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Enard, D.

Publications and source records attributed to Enard, D..

At least 19 recordsLinked to original sources
bioRxiv2026

Flex-sweep 2.0: more flexible and faster selective sweeps detection

Flex-sweep is a convolutional neural network-based method able to detect a wide range of selective sweeps, including those thousands of generations old, from single population genomic data, while robust to background selection. Here we present a substantial update that streamlines the entire workflow. The new version vastly reduces memory needs and vastly speeds up summary-statistic computation over fully customizable statistics combinations and genomic regions, relaxes CNN constraints by supporting custom architectures and haplotype matrix sorting methods. Domain-Adaptive Neural Network (DANN) training is now supported, as well as ancestral-state polarization and a robust, clustering and confounder-aware gene set sweep enrichment pipeline robust for downstream analysis. Flex-sweep 2.0 scales to hundreds of thousands of training simulations, and enables genome-wide inference on a standard workstation.

evolutionary biology↗
bioRxiv2025

Stuck in the cell: trapping viruses in infected cells was a frequent adaptation strategy in human hosts

Hosts and viruses are in a constant evolutionary arms race, in which viruses physically interact with many host proteins (immune and non-immune) in order to replicate. Here, we manually classify [~]2,500 human virus interacting proteins (VIPs) as a function of their involvement during specific viral replication steps in order to quantify host adaptation across the viral replication cycle. We use an extension of the McDonald-Kreitman test, ABC-MK, to quantify adaptation in human VIPs compared to confounder-matched non-VIPs at different steps of the viral replication cycle. We find significant adaptation at viral replication cycle steps related to entry and release of virions from the cell, with release in particular having experienced extremely high adaptation during human evolution. In contrast to the strategy of host adaptation at entry, which prevents the virus from getting in the cell and replicating in the first place, adaptation at the release stage traps new virions in the cell to prevent continued infection. We explain this unique pattern of adaptation under the framework of a process called intergenerational phenotypic mixing. This adaptation that prevents new viral particles from exiting the cell to continue infection in the host was such a frequent and important strategy in human hosts that the evidence of it can still be found in the form of extremely strong measures of positive selection. Author SummaryViruses have been a powerful driver of evolution throughout human history. Though there have been many studies that have examined the interactions between viruses and the human immune system, few have approached the question from the perspective of what the virus needs from a host cell in order to replicate. As a virus interacts with many host proteins of various functions, whether it is hijacking or suppressing the normal cellular functions of these proteins, identifying adaptation where human hosts defeated viruses in the past may provide key insights that could lead to a better understanding of host-virus interactions, as well as new potential antiviral drug targets. Here, we test for positive selection in manually curated gene sets that span the viral replication cycle in host cells (e.g. entry into the cell, replication, transport within the cell). We identify specifically the step of viral release from the cell, wherein newly assembled viral particles exit an infected cell to go infect another, as a hotspot of extremely elevated adaptation. This result gives new insight into how human hosts defended against viruses in the past and identifies specific functional classes of proteins that were the targets of repeated, strong adaptation.

evolutionary biology↗
bioRxiv2025

Empirical validation of the nearly neutral theory at divergence and population genomic scale using 150 mammals genomes

