Contrasting Patterns in the Early Stage of SARS-CoV-2 Evolution between Humans and Minks.

One of the unique features of SARS-CoV-2 is its apparent neutral evolution during the early pandemic (before February 2020). This contrasts with the preceding SARS-CoV epidemics, where viruses evolved adaptively. SARS-CoV-2 may exhibit a unique or adaptive feature which deviates from other coronaviruses. Alternatively, the virus may have been cryptically circulating in humans for a sufficient time to have acquired adaptive changes before the onset of the current pandemic. To test the scenarios above, we analyzed the SARS-CoV-2 sequences from minks (Neovision vision) and parental humans. In the early phase of the mink epidemic (April to May 2020), nonsynonymous to synonymous mutation ratio per site in the spike protein is 2.93, indicating a selection process favoring adaptive amino acid changes. Mutations in the spike protein were concentrated within its receptor-binding domain and receptor-binding motif. An excess of high-frequency derived variants produced by genetic hitchhiking was found during the middle (June to July 2020) and late phase I (August to September 2020) of the mink epidemic. In contrast, the site frequency spectra of early SARS-CoV-2 in humans only show an excess of low-frequency mutations, consistent with the recent outbreak of the virus. Strong positive selection in the mink SARS-CoV-2 implies that the virus may not be preadapted to a wide range of hosts and illustrates how a virus evolves to establish a continuous infection in a new host. Therefore, the lack of positive selection signal during the early pandemic in humans deserves further investigation.

Interchromosomal linkage disequilibrium and linked fitness cost loci associated with selection for herbicide resistance.

The adaptation of weeds to herbicide is both a significant problem in agriculture and a model of rapid adaptation. However, significant gaps remain in our knowledge of resistance controlled by many loci and the evolutionary factors that influence the maintenance of resistance. Here, using herbicide-resistant populations of the common morning glory (Ipomoea purpurea), we perform a multilevel analysis of the genome and transcriptome to uncover putative loci involved in nontarget-site herbicide resistance (NTSR) and to examine evolutionary forces underlying the maintenance of resistance in natural populations. We found loci involved in herbicide detoxification and stress sensing to be under selection and confirmed that detoxification is responsible for glyphosate (RoundUp) resistance using a functional assay. We identified interchromosomal linkage disequilibrium (ILD) among loci under selection reflecting either historical processes or additive effects leading to the resistance phenotype. We further identified potential fitness cost loci that were strongly linked to resistance alleles, indicating the role of genetic hitchhiking in maintaining the cost. Overall, our work suggests that NTSR glyphosate resistance in I. purpurea is conferred by multiple genes which are potentially maintained through generations via ILD, and that the fitness cost associated with resistance in this species is likely a by-product of genetic hitchhiking.

Hazardous Loss of Genetic Diversity through Selective Sweeps in Asexual Populations.

AbstractWith the twofold cost of sex, derived asexual organisms have an immediate reproductive advantage over their sexual sisters. Yet the "twiggy" phylogenetic distribution of asexual lineages implies that they become extinct relatively quickly over evolutionary time. Meanwhile, bacteria and archaea have persisted for billions of years without requiring sexual reproduction. A simple explanation for this difference is that prokaryotes have very large population sizes that are not subject to the accumulation of deleterious mutations, but this implies that drift and mutational meltdown dominate derived asexual populations. Here, we explore a different hazard, quantifying the degree to which genetic variation is lost in asexual populations experiencing selective sweeps. Even though large populations generate diversity by mutation during sweeps, we find that populations that are safe from mutational meltdown may still be reduced to dangerous effective population sizes by sweeps. Thus, ironically, adaptation itself reduces further adaptive potential and may predispose asexual populations to extinction. We derive a simple approximation for the effective population size after a hard sweep and explore the impact of recent sweeps on evolutionary rescue. These factors may help to explain the phylogenetic twigginess of asexuals, the maintenance of sex and recombination, and the evolutionary persistence of prokaryotes.

Some complexities in interpreting apparent effects of hitchhiking: A commentary on Gompert et al. (2022).

