Search

Family-based genome-wide association studies (GWASs) are often claimed to provide an unbiased estimate of the average causal effects (or average treatment effects; ATEs) of alleles, on the basis of an analogy between the random transmission of alleles from parents to children and a randomized controlled trial. We show that this claim does not hold in general. Because Mendelian segregation only randomizes alleles among children of heterozygotes, the effects of alleles in the children of homozygotes are not observable. This feature will matter if an allele has different average effects in the children of homozygotes and heterozygotes, as can arise in the presence of gene-by-environment interactions, gene-by-gene interactions, or differences in linkage disequilibrium patterns. At a single locus, family-based GWAS can be thought of as providing an unbiased estimate of the average effect in the children of heterozygotes (i.e., a local average treatment effect; LATE). This interpretation does not extend to polygenic scores (PGSs), however, because different sets of SNPs are heterozygous in each family. Therefore, other than under specific conditions, the within-family regression slope of a PGS cannot be assumed to provide an unbiased estimate of the LATE for any subset or weighted average of families. In practice, the potential biases of a family-based GWAS are likely smaller than those that can arise from confounding in a standard, population-based GWAS, and so family studies remain important for the dissection of genetic contributions to phenotypic variation. Nonetheless, their causal interpretation is less straightforward than has been widely appreciated., Competing Interests: Competing interests statement:The authors declare no competing interest.

We introduce a modified spatial Λ-Fleming-Viot process to model the ancestry of individuals in a population occupying a continuous spatial habitat divided into two areas by a sharp discontinuity of the dispersal rate and effective population density. We derive an analytical formula for the expected number of shared haplotype segments between two individuals depending on their sampling locations. This formula involves the transition density of a skew diffusion which appears as a scaling limit of the ancestral lineages of individuals in this model. We then show that this formula can be used to infer the dispersal parameters and the effective population density of both regions, using a composite likelihood approach, and we demonstrate the efficiency of this method on a range of simulated data sets., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest relating to the content of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Genomic evidence supports an important role for selection in shaping patterns of introgression along the genome, but frameworks for understanding the evolutionary dynamics within hybrid populations that underlie these patterns have been lacking. Due to the clock-like effect of recombination in hybrids breaking up parental haplotypes, drift and selection produce predictable patterns of ancestry variation at varying spatial genomic scales through time. Here, we develop methods based on the Discrete Wavelet Transform to study the genomic scale of local ancestry variation and its association with recombination rates and show that these methods capture temporal dynamics of drift and genome-wide selection after hybridization. We apply these methods to published datasets from hybrid populations of swordtail fish ( Xiphophorus ) and baboons ( Papio ) and to inferred Neanderthal introgression in modern humans. Across systems, upward of 20% of variation in local ancestry at the broadest genomic scales can be attributed to systematic selection against introgressed alleles, consistent with strong selection acting on early-generation hybrids. Signatures of selection at fine genomic scales suggest selection over longer time scales; however, we suggest that our ability to confidently infer selection at fine scales is likely limited by inherent biases in current methods for estimating local ancestry from contiguous segments of genomic similarity. Wavelet approaches will become widely applicable as genomic data from systems with introgression become increasingly available and can help shed light on generalities of the genomic consequences of interspecific hybridization., Competing Interests: Competing interests statement:The authors declare no competing interest.

Sexual antagonism occurs when males and females differ in their phenotypic fitness optima but are constrained in their evolution to these optima because of their shared genome. The sex chromosomes, which have distinct evolutionary "interests" relative to the autosomes, are theorized to play an important role in sexually antagonistic conflict. However, the evolutionary responses of sex chromosomes and autosomes have usually been considered independently, that is, via contrasting the response of a gene located on either an X chromosome or an autosome. Here, we study the coevolutionary response of the X chromosome and autosomes to sexually antagonistic selection acting on a polygenic phenotype. We model a phenotype initially under stabilizing selection around a single optimum, followed by a sudden divergence of the male and female optima. We find that, in the absence of dosage compensation, the X chromosome promotes evolution toward the female optimum, inducing coevolutionary male-biased responses on the autosomes. Dosage compensation obscures the female-biased interests of the X, causing it to contribute equally to male and female phenotypic change. We further demonstrate that fluctuations in an adaptive landscape can generate prolonged intragenomic conflict and accentuate the differential responses of the X and autosomes to this conflict., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE). All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Genomic time series from experimental evolution studies and ancient DNA datasets offer us a chance to directly observe the interplay of various evolutionary forces. We show how the genome-wide variance in allele frequency change between two time points can be decomposed into the contributions of gene flow, genetic drift, and linked selection. In closed populations, the contribution of linked selection is identifiable because it creates covariances between time intervals, and genetic drift does not. However, repeated gene flow between populations can also produce directionality in allele frequency change, creating covariances. We show how to accurately separate the fraction of variance in allele frequency change due to admixture and linked selection in a population receiving gene flow. We use two human ancient DNA datasets, spanning around 5,000 y, as time transects to quantify the contributions to the genome-wide variance in allele frequency change. We find that a large fraction of genome-wide change is due to gene flow. In both cases, after correcting for known major gene flow events, we do not observe a signal of genome-wide linked selection. Thus despite the known role of selection in shaping long-term polymorphism levels, and an increasing number of examples of strong selection on single loci and polygenic scores from ancient DNA, it appears to be gene flow and drift, and not selection, that are the main determinants of recent genome-wide allele frequency change. Our approach should be applicable to the growing number of contemporary and ancient temporal population genomics datasets., Competing Interests: Competing interests statement:The authors declare no competing interest.

