated by maximum likelihood shows that sika have increased at ~9.2% yr-1 from low frequency and disperse at a rate of ~3.7 km yr-1. Introgression into the red-like population is greater in the south, while introgression into sika varies little along the transect. For both sika- and red-like populations, the degree of introgression is 30-40% of that predicted from the rates of current hybridization inferred from linkage disequilibria; however, in neither case is this statistically significant evidence for selection against introgression.}, author = {Goodman, Simon and Barton, Nicholas H and Swanson, Graeme and Abernethy, Kate and Pemberton, Josephine}, issn = {0016-6731}, journal = {Genetics}, number = {1}, pages = {355 -- 371}, publisher = {Genetics Society of America}, title = {{Introgression through rare hybridisation: A genetic study of a hybrid zone between red and sika deer (genus Cervus), in Argyll, Scotland}}, doi = {10.1093/genetics/152.1.355}, volume = {152}, year = {1999}, } @article{3628, abstract = {Determining the way in which deleterious mutations interact in their effects on fitness is crucial to numerous areas in population genetics and evolutionary biology. For example, if each additional mutation leads to a greater decrease in log fitness than the last (synergistic epistasis), then the evolution of sex and recombination may be favored to facilitate the elimination of deleterious mutations. However, there is a severe shortage of relevant data. Three relatively simple experimental methods to test for epistasis between deleterious mutations in haploid species have recently been proposed. These methods involve crossing individuals and examining the mean and/or skew in log fitness of the offspring and parents. The main aim of this paper is to formalize these methods, and determine the most effective way in which tests for epistasis could be carried out. We show that only one of these methods is likely to give useful results: crossing individuals that have very different numbers of deleterious mutations, and comparing the mean log fitness of the parents with that of their offspring. We also reconsider experimental data collected on Chlamydomonas moewussi using two of the three methods. Finally, we suggest how the test could be applied to diploid species.}, author = {West, Stuart and Peters, Andrew and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {1}, pages = {435 -- 444}, publisher = {Genetics Society of America}, title = {{Testing for epistasis between deleterious mutations}}, doi = {10.1093/genetics/149.1.435}, volume = {149}, year = {1998}, } @article{3630, abstract = {This paper derives the long-term effective size, Ne, for a general model of population subdivision, allowing for differential deme fitness, variable emigration and immigration rates, extinction, colonization, and correlations across generations in these processes. We show that various long-term measures of Ne are equivalent. The effective size of a metapopulation can be expressed in a variety of ways. At a demographic equilibrium, Ne can be derived from the demography by combining information about the ultimate contribution of each deme to the future genetic make-up of the population and Wright's FST's. The effective size is given by Ne = 1/(1 + var (upsilon) ((1 - FST)/Nin), where n is the number of demes, theta i is the eventual contribution of individuals in deme i to the whole population (scaled such that sigma theta i = n), and < > denotes an average weighted by theta i. This formula is applied to a catastrophic extinction model (where sites are either empty or at carrying capacity) and to a metapopulation model with explicit dynamics, where extinction is caused by demographic stochasticity and by chaos. Contrary to the expectation from the standard island model, the usual effect of population subdivision is to decrease the effective size relative to a panmictic population living on the same resource.}, author = {Whitlock, Michael and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {1}, pages = {427 -- 441}, publisher = {Genetics Society of America}, title = {{The effective size of a subdivided population}}, doi = {10.1093/genetics/146.1.427}, volume = {146}, year = {1997}, } @article{4285, abstract = {One of the oldest hypotheses for the advantage of recombination is that recombination allo rvs beneficial mutations that arise in different individuals to be placed together on the same chromosome. Unless recombination occurs, one of the beneficial alleles is doomed to extinction, slowing the rate at which adaptive mutations are incorporated within a population. We model the effects of a modifier of recombination on the fixation probability of beneficial mutations when beneficial alleles are segregating at other loci. We find that modifier alleles that increase recombination do increase the fixation probability of beneficial mutants and subsequently hitchhike along as the mutants rise in frequency. The strength of selection favoring a modifier that increases recombination is proportional to lambda(2)S delta r/r when linkage is tight and lambda(2)S(3) delta r/N when linkage is loose, where lambda is the beneficial mutation rate per genome per generation throughout a population of size N, S is the average mutant effect, r is the average recombination rate, and delta ris the amount that recombination is modified. We conclude that selection for recombination will be substantial only if there is tight linkage within the genome or if many loci are subject to directional selection as during periods of rapid evolutionary change.}, author = {Otto, Sarah and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {879 -- 906}, publisher = {Genetics Society of America}, title = {{The evolution of recombination: Removing the limits to natural selection}}, doi = {10.1093/genetics/147.2.879}, volume = {147}, year = {1997}, }