We write to address recent claims by regarding the potentially important and underappreciated phenomena of "indirect selection," the observation that neutral regions may be affected by natural selection. We argue both that this phenomenon-generally known as genetic hitchhiking-is neither new nor poorly studied, and that the patterns described by the authors have multiple alternative explanations.

The Role of Phylogenetically Conserved Elements in Shaping Patterns of Human Genomic Diversity.

Evolutionary genetic studies have shown a positive correlation between levels of nucleotide diversity and either rates of recombination or genetic distance to genes. Both positive-directional and purifying selection have been offered as the source of these correlations via genetic hitchhiking and background selection, respectively. Phylogenetically conserved elements (CEs) are short (∼100 bp), widely distributed (comprising ∼5% of genome), sequences that are often found far from genes. While the function of many CEs is unknown, CEs also are associated with reduced diversity at linked sites. Using high coverage (>80×) whole genome data from two human populations, the Yoruba and the CEU, we perform fine scale evaluations of diversity, rates of recombination, and linkage to genes. We find that the local rate of recombination has a stronger effect on levels of diversity than linkage to genes, and that these effects of recombination persist even in regions far from genes. Our whole genome modeling demonstrates that, rather than recombination or GC-biased gene conversion, selection on sites within or linked to CEs better explains the observed genomic diversity patterns. A major implication is that very few sites in the human genome are predicted to be free of the effects of selection. These sites, which we refer to as the human "neutralome," comprise only 1.2% of the autosomes and 5.1% of the X chromosome. Demographic analysis of the neutralome reveals larger population sizes and lower rates of growth for ancestral human populations than inferred by previous analyses.

Evolution of sex: Using experimental genomics to select among competing theories.

Few topics have intrigued biologists as much as the evolution of sex. Understanding why sex persists despite its costs requires not just rigorous theoretical study, but also empirical data on related fundamental issues, including the nature of genetic variance for fitness, patterns of genetic interactions, and the dynamics of adaptation. The increasing feasibility of examining genomes in an experimental context is now shedding new light on these problems. Using this approach, McDonald et al. recently demonstrated that sex uncouples beneficial and deleterious mutations, allowing selection to proceed more effectively with sex than without. Here we discuss the insights provided by this study, along with other recent empirical work, in the context of the major theoretical models for the evolution of sex.

Recombination Rate Variation, Hitchhiking, and Demographic History Shape Deleterious Load in Poplar.

Deleterious alleles are expected to be purged by purifying selection or maintained at low frequency. However, many additional evolutionary forces may shape the pattern of deleterious mutations across the genome and among populations, including selection, hitchhiking, recombination, and demographic history. We used exome capture data to estimate the genome-wide distribution of deleterious alleles across natural populations of the model tree black cottonwood (Populus trichocarpa). Although deleterious alleles were on average present at low frequency suggesting purifying selection, they were preferentially enriched both within genomic regions of low-recombination and in regions showing evidence of positive selection. The demographic history of this species also appeared to play a role in the distribution of deleterious alleles among populations, with peripheral populations having higher rates of deleterious homozygosity. This be due to less efficient selection arising from smaller effective population sizes at the edges of the range, and possibly also due to recent bottlenecks associated with postglacial recolonization. Finally, correlations between deleterious homozygosity and plant growth suggest a significant effect of deleterious load on fitness. Our results show that both genomic context and historical demography play a role in shaping the distribution of deleterious alleles across the genome and range of P. trichocarpa.

Genomewide patterns of variation in genetic diversity are shared among populations, species and higher-order taxa.