A reply to Harden's response to Coop and Przeworski (2022)., (© 2022 The Authors. Evolution published by Wiley Periodicals LLC on behalf of The Society for the Study of Evolution.)

Hybridization and subsequent genetic introgression are now known to be common features of the histories of many species, including our own. Following hybridization, selection often purges introgressed DNA genome-wide. While assortative mating can limit hybridization in the first place, it is also known to play an important role in postzygotic selection against hybrids and, thus, the purging of introgressed DNA. However, this role is usually thought of as a direct one: a tendency for mates to be conspecific reduces the sexual fitness of hybrids, reducing the transmission of introgressed ancestry. Here, we explore a second, indirect role of assortative mating as a postzygotic barrier to gene flow. Under assortative mating, parents covary in their ancestry, causing ancestry to be "bundled" in their offspring and later generations. This bundling effect increases ancestry variance in the population, enhancing the efficiency with which postzygotic selection purges introgressed DNA. Using whole-genome simulations, we show that the bundling effect can comprise a substantial portion of mate choice's overall effect as a postzygotic barrier to gene flow. We then derive a simple method for estimating the impact of the bundling effect from standard metrics of assortative mating. Applying this method to data from a diverse set of hybrid zones, we find that the bundling effect increases the purging of introgressed DNA by between 1.2-fold (in a baboon system with weak assortative mating) and 14-fold (in a swordtail system with strong assortative mating). Thus, assortative mating's bundling effect contributes substantially to the genetic isolation of species.

Given the many small-effect loci uncovered by genome-wide association studies (GWAS), polygenic scores have become central to genomic medicine, and have found application in diverse settings including evolutionary studies of adaptation. Despite their promise, polygenic scores have been found to suffer from limited portability across human populations. This at first seems in conflict with the observation that most common genetic variation is shared among populations. We investigate one potential cause of this discrepancy: stabilizing selection on complex traits. Counterintuitively, while stabilizing selection constrains phenotypic evolution, it accelerates the loss and fixation of alleles underlying trait variation within populations (GWAS loci). Thus even when populations share an optimum phenotype, stabilizing selection erodes the variance contributed by their shared GWAS loci, such that predictions from GWAS in one population explain less of the phenotypic variation in another. We develop theory to quantify how stabilizing selection is expected to reduce the prediction accuracy of polygenic scores in populations not represented in GWAS samples. In addition, we find that polygenic scores can substantially overstate average genetic differences of phenotypes among populations. We emphasize stabilizing selection around a common optimum as a useful null model to connect patterns of allele frequency and polygenic score differentiation. This article is part of the theme issue 'Celebrating 50 years since Lewontin's apportionment of human diversity'.

A book review of "The genetic lottery: why DNA matters for social equality." (Princeton University Press, 2021) by Kathryn Paige Harden., (© 2022, Society for the Study of Evolution.)

While often deleterious, hybridization can also be a key source of genetic variation and pre-adapted haplotypes, enabling rapid evolution and niche expansion. Here we evaluate these opposing selection forces on introgressed ancestry between maize (Zea mays ssp. mays) and its wild teosinte relative, mexicana (Zea mays ssp. mexicana). Introgression from ecologically diverse teosinte may have facilitated maize's global range expansion, in particular to challenging high elevation regions (> 1500 m). We generated low-coverage genome sequencing data for 348 maize and mexicana individuals to evaluate patterns of introgression in 14 sympatric population pairs, spanning the elevational range of mexicana, a teosinte endemic to the mountains of Mexico. While recent hybrids are commonly observed in sympatric populations and mexicana demonstrates fine-scale local adaptation, we find that the majority of mexicana ancestry tracts introgressed into maize over 1000 generations ago. This mexicana ancestry seems to have maintained much of its diversity and likely came from a common ancestral source, rather than contemporary sympatric populations, resulting in relatively low FST between mexicana ancestry tracts sampled from geographically distant maize populations. Introgressed mexicana ancestry in maize is reduced in lower-recombination rate quintiles of the genome and around domestication genes, consistent with pervasive selection against introgression. However, we also find mexicana ancestry increases across the sampled elevational gradient and that high introgression peaks are most commonly shared among high-elevation maize populations, consistent with introgression from mexicana facilitating adaptation to the highland environment. In the other direction, we find patterns consistent with adaptive and clinal introgression of maize ancestry into sympatric mexicana at many loci across the genome, suggesting that maize also contributes to adaptation in mexicana, especially at the lower end of its elevational range. In sympatric maize, in addition to high introgression regions we find many genomic regions where selection for local adaptation maintains steep gradients in introgressed mexicana ancestry across elevation, including at least two inversions: the well-characterized 14 Mb Inv4m on chromosome 4 and a novel 3 Mb inversion Inv9f surrounding the macrohairless1 locus on chromosome 9. Most outlier loci with high mexicana introgression show no signals of sweeps or local sourcing from sympatric populations and so likely represent ancestral introgression sorted by selection, resulting in correlated but distinct outcomes of introgression in different contemporary maize populations., Competing Interests: The authors have declared that no competing interests exist.