By limiting the efficacy of selection, random drift is expected to play a major role in genome evolution. Formalizing this idea, the nearly-neutral theory predicts that the ratio of non-synonymous over synonymous polymorphism ({pi}N /{pi}S) within populations, and divergence (dN /dS) between species, should both correlate negatively with Ne. This has previously been tested in mammals and other groups. However, most studies have focused on either dN /dS or on{pi} N /{pi}S, thus not addressing the problem across evolutionary scales. In addition, many studies at the macro scale have used life-history traits (LHT) as a proxy of Ne, assuming that large-bodied organisms have lower Ne than small-bodied species. However, this assumption itself has rarely been validated against more objective measures of Ne, such as genetic diversity{pi} S = 4Ne{micro}, in part because{pi} S estimates are scarce. Here we propose an integrative test of the nearly-neutral predictions on 150 mammalian species, using 6000 orthologous genes, spanning the macro and the micro-evolutionary scale, using for the latter a measure of heterozygosity on each of the assembled diploid genomes. At the micro scale, we observe, for the first time in mammalian nuclear genomes, a relationship between{pi} N /{pi}S and{pi} S. At the macro scale, we confirm the positive correlation between dN /dS and LHT but, more importantly, establish that LHT and dN /dS are correlated with{pi} S, although weakly so. Together, these results provide the first global test of the nearly-neutral theory in mammals across time scales, suggesting all variables are correlated with a single hidden variable: Ne. Significance StatementNatural selection eliminates large-effect deleterious mutations but has limited efficacy for purging mutations of small effects. The effective population size (called Ne) is what determines the cutoff below which selection is inefficient. Since Ne varies between species, the prediction is that more mutations of intermediate effect should segregate and reach fixation in species with small populations. This has been widely studied both between species (macro-evolution) and within species (micro-evolution), although never in a fully integrated manner. Here, we analysed 144 genomes of placental mammals and 6002 orthologous genes, using the original sequence reads produced for genome assembly to estimate within-species genetic diversity based on the heterozygosity of the diploid individual whose genome has been sequenced. We show consistent relationships between genetic diversity within species, life-history traits such as body mass or longevity and selection efficacy simultaneously at the micro- and macro-evolutionary levels. Our analysis provides a globally consistent picture confirming the role of effective population size in tuning selection efficacy in placental mammals.

evolutionary biology↗
bioRxiv2025

Genomic and functional adaptations in guanylate-binding protein 5 (GBP5) highlight specificities of bat antiviral innate immunity

Bats are asymptomatic reservoirs of several zoonotic viruses. This may result from long-term coevolution between viruses and bats, that have led to host adaptations contributing to an effective balance between strong antiviral responses with innate immune tolerance. To better understand these virus-host interactions, we combined comparative transcriptomics, phylogenomics and functional assays to characterize the evolution of bat innate immune antiviral factors. First, we stimulated the type I interferon immune pathway in Myotis yumanensis primary cells and identified guanylate-binding protein 5 (GBP5) as the most differentially expressed interferon-stimulated gene (ISG). Phylogenomic analyses showed that bat GBP5 has been under strong episodic positive selection, with numerous rapidly evolving sites and species-specific gene duplications, suggesting past evolutionary arms races. Functional tests on GBP5 orthologs from ten bat species covering the >60 million years of Chiroptera evolution revealed species- and virus-specific restrictions against RNA viruses (retrovirus HIV, and rhabdoviruses European bat lyssavirus and VSV), which are typical signatures of adaptations to past viral epidemics. Interestingly, we also observed a lineage-specific loss of the GBP5 prenylation motif in the common ancestor of Pipistrellus and Eptesicus bats, associated with different GBP5 subcellular localization and loss of antiviral functions. Resurrection of the ancestral prenylation motif in Eptesicus fuscus GBP5 rescued its subcellular localization, but not the complete antiviral activities, suggesting that additional determinants are necessary for the antiviral restriction. Altogether, our results highlight adaptations that contribute to bat specific immunity and provide insights into the functional evolution of antiviral effector GBP5. Key FindingsO_LIGBP5 is the most differentially expressed gene upon type I interferon stimulation of Myotis yumanensis primary cells. C_LIO_LIBat GBP5 has evolved under strong episodic genomic and genetic diversification, including early stop codon leading to protein truncation and loss of prenylation motif. C_LIO_LIGBP5 diversification in bats impacts their subcellular localization and antiviral functions. C_LIO_LIBat GBP5s exhibit species- and virus-specificity in their ability to inhibit infectivity of viral particles, bearing glycoproteins from retroviral HIV, vesicular stomatitis virus and European bat lyssavirus-1. C_LIO_LIResurrection of the ancestral prenylation motif in a bat GBP5 rescues its subcellular localization but not its full antiviral activity C_LI

immunology↗
bioRxiv2024

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats

Summary ParagraphThe genus Myotis is one of the largest clades of bats, and exhibits some of the most extreme variation in lifespans among mammals alongside unique adaptations to viral tolerance and immune defense1-3. To study the evolution of these phenotypes we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation, and functional experiments in primary cells, we identify patterns of adaptation contributing to longevity, cancer resistance, and viral interactions. We demonstrate distinct modes of adaptation to DNA and RNA viruses compared to all other mammals, with bats exhibiting genome-wide overrepresentation of positive selection for DNA virus-interacting proteins and elevated rates of copy number variation for RNA virus-interacting proteins. Characterization of Myotis-specific duplications of the key immune factor protein kinase R (PKR) reveals multiple ancient segregating trans-species copy number polymorphisms. We show that the recurrent evolution of longevity seen in Myotis is associated with positive selection in cancer pathways, and demonstrate a unique response to DNA damage in primary cells of the long-lived M. lucifugus. Together, our results suggest that bats remarkable longevity and immunity are linked through pleiotropic adaptations to viruses and aging-related disease.