Genomewide screens of genetic variation within and between populations can reveal signatures of selection implicated in adaptation and speciation. Genomic regions with low genetic diversity and elevated differentiation reflective of locally reduced effective population sizes (Ne ) are candidates for barrier loci contributing to population divergence. Yet, such candidate genomic regions need not arise as a result of selection promoting adaptation or advancing reproductive isolation. Linked selection unrelated to lineage-specific adaptation or population divergence can generate comparable signatures. It is challenging to distinguish between these processes, particularly when diverging populations share ancestral genetic variation. In this study, we took a comparative approach using population assemblages from distant clades assessing genomic parallelism of variation in Ne . Utilizing population-level polymorphism data from 444 resequenced genomes of three avian clades spanning 50 million years of evolution, we tested whether population genetic summary statistics reflecting genomewide variation in Ne would covary among populations within clades, and importantly, also among clades where lineage sorting has been completed. All statistics including population-scaled recombination rate (ρ), nucleotide diversity (π) and measures of genetic differentiation between populations (FST , PBS, dxy ) were significantly correlated across all phylogenetic distances. Moreover, genomic regions with elevated levels of genetic differentiation were associated with inferred pericentromeric and subtelomeric regions. The phylogenetic stability of diversity landscapes and stable association with genomic features support a role of linked selection not necessarily associated with adaptation and speciation in shaping patterns of genomewide heterogeneity in genetic diversity.

The escalatory Red Queen: Population extinction and replacement following arms race dynamics in poplar rust.

Host-parasite systems provide convincing examples of Red Queen co-evolutionary dynamics. Yet, a key process underscored in Van Valen's theory - that arms race dynamics can result in extinction - has never been documented. One reason for this may be that most sampling designs lack the breadth needed to illuminate the rapid pace of adaptation by pathogen populations. In this study, we used a 25-year temporal sampling to decipher the demographic history of a plant pathogen: the poplar rust fungus, Melampsora larici-populina. A major adaptive event occurred in 1994 with the breakdown of R7 resistance carried by several poplar cultivars widely planted in Western Europe since 1982. The corresponding virulence rapidly spread in M. larici-populina populations and nearly reached fixation in northern France, even on susceptible hosts. Using both temporal records of virulence profiles and temporal population genetic data, our analyses revealed that (i) R7 resistance breakdown resulted in the emergence of a unique and homogeneous genetic group, the so-called cultivated population, which predominated in northern France for about 20 years, (ii) selection for Vir7 individuals brought with it multiple other virulence types via hitchhiking, resulting in an overall increase in the population-wide number of virulence types and (iii) - above all - the emergence of the cultivated population superseded the initial population which predominated at the same place before R7 resistance breakdown. Our temporal analysis illustrates how antagonistic co-evolution can lead to population extinction and replacement, hence providing direct evidence for the escalation process which is at the core of Red Queen dynamics.

Patterns of linkage disequilibrium and long range hitchhiking in evolving experimental Drosophila melanogaster populations.

Whole-genome resequencing of experimental populations evolving under a specific selection regime has become a popular approach to determine genotype-phenotype maps and understand adaptation to new environments. Despite its conceptual appeal and success in identifying some causative genes, it has become apparent that many studies suffer from an excess of candidate loci. Several explanations have been proposed for this phenomenon, but it is clear that information about the linkage structure during such experiments is needed. Until now only Pool-Seq (whole-genome sequencing of pools of individuals) data were available, which do not provide sufficient information about the correlation between linked sites. We address this problem in two complementary analyses of three replicate Drosophila melanogaster populations evolving to a new hot temperature environment for almost 70 generations. In the first analysis, we sequenced 58 haploid genomes from the founder population and evolved flies at generation 67. We show that during the experiment linkage disequilibrium (LD) increased almost uniformly over much greater distances than typically seen in Drosophila. In the second analysis, Pool-Seq time series data of the three replicates were combined with haplotype information from the founder population to follow blocks of initial haplotypes over time. We identified 17 selected haplotype-blocks that started at low frequencies in the base population and increased in frequency during the experiment. The size of these haplotype-blocks ranged from 0.082 to 4.01 Mb. Moreover, between 42% and 46% of the top candidate single nucleotide polymorphisms from the comparison of founder and evolved populations fell into the genomic region covered by the haplotype-blocks. We conclude that LD in such rising haplotype-blocks results in long range hitchhiking over multiple kilobase-sized regions. LD in such haplotype-blocks is therefore a major factor contributing to an excess of candidate loci. Although modifications of the experimental design may help to reduce the hitchhiking effect and allow for more precise mapping of causative variants, we also note that such haplotype-blocks might be well suited to study the dynamics of selected genomic regions during experimental evolution studies.