Admixture has the potential to facilitate adaptation by providing alleles that are immediately adaptive in a new environment or by simply increasing the long-term reservoir of genetic diversity for future adaptation. A growing number of cases of adaptive introgression are being identified in species across the tree of life, however the timing of selection, and therefore the importance of the different evolutionary roles of admixture, is typically unknown. Here, we investigate the spatio-temporal history of selection favoring Neanderthal-introgressed alleles in modern human populations. Using both ancient and present-day samples of modern humans, we integrate the known demographic history of populations, namely population divergence and migration, with tests for selection. We model how a sweep placed along different branches of an admixture graph acts to modify the variance and covariance in neutral allele frequencies among populations at linked loci. Using a method based on this model of allele frequencies, we study previously identified cases of adaptive Neanderthal introgression. From these, we identify cases in which Neanderthal-introgressed alleles were quickly beneficial and other cases in which they persisted at low frequency for some time. For some of the alleles that persisted at low frequency, we show that selection likely independently favored them later on in geographically separated populations. Our work highlights how admixture with ancient hominins has contributed to modern human adaptation and contextualizes observed levels of Neanderthal ancestry in present-day and ancient samples., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Recent biological invasions offer 'natural' laboratories to understand the genetics and ecology of adaptation, hybridization, and range limits. One of the most impressive and well-documented biological invasions of the 20th century began in 1957 when Apis mellifera scutellata honey bees swarmed out of managed experimental colonies in Brazil. This newly-imported subspecies, native to southern and eastern Africa, both hybridized with and out-competed previously-introduced European honey bee subspecies. Populations of scutellata-European hybrid honey bees rapidly expanded and spread across much of the Americas in less than 50 years. We use broad geographic sampling and whole genome sequencing of over 300 bees to map the distribution of scutellata ancestry where the northern and southern invasions have presently stalled, forming replicated hybrid zones with European bee populations in California and Argentina. California is much farther from Brazil, yet these hybrid zones occur at very similar latitudes, consistent with the invasion having reached a climate barrier. At these range limits, we observe genome-wide clines for scutellata ancestry, and parallel clines for wing length that span hundreds of kilometers, supporting a smooth transition from climates favoring scutellata-European hybrid bees to climates where they cannot survive winter. We find no large effect loci maintaining exceptionally steep ancestry transitions. Instead, we find most individual loci have concordant ancestry clines across South America, with a build-up of somewhat steeper clines in regions of the genome with low recombination rates, consistent with many loci of small effect contributing to climate-associated fitness trade-offs. Additionally, we find no substantial reductions in genetic diversity associated with rapid expansions nor complete dropout of scutellata ancestry at any individual loci on either continent, which suggests that the competitive fitness advantage of scutellata ancestry at lower latitudes has a polygenic basis and that scutellata-European hybrid bees maintained large population sizes during their invasion. To test for parallel selection across continents, we develop a null model that accounts for drift in ancestry frequencies during the rapid expansion. We identify several peaks within a larger genomic region where selection has pushed scutellata ancestry to high frequency hundreds of kilometers past the present cline centers in both North and South America and that may underlie high-fitness traits driving the invasion., Competing Interests: The authors have declared that no competing interests exist.

Rapid phenotypic adaptation is often observed in natural populations and selection experiments. However, detecting the genome-wide impact of this selection is difficult since adaptation often proceeds from standing variation and selection on polygenic traits, both of which may leave faint genomic signals indistinguishable from a noisy background of genetic drift. One promising signal comes from the genome-wide covariance between allele frequency changes observable from temporal genomic data (e.g., evolve-and-resequence studies). These temporal covariances reflect how heritable fitness variation in the population leads changes in allele frequencies at one time point to be predictive of the changes at later time points, as alleles are indirectly selected due to remaining associations with selected alleles. Since genetic drift does not lead to temporal covariance, we can use these covariances to estimate what fraction of the variation in allele frequency change through time is driven by linked selection. Here, we reanalyze three selection experiments to quantify the effects of linked selection over short timescales using covariance among time points and across replicates. We estimate that at least 17 to 37% of allele frequency change is driven by selection in these experiments. Against this background of positive genome-wide temporal covariances, we also identify signals of negative temporal covariance corresponding to reversals in the direction of selection for a reasonable proportion of loci over the time course of a selection experiment. Overall, we find that in the three studies we analyzed, linked selection has a large impact on short-term allele frequency dynamics that is readily distinguishable from genetic drift., Competing Interests: The authors declare no competing interest.

One of the most useful models in population genetics is that of a selective sweep and the consequent hitch-hiking of linked neutral alleles. While variations on this model typically assume constant population size, many instances of strong selection and rapid adaptation in nature may co-occur with complex demography. Here, we extend the hitch-hiking model to evolutionary rescue, where adaptation and demography not only co-occur but are intimately entwined. Our results show how this feedback between demography and evolution determines-and restricts-the genetic signatures of evolutionary rescue, and how these differ from the signatures of sweeps in populations of constant size. In particular, we find rescue to harden sweeps from standing variance or new mutation (but not from migration), reduce genetic diversity both at the selected site and genome-wide, and increase the range of observed Tajima's D values. For a given initial rate of population decline, the feedback between demography and evolution makes all of these differences more dramatic under weaker selection, where bottlenecks are prolonged. Nevertheless, it is likely difficult to infer the co-incident timing of the sweep and bottleneck from these simple signatures, never mind a feedback between them. Temporal samples spanning contemporary rescue events may offer one way forward., (Copyright © 2020 by the Genetics Society of America.)

Direct-to-consumer (DTC) genetics services are increasingly popular, with tens of millions of customers. Several DTC genealogy services allow users to upload genetic data to search for relatives, identified as people with genomes that share identical by state (IBS) regions. Here, we describe methods by which an adversary can learn database genotypes by uploading multiple datasets. For example, an adversary who uploads approximately 900 genomes could recover at least one allele at SNP sites across up to 82% of the genome of a median person of European ancestries. In databases that detect IBS segments using unphased genotypes, approximately 100 falsified uploads can reveal enough genetic information to allow genome-wide genetic imputation. We provide a proof-of-concept demonstration in the GEDmatch database, and we suggest countermeasures that will prevent the exploits we describe., Competing Interests: ME No competing interests declared, GC Reviewing editor, eLife, (© 2020, Edge and Coop.)

The majority of empirical population genetic studies have tried to understand the evolutionary processes that have shaped genetic variation in a single sample taken from a present-day population. However, genomic data collected over tens of generations in both natural and laboratory populations are increasingly used to find selected loci underpinning adaptation over these short timescales. Although these studies have been quite successful in detecting selection on large-effect loci, the fitness differences between individuals are often polygenic, such that selection leads to allele frequency changes that are difficult to distinguish from genetic drift. However, one promising signal comes from polygenic selection's effect on neutral sites that become stochastically associated with the genetic backgrounds that lead to fitness differences between individuals. Previous theoretical work has established that the random associations between a neutral allele and heritable fitness backgrounds act to reduce the effective population size experienced by this neutral allele. These associations perturb neutral allele frequency trajectories, creating autocovariance in the allele frequency changes across generations. Here, we show how temporal genomic data allow us to measure the temporal autocovariance in allele frequency changes and characterize the genome-wide impact of polygenic selection. We develop expressions for these temporal autocovariances, showing that their magnitude is determined by the level of additive genetic variation, recombination, and linkage disequilibria in a region. Furthermore, by using analytic expressions for the temporal variances and autocovariances in allele frequency, we demonstrate that one can estimate the additive genetic variation for fitness and the drift-effective population size from temporal genomic data. We also show how the proportion of total variation in allele frequency change due to linked selection can be estimated from temporal data. Overall, we demonstrate that temporal genomic data offer opportunities to identify the role of linked selection on genome-wide diversity over short timescales, and can help bridge population genetic and quantitative genetic studies of adaptation., (Copyright © 2019 by the Genetics Society of America.)

Convergent adaptation is the independent evolution of similar traits conferring a fitness advantage in two or more lineages. Cases of convergent adaptation inform our ideas about the ecological and molecular basis of adaptation. In judging the degree to which putative cases of convergent adaptation provide an independent replication of the process of adaptation, it is necessary to establish the degree to which the evolutionary change is unexpected under null models and to show that selection has repeatedly, independently driven these changes. Here, we discuss the issues that arise from these questions particularly for closely related populations, where gene flow and standing variation add additional layers of complexity. We outline a conceptual framework to guide intuition as to the extent to which evolutionary change represents the independent gain of information owing to selection and show that this is a measure of how surprised we should be by convergence. Additionally, we summarize the ways population and quantitative genetics and genomics may help us address questions related to convergent adaptation, as well as open new questions and avenues of research. This article is part of the theme issue 'Convergent evolution in the genomics era: new insights and directions'.

Several recent papers have reported strong signals of selection on European polygenic height scores. These analyses used height effect estimates from the GIANT consortium and replication studies. Here, we describe a new analysis based on the the UK Biobank (UKB), a large, independent dataset. We find that the signals of selection using UKB effect estimates are strongly attenuated or absent. We also provide evidence that previous analyses were confounded by population stratification. Therefore, the conclusion of strong polygenic adaptation now lacks support. Moreover, these discrepancies highlight (1) that methods for correcting for population stratification in GWAS may not always be sufficient for polygenic trait analyses, and (2) that claims of differences in polygenic scores between populations should be treated with caution until these issues are better understood., Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., Competing Interests: JB, AH, NS, AJ, HM, YF, EB, XZ, FR, JP, GC No competing interests declared, (© 2019, Berg et al.)