On the relative roles of background selection and genetic hitchhiking in shaping human cytomegalovirus genetic diversity.

A central focus of population genetics has been examining the contribution of selective and neutral processes in shaping patterns of intraspecies diversity. In terms of selection specifically, surveys of higher organisms have shown considerable variation in the relative contributions of background selection and genetic hitchhiking in shaping the distribution of polymorphisms, although these analyses have rarely been extended to bacteria and viruses. Here, we study the evolution of a ubiquitous, viral pathogen, human cytomegalovirus (HCMV), by analysing the relationship among intraspecies diversity, interspecies divergence and rates of recombination. We show that there is a strong correlation between diversity and divergence, consistent with expectations of neutral evolution. However, after correcting for divergence, there remains a significant correlation between intraspecies diversity and recombination rates, with additional analyses suggesting that this correlation is largely due to the effects of background selection. In addition, a small number of loci, centred on long noncoding RNAs, also show evidence of selective sweeps. These data suggest that HCMV evolution is dominated by neutral mechanisms as well as background selection, expanding our understanding of linked selection to a novel class of organisms.

GWAS-identified schizophrenia risk SNPs at TSPAN18 are highly diverged between Europeans and East Asians.

Genome-wide association studies (GWASs) have identified multiple schizophrenia (SCZ) risk variants for samples of European and East Asian descent, but most of the identified susceptibility variants are population-specific to either Europeans or East Asians. This strong genetic heterogeneity suggests that differential population histories may play a role in SCZ susceptibility. Here, we explored this possibility by examining the allele frequency divergence of 136 previously reported genome-wide SCZ risk SNPs between European and East Asian populations. Our results showed that two SNPs (rs11038167 and rs11038172) at TSPAN18, reported as genome-wide significant SCZ risk variants in Han Chinese, were entirely monomorphic in Europeans, indicating a deep between-population divergence at this gene locus. To explore the evolutionary history of TSPAN18 in East Asians, we conducted population genetic analyses including multiple neutrality tests, the haplotype-based iHS and EHH tests, as well as haplotype bifurcation map and network constructions. We found that the protective allele of rs11038172 (G allele) had a long extended haplotype with much slower decay compared to the A allele. The star-like shape of the G-allele-carrying haplotypes indicates a recent enrichment in East Asians. Together, the evidences suggest that the protective allele of rs11038172 has experienced recent Darwinian positive selection in East Asians. These findings provide new insights that may help explain the strong genetic heterogeneity in SCZ risk and previous inconsistent association results for SCZ among both Europeans and East Asians. © 2016 Wiley Periodicals, Inc.

Differential strengths of positive selection revealed by hitchhiking effects at small physical scales in Drosophila melanogaster.

The long time scale of adaptive evolution makes it difficult to directly observe the spread of most beneficial mutations through natural populations. Therefore, inferring attributes of beneficial mutations by studying the genomic signals left by directional selection is an important component of population genetics research. One kind of signal is a trough in nearby neutral genetic variation due to selective fixation of initially rare alleles, a phenomenon known as "genetic hitchhiking." Accumulated evidence suggests that a considerable fraction of substitutions in the Drosophila genome results from positive selection, most of which are expected to have small selection coefficients and influence the population genetics of sites in the immediate vicinity. Using Drosophila melanogaster population genomic data, we found that the heterogeneity in synonymous polymorphism surrounding different categories of coding fixations is readily observable even within 25 bp of focal substitutions, which we interpret as the result of small-scale hitchhiking effects. The strength of natural selection on different sites appears to be quite heterogeneous. Particularly, neighboring fixations that changed amino acid polarities in a way that maintained the overall polarities of a protein were under stronger selection than other categories of fixations. Interestingly, we found that substitutions in slow-evolving genes are associated with stronger hitchhiking effects. This is consistent with the idea that adaptive evolution may involve few substitutions with large effects or many substitutions with small effects. Because our approach only weakly depends on the numbers of recent nonsynonymous substitutions, it can provide a complimentary view to the adaptive evolution inferred by other divergence-based evolutionary genetic methods.