Adaptation in quantitative traits often occurs through subtle shifts in allele frequencies at many loci-a process called polygenic adaptation. While a number of methods have been developed to detect polygenic adaptation in human populations, we lack clear strategies for doing so in many other systems. In particular, there is an opportunity to develop new methods that leverage datasets with genomic data and common garden trait measurements to systematically detect the quantitative traits important for adaptation. Here, we develop methods that do just this, using principal components of the relatedness matrix to detect excess divergence consistent with polygenic adaptation, and using a conditional test to control for confounding effects due to population structure. We apply these methods to inbred maize lines from the United States Department of Agriculture germplasm pool and maize landraces from Europe. Ultimately, these methods can be applied to additional domesticated and wild species to give us a broader picture of the specific traits that contribute to adaptation and the overall importance of polygenic adaptation in shaping quantitative trait variation., (Copyright © 2019 by the Genetics Society of America.)

A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual processes underlying these changes-variation in individual survival, reproductive success, and movement-are often difficult to quantify. Fully understanding these processes requires the population pedigree, the set of relationships among all individuals in the population through time. Here, we use extensive pedigree and genomic information from a long-studied natural population of Florida Scrub-Jays ( Aphelocoma coerulescens ) to directly characterize the relative roles of different evolutionary processes in shaping patterns of genetic variation through time. We performed gene dropping simulations to estimate individual genetic contributions to the population and model drift on the known pedigree. We found that observed allele frequency changes are generally well predicted by accounting for the different genetic contributions of founders. Our results show that the genetic contribution of recent immigrants is substantial, with some large allele frequency shifts that otherwise may have been attributed to selection actually due to gene flow. We identified a few SNPs under directional short-term selection after appropriately accounting for gene flow. Using models that account for changes in population size, we partitioned the proportion of variance in allele frequency change through time. Observed allele frequency changes are primarily due to variation in survival and reproductive success, with gene flow making a smaller contribution. This study provides one of the most complete descriptions of short-term evolutionary change in allele frequencies in a natural population to date., Competing Interests: The authors declare no conflict of interest.

Genome-wide association studies (GWAS) have revealed that many traits are highly polygenic, in that their within-population variance is governed, in part, by small-effect variants at many genetic loci. Standard population-genetic methods for inferring evolutionary history are ill-suited for polygenic traits: when there are many variants of small effect, signatures of natural selection are spread across the genome and are subtle at any one locus. In the last several years, various methods have emerged for detecting the action of natural selection on polygenic scores, sums of genotypes weighted by GWAS effect sizes. However, most existing methods do not reveal the timing or strength of selection. Here, we present a set of methods for estimating the historical time course of a population-mean polygenic score using local coalescent trees at GWAS loci. These time courses are estimated by using coalescent theory to relate the branch lengths of trees to allele-frequency change. The resulting time course can be tested for evidence of natural selection. We present theory and simulations supporting our procedures, as well as estimated time courses of polygenic scores for human height. Because of its grounding in coalescent theory, the framework presented here can be extended to a variety of demographic scenarios, and its usefulness will increase as both GWAS and ancestral-recombination-graph inference continue to progress., (Copyright © 2019 by the Genetics Society of America.)

The haplotypes of a beneficial allele carry information about its history that can shed light on its age and the putative cause for its increase in frequency. Specifically, the signature of an allele's age is contained in the pattern of variation that mutation and recombination impose on its haplotypic background. We provide a method to exploit this pattern and infer the time to the common ancestor of a positively selected allele following a rapid increase in frequency. We do so using a hidden Markov model which leverages the length distribution of the shared ancestral haplotype, the accumulation of derived mutations on the ancestral background, and the surrounding background haplotype diversity. Using simulations, we demonstrate how the inclusion of information from both mutation and recombination events increases accuracy relative to approaches that only consider a single type of event. We also show the behavior of the estimator in cases where data do not conform to model assumptions, and provide some diagnostics for assessing and improving inference. Using the method, we analyze population-specific patterns in the 1000 Genomes Project data to estimate the timing of adaptation for several variants which show evidence of recent selection and functional relevance to diet, skin pigmentation, and morphology in humans.

Geographically separated populations can convergently adapt to the same selection pressure. Convergent evolution at the level of a gene may arise via three distinct modes. The selected alleles can (1) have multiple independent mutational origins, (2) be shared due to shared ancestral standing variation, or (3) spread throughout subpopulations via gene flow. We present a model-based, statistical approach that utilizes genomic data to detect cases of convergent adaptation at the genetic level, identify the loci involved and distinguish among these modes. To understand the impact of convergent positive selection on neutral diversity at linked loci, we make use of the fact that hitchhiking can be modeled as an increase in the variance in neutral allele frequencies around a selected site within a population. We build on coalescent theory to show how shared hitchhiking events between subpopulations act to increase covariance in allele frequencies between subpopulations at loci near the selected site, and extend this theory under different models of migration and selection on the same standing variation. We incorporate this hitchhiking effect into a multivariate normal model of allele frequencies that also accounts for population structure. Based on this theory, we present a composite-likelihood-based approach that utilizes genomic data to identify loci involved in convergence, and distinguishes among alternate modes of convergent adaptation. We illustrate our method on genome-wide polymorphism data from two distinct cases of convergent adaptation. First, we investigate the adaptation for copper toxicity tolerance in two populations of the common yellow monkey flower, Mimulus guttatus We show that selection has occurred on an allele that has been standing in these populations prior to the onset of copper mining in this region. Lastly, we apply our method to data from four populations of the killifish, Fundulus heteroclitus , that show very rapid convergent adaptation for tolerance to industrial pollutants. Here, we identify a single locus at which both independent mutation events and selection on an allele shared via gene flow, either slightly before or during selection, play a role in adaptation across the species' range., (Copyright © 2017 by the Genetics Society of America.)

Geographically limited dispersal can shape genetic population structure and result in a correlation between genetic and geographic distance, commonly called isolation-by-distance. Despite the prevalence of isolation-by-distance in nature, to date few studies have empirically demonstrated the processes that generate this pattern, largely because few populations have direct measures of individual dispersal and pedigree information. Intensive, long-term demographic studies and exhaustive genomic surveys in the Florida Scrub-Jay (Aphelocoma coerulescens) provide an excellent opportunity to investigate the influence of dispersal on genetic structure. Here, we used a panel of genome-wide SNPs and extensive pedigree information to explore the role of limited dispersal in shaping patterns of isolation-by-distance in both sexes, and at an exceedingly fine spatial scale (within ~10 km). Isolation-by-distance patterns were stronger in male-male and male-female comparisons than in female-female comparisons, consistent with observed differences in dispersal propensity between the sexes. Using the pedigree, we demonstrated how various genealogical relationships contribute to fine-scale isolation-by-distance. Simulations using field-observed distributions of male and female natal dispersal distances showed good agreement with the distribution of geographic distances between breeding individuals of different pedigree relationship classes. Furthermore, we built coalescent simulations parameterized by the observed dispersal curve, population density, and immigration rate, and showed how incorporating these extensions to Malécot's theory of isolation-by-distance allows us to accurately reconstruct observed sex-specific isolation-by-distance patterns in autosomal and Z-linked SNPs. Therefore, patterns of fine-scale isolation-by-distance in the Florida Scrub-Jay can be well understood as a result of limited dispersal over contemporary timescales.

The interplay of divergent selection and gene flow is key to understanding how populations adapt to local environments and how new species form. Here, we use DNA polymorphism data and genome-wide variation in recombination rate to jointly infer the strength and timing of selection, as well as the baseline level of gene flow under various demographic scenarios. We model how divergent selection leads to a genome-wide negative correlation between recombination rate and genetic differentiation among populations. Our theory shows that the selection density (i.e., the selection coefficient per base pair) is a key parameter underlying this relationship. We then develop a procedure for parameter estimation that accounts for the confounding effect of background selection. Applying this method to two datasets from Mimulus guttatus , we infer a strong signal of adaptive divergence in the face of gene flow between populations growing on and off phytotoxic serpentine soils. However, the genome-wide intensity of this selection is not exceptional compared with what M. guttatus populations may typically experience when adapting to local conditions. We also find that selection against genome-wide introgression from the selfing sister species M. nasutus has acted to maintain a barrier between these two species over at least the last 250 ky. Our study provides a theoretical framework for linking genome-wide patterns of divergence and recombination with the underlying evolutionary mechanisms that drive this differentiation., Competing Interests: The authors declare no conflict of interest.

Recently it has become feasible to detect long blocks of nearly identical sequence shared between pairs of genomes. These identity-by-descent (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 formulas 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 formulas. 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 Population Reference Sample data set. We show that ancestry diffusing with a rate of [Formula: see text] during the last centuries, combined with accelerating population growth, can explain the observed exponential decay of block sharing with increasing pairwise sample distance., (Copyright © 2017 by the Genetics Society of America.)

Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral-and segregating at high frequency-in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought., Competing Interests: The authors have declared that no competing interests exist.

Close relatives can share large segments of their genome identical by descent (IBD) that can be identified in genome-wide polymorphism data sets. There are a range of methods to use these IBD segments to identify relatives and estimate their relationship. These methods have focused on sharing on the autosomes, as they provide a rich source of information about genealogical relationships. We hope to learn additional information about recent ancestry through shared IBD segments on the X chromosome, but currently lack the theoretical framework to use this information fully. Here, we fill this gap by developing probability distributions for the number and length of X chromosome segments shared IBD between an individual and an ancestor k generations back, as well as between half- and full-cousin relationships. Due to the inheritance pattern of the X and the fact that X homologous recombination occurs only in females (outside of the pseudoautosomal regions), the number of females along a genealogical lineage is a key quantity for understanding the number and length of the IBD segments shared among relatives. When inferring relationships among individuals, the number of female ancestors along a genealogical lineage will often be unknown. Therefore, our IBD segment length and number distributions marginalize over this unknown number of recombinational meioses through a distribution of recombinational meioses we derive. By using Bayes' theorem to invert these distributions, we can estimate the number of female ancestors between two relatives, giving us details about the genealogical relations between individuals not possible with autosomal data alone., (Copyright © 2016 by the Genetics Society of America.)