Hitchhiking selection is driving intron gain in a pathogenic fungus.

The variability of intron density among eukaryotes is puzzling and still debated. Most previous studies have been limited because of the near absence of intron presence-absence polymorphism (IPAP) within species or because comparisons could be made only between distantly related species. We conducted population genetic analyses on eight loci showing IPAP to investigate the effect of natural selection on intron dynamics in a global collection of the panmictic fungal plant pathogen Zymoseptoria tritici and its very close relatives. Five of these loci likely represent recent intron gains because their absence is fixed among the closest relatives of Z. tritici, and three likely represent recent intron losses because their presence is fixed among the close relatives. We analyzed signatures of selection by comparing allele frequencies, nucleotide diversities, and rates of recombination and found compelling evidence that at least two out of the five intron-gain loci, a SWIM zinc-finger gene and a sugar transporter, are under directional selection favoring alleles that gained the intron. Our results suggest that the intron-present alleles of these loci are sweeping to fixation, providing a genetic hitchhiking mechanism to explain rapid intron gain in Z. tritici. The overall findings are consistent with the hypothesis that intron gains are more likely to be driven by selection while intron losses are more likely to be due to neutral processes such as genetic drift.

The genomic signature of parallel adaptation from shared genetic variation.

Parallel adaptation is common and may often occur from shared genetic variation, but the genomic consequences of this process remain poorly understood. We first use individual-based simulations to demonstrate that comparisons between populations adapted in parallel to similar environments from shared variation reveal a characteristic genomic signature around a selected locus: a low-divergence valley centred at the locus and flanked by twin peaks of high divergence. This signature is initiated by the hitchhiking of haplotype tracts differing between derived populations in the broader neighbourhood of the selected locus (driving the high-divergence twin peaks) and shared haplotype tracts in the tight neighbourhood of the locus (driving the low-divergence valley). This initial hitchhiking signature is reinforced over time because the selected locus acts as a barrier to gene flow from the source to the derived populations, thus promoting divergence by drift in its close neighbourhood. We next empirically confirm the peak-valley-peak signature by combining targeted and RAD sequence data at three candidate adaptation genes in multiple marine (source) and freshwater (derived) populations of threespine stickleback. Finally, we use a genome-wide screen for the peak-valley-peak signature to discover additional genome regions involved in parallel marine-freshwater divergence. Our findings offer a new explanation for heterogeneous genomic divergence and thus challenge the standard view that peaks in population divergence harbour divergently selected loci and that low-divergence regions result from balancing selection or localized introgression. We anticipate that genome scans for peak-valley-peak divergence signatures will promote the discovery of adaptation genes in other organisms.

Genome-wide congealing and rapid transitions across the speciation continuum during speciation with gene flow.

Our current understanding of speciation is often based on considering a relatively small number of genes, sometimes in isolation of one another. Here, we describe a possible emergent genome process involving the aggregate effect of many genes contributing to the evolution of reproductive isolation across the speciation continuum. When a threshold number of divergently selected mutations of modest to low fitness effects accumulate between populations diverging with gene flow, nonlinear transitions can occur in which levels of adaptive differentiation, linkage disequilibrium, and reproductive isolation dramatically increase. In effect, the genomes of the populations start to "congeal" into distinct entities representing different species. At this stage, reproductive isolation changes from being a characteristic of specific, divergently selected genes to a property of the genome. We examine conditions conducive to such genome-wide congealing (GWC), describe how to empirically test for GWC, and highlight a putative empirical example involving Rhagoletis fruit flies. We conclude with cautious optimism that the models and concepts discussed here, once extended to large numbers of neutral markers, may provide a framework for integrating information from genome scans, selection experiments, quantitative trait loci mapping, association studies, and natural history to develop a deeper understanding of the genomics of speciation.

Human deleterious mutation rate implies high fitness variance, with declining mean fitness compensated by rarer beneficial mutations of larger effect.