Natural selection at one site shapes patterns of genetic variation at linked sites. Quantifying the effects of "linked selection" on levels of genetic diversity is key to making reliable inference about demography, building a null model in scans for targets of adaptation, and learning about the dynamics of natural selection. Here, we introduce the first method that jointly infers parameters of distinct modes of linked selection, notably background selection and selective sweeps, from genome-wide diversity data, functional annotations and genetic maps. The central idea is to calculate the probability that a neutral site is polymorphic given local annotations, substitution patterns, and recombination rates. Information is then combined across sites and samples using composite likelihood in order to estimate genome-wide parameters of distinct modes of selection. In addition to parameter estimation, this approach yields a map of the expected neutral diversity levels along the genome. To illustrate the utility of our approach, we apply it to genome-wide resequencing data from 125 lines in Drosophila melanogaster and reliably predict diversity levels at the 1Mb scale. Our results corroborate estimates of a high fraction of beneficial substitutions in proteins and untranslated regions (UTR). They allow us to distinguish between the contribution of sweeps and other modes of selection around amino acid substitutions and to uncover evidence for pervasive sweeps in untranslated regions (UTRs). Our inference further suggests a substantial effect of other modes of linked selection and of adaptation in particular. More generally, we demonstrate that linked selection has had a larger effect in reducing diversity levels and increasing their variance in D. melanogaster than previously appreciated.

Species often encounter, and adapt to, many patches of similar environmental conditions across their range. Such adaptation can occur through convergent evolution if different alleles arise in different patches, or through the spread of shared alleles by migration acting to synchronize adaptation across the species. The tension between the two reflects the constraint imposed on evolution by the underlying genetic architecture versus how effectively selection and geographic isolation act to inhibit the geographic spread of locally adapted alleles. This paper studies the balance between these two routes to adaptation in a model of continuous environments with patchy selection pressures. We address the following questions: How long does it take for a novel allele to appear in a patch where it is locally adapted through mutation? Or, through migration from another, already adapted patch? Which is more likely to occur, as a function of distance between the patches? What population genetic signal is left by the spread of migrant alleles? To answer these questions we examine the family structure underlying migration-selection equilibrium surrounding an already adapted patch, treating those rare families that reach new patches as spatial branching processes. A main result is that patches further apart than a critical distance will likely evolve independent locally adapted alleles; this distance is proportional to the spatial scale of selection ([Formula: see text], where σ is the dispersal distance and sm is the selective disadvantage of these alleles between patches), and depends linearly on log(sm/μ), where μ is the mutation rate. This provides a way to understand the role of geographic separation between patches in promoting convergent adaptation and the genomic signals it leaves behind. We illustrate these ideas using the convergent evolution of cryptic coloration in the rock pocket mouse, Chaetodipus intermedius, as an empirical example.

The extent to which populations experiencing shared selective pressures adapt through a shared genetic response is relevant to many questions in evolutionary biology. In this article, we explore how standing genetic variation contributes to convergent genetic responses in a geographically spread population. Geographically limited dispersal slows the spread of each selected allele, hence allowing other alleles to spread before any one comes to dominate the population. When selectively equivalent alleles meet, their progress is substantially slowed, dividing the species range into a random tessellation, which can be well understood by analogy to a Poisson process model of crystallization. In this framework, we derive the geographic scale over which an allele dominates and the proportion of adaptive alleles that arise from standing variation. Finally, we explore how negative pleiotropic effects of alleles can bias the subset of alleles that contribute to the species' adaptive response. We apply the results to the malaria-resistance glucose-6-phosphate dehydrogenase-deficiency alleles, where the large mutational target size makes it a likely candidate for adaptation from deleterious standing variation. Our results suggest that convergent adaptation may be common. Therefore, caution must be exercised when arguing that strongly geographically restricted alleles are the outcome of local adaptation. We close by discussing the implications of these results for ideas of species coherence and the nature of divergence between species.

The use of genetic polymorphism data to understand the dynamics of adaptation and identify the loci that are involved has become a major pursuit of modern evolutionary genetics. In addition to the classical "hard sweep" hitchhiking model, recent research has drawn attention to the fact that the dynamics of adaptation can play out in a variety of different ways and that the specific signatures left behind in population genetic data may depend somewhat strongly on these dynamics. One particular model for which a large number of empirical examples are already known is that in which a single derived mutation arises and drifts to some low frequency before an environmental change causes the allele to become beneficial and sweeps to fixation. Here, we pursue an analytical investigation of this model, bolstered and extended via simulation study. We use coalescent theory to develop an analytical approximation for the effect of a sweep from standing variation on the genealogy at the locus of the selected allele and sites tightly linked to it. We show that the distribution of haplotypes that the selected allele is present on at the time of the environmental change can be approximated by considering recombinant haplotypes as alleles in the infinite-alleles model. We show that this approximation can be leveraged to make accurate predictions regarding patterns of genetic polymorphism following such a sweep. We then use simulations to highlight which sources of haplotypic information are likely to be most useful in distinguishing this model from neutrality, as well as from other sweep models, such as the classic hard sweep and multiple-mutation soft sweeps. We find that in general, adaptation from a unique standing variant will likely be difficult to detect on the basis of genetic polymorphism data from a single population time point alone, and when it can be detected, it will be difficult to distinguish from other varieties of selective sweeps. Samples from multiple populations and/or time points have the potential to ease this difficulty., (Copyright © 2015 by the Genetics Society of America.)