Each new human has an expected Ud = 2 - 10 new deleterious mutations. This deluge of deleterious mutations cannot all be purged, and therefore accumulate in a declining fitness ratchet. Using a novel simulation framework designed to efficiently handle genome-wide linkage disequilibria across many segregating sites, we find that rarer, beneficial mutations of larger effect are sufficient to compensate fitness declines due to the fixation of many slightly deleterious mutations. Drift barrier theory posits a similar asymmetric pattern of fixations to explain ratcheting genome size and complexity, but in our theory, the cause is Ud > 1 rather than small population size. In our simulations, Ud ~2 - 10 generates high within-population variance in relative fitness; two individuals will typically differ in fitness by 15-40%. Ud ~2 - 10 also slows net adaptation by ~13%-39%. Surprisingly, fixation rates are more sensitive to changes in the beneficial than the deleterious mutation rate, e.g. a 10% increase in overall mutation rate leads to faster adaptation; this puts to rest dysgenic fears about increasing mutation rates due to rising paternal age.

Evaluating power to detect recurrent selective sweeps under increasingly realistic evolutionary null models.

The detection of selective sweeps from population genomic data often relies on the premise that the beneficial mutations in question have fixed very near the sampling time. As it has been previously shown that the power to detect a selective sweep is strongly dependent on the time since fixation as well as the strength of selection, it is naturally the case that strong, recent sweeps leave the strongest signatures. However, the biological reality is that beneficial mutations enter populations at a rate, one that partially determines the mean wait time between sweep events and hence their age distribution. An important question thus remains about the power to detect recurrent selective sweeps when they are modeled by a realistic mutation rate and as part of a realistic distribution of fitness effects, as opposed to a single, recent, isolated event on a purely neutral background as is more commonly modeled. Here we use forward-in-time simulations to study the performance of commonly used sweep statistics, within the context of more realistic evolutionary baseline models incorporating purifying and background selection, population size change, and mutation and recombination rate heterogeneity. Results demonstrate the important interplay of these processes, necessitating caution when interpreting selection scans; specifically, false-positive rates are in excess of true-positive across much of the evaluated parameter space, and selective sweeps are often undetectable unless the strength of selection is exceptionally strong.

A numerical framework for genetic hitchhiking in populations of variable size.

Natural selection on beneficial or deleterious alleles results in an increase or decrease, respectively, of their frequency within the population. Due to chromosomal linkage, the dynamics of the selected site affect the genetic variation at nearby neutral loci in a process commonly referred to as genetic hitchhiking. Changes in population size, however, can yield patterns in genomic data that mimic the effects of selection. Accurately modeling these dynamics is thus crucial to understanding how selection and past population size changes impact observed patterns of genetic variation. Here, we model the evolution of haplotype frequencies with the Wright-Fisher diffusion to study the impact of selection on linked neutral variation. Explicit solutions are not known for the dynamics of this diffusion when selection and recombination act simultaneously. Thus, we present a method for numerically evaluating the Wright-Fisher diffusion dynamics of 2 linked loci separated by a certain recombination distance when selection is acting. We can account for arbitrary population size histories explicitly using this approach. A key step in the method is to express the moments of the associated transition density, or sampling probabilities, as solutions to ordinary differential equations. Numerically solving these differential equations relies on a novel accurate and numerically efficient technique to estimate higher order moments from lower order moments. We demonstrate how this numerical framework can be used to quantify the reduction and recovery of genetic diversity around a selected locus over time and elucidate distortions in the site-frequency-spectra of neutral variation linked to loci under selection in various demographic settings. The method can be readily extended to more general modes of selection and applied in likelihood frameworks to detect loci under selection and infer the strength of the selective pressure.

On the prospect of achieving accurate joint estimation of selection with population history.

As both natural selection and population history can affect genome-wide patterns of variation, disentangling the contributions of each has remained as a major challenge in population genetics. We here discuss historical and recent progress towards this goal-highlighting theoretical and computational challenges that remain to be addressed, as well as inherent difficulties in dealing with model complexity and model violations-and offer thoughts on potentially fruitful next steps.