Recent genomic studies have highlighted the important role of admixture in shaping genome-wide patterns of diversity. Past admixture leaves a population genomic signature of linkage disequilibrium (LD), reflecting the mixing of parental chromosomes by segregation and recombination. These patterns of LD can be used to infer the timing of admixture, but the results of inference can depend strongly on the assumed demographic model. Here, we introduce a theoretical framework for modeling patterns of LD in a geographic contact zone where two differentiated populations have come into contact and are mixing by diffusive local migration. Assuming that this secondary contact is recent enough that genetic drift can be ignored, we derive expressions for the expected LD and admixture tract lengths across geographic space as a function of the age of the contact zone and the dispersal distance of individuals. We develop an approach to infer age of contact zones, using population genomic data from multiple spatially sampled populations by fitting our model to the decay of LD with recombination distance. To demonstrate an application of our model, we use our approach to explore the fit of a geographic contact zone model to three human genomic data sets from populations in Indonesia, Central Asia, and India and compare our results to inference under different demographic models. We obtain substantially different results from those of the commonly used model of panmictic admixture, highlighting the sensitivity of admixture timing results to the choice of demographic model., (Copyright © 2015 by the Genetics Society of America.)

One of the most celebrated examples of sympatric speciation in nature are monophyletic radiations of cichlid fishes endemic to Cameroon crater lakes. However, phylogenetic inference of monophyly may not detect complex colonization histories involving some allopatric isolation, such as double invasions obscured by genome-wide gene flow. Population genomic approaches are better suited to test hypotheses of sympatric speciation in these cases. Here, we use comprehensive sampling from all four sympatric crater lake cichlid radiations in Cameroon and outgroups across Africa combined with next-generation sequencing to genotype tens of thousands of SNPs. We find considerable evidence of gene flow between all four radiations and neighboring riverine populations after initial colonization. In a few cases, some sympatric species are more closely related to outgroups than others, consistent with secondary gene flow facilitating their speciation. Our results do not rule out sympatric speciation in Cameroon cichlids, but rather reveal a complex history of speciation with gene flow, including allopatric and sympatric phases, resulting in both reproductively isolated species and incipient species complexes. The best remaining non-cichlid examples of sympatric speciation all involve assortative mating within microhabitats. We speculate that this feature may be necessary to complete the process of sympatric speciation in nature., (© 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.)

Genomic conflicts arise when an allele gains an evolutionary advantage at a cost to organismal fitness. Oögenesis is inherently susceptible to such conflicts because alleles compete for inclusion into the egg. Alleles that distort meiosis in their favor (i.e., meiotic drivers) often decrease organismal fitness, and therefore indirectly favor the evolution of mechanisms to suppress meiotic drive. In this light, many facets of oögenesis and gametogenesis have been interpreted as mechanisms of protection against genomic outlaws. That females of many animal species do not complete meiosis until after fertilization, appears to run counter to this interpretation, because this delay provides an opportunity for sperm-acting alleles to meddle with the outcome of female meiosis and help like alleles drive in heterozygous females. Contrary to this perceived danger, the population genetic theory presented herein suggests that, in fact, sperm nearly always evolve to increase the fairness of female meiosis in the face of genomic conflicts. These results are consistent with the apparent sperm dependence of the best characterized female meiotic driversin animals. Rather than providing an opportunity for sperm collaboration in female meiotic drive, the "fertilization requirement" indirectly protects females from meiotic drivers by providing sperm an opportunity to suppress drive., (© 2015 The Author(s).)

Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We use a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model, we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of [Q(ST)/F(ST)] comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.

Mimulus guttatus and M. nasutus are an evolutionary and ecological model sister species pair differentiated by ecology, mating system, and partial reproductive isolation. Despite extensive research on this system, the history of divergence and differentiation in this sister pair is unclear. We present and analyze a population genomic data set which shows that M. nasutus budded from a central Californian M. guttatus population within the last 200 to 500 thousand years. In this time, the M. nasutus genome has accrued genomic signatures of the transition to predominant selfing, including an elevated proportion of nonsynonymous variants, an accumulation of premature stop codons, and extended levels of linkage disequilibrium. Despite clear biological differentiation, we document genomic signatures of ongoing, bidirectional introgression. We observe a negative relationship between the recombination rate and divergence between M. nasutus and sympatric M. guttatus samples, suggesting that selection acts against M. nasutus ancestry in M. guttatus.