genomics↗
bioRxiv2023

Phylogenomics reveals an almost perfect polytomy among the almost ungulates (Paenungulata)

Phylogenetic studies have resolved most relationships among Eutherian Orders. However, the branching order of elephants (Proboscidea), hyraxes (Hyracoidea), and sea cows (Sirenia) (i.e., the Paenungulata) has remained uncertain since at least 1758, when Linnaeus grouped elephants and manatees into a single Order (Bruta) to the exclusion of hyraxes. Subsequent morphological, molecular, and large-scale phylogenomic datasets have reached conflicting conclusions on the branching order within Paenungulates. We use a phylogenomic dataset of alignments from 13,388 protein-coding genes across 261 Eutherian mammals to infer phylogenetic relationships within Paenungulates. We find that gene trees almost equally support the three alternative resolutions of Paenungulate relationships and that despite strong support for a Proboscidea+Hyracoidea split in the multispecies coalescent (MSC) tree, there is significant evidence for gene tree uncertainty, incomplete lineage sorting, and introgression among Proboscidea, Hyracoidea, and Sirenia. Indeed, only 8-10% of genes have statistically significant phylogenetic signal to reject the hypothesis of a Paenungulate polytomy. These data indicate little support for any resolution for the branching order Proboscidea, Hyracoidea, and Sirenia within Paenungulata and suggest that Paenungulata may be as close to a real, or at least unresolvable, polytomy as possible.

evolutionary biology↗
bioRxiv2023

Positive selection analyses identify a single WWE domain residue that shapes ZAP into a super restriction factor

The host interferon pathway upregulates intrinsic restriction factors in response to viral infection. Many of them block a diverse range of viruses, suggesting that their antiviral functions might have been shaped by multiple viral families during evolution. Virus-host conflicts have led to the rapid adaptation of viral and host proteins at their interaction hotspots. Hence, we can use evolutionary genetic analyses to elucidate antiviral mechanisms and domain functions of restriction factors. Zinc finger antiviral protein (ZAP) is a restriction factor against RNA viruses such as alphaviruses, in addition to other RNA, retro-, and DNA viruses, yet its precise antiviral mechanism is not fully characterized. Previously, an analysis of 13 primate ZAP identified 3 positively selected residues in the poly(ADP-ribose) polymerase-like domain. However, selective pressure from ancient alphaviruses and others likely drove ZAP adaptation in a wider representation of mammals. We performed positive selection analyses in 261 mammalian ZAP using more robust methods with complementary strengths and identified 7 positively selected sites in all domains of the protein. We generated ZAP inducible cell lines in which the positively selected residues of ZAP are mutated and tested their effects on alphavirus replication and known ZAP activities. Interestingly, the mutant in the second WWE domain of ZAP (N658A) is dramatically better than wild-type ZAP at blocking replication of Sindbis virus and other ZAP-sensitive alphaviruses due to enhanced viral translation inhibition. The N658A mutant inhabits the space surrounding the previously reported poly(ADP-ribose) (PAR) binding pocket, but surprisingly has reduced binding to PAR. In summary, the second WWE domain is critical for engineering a super restrictor ZAP and fluctuations in PAR binding modulate ZAP antiviral activity. Our study has the potential to unravel the role of ADP-ribosylation in the host innate immune defense and viral evolutionary strategies that antagonize this post-translational modification. Author summaryHost proteins and viral proteins that encounter one another are locked in a perpetual genetic arms race. In this evolutionary race, a mutation that confers a survival advantage will become more frequent in the population. By looking at the sequences of genes that are known to have antiviral roles in mammals, we can identify the exact sites where a host and viral protein have interacted and gain insight into how an antiviral protein works. Here, we identified these sites in zinc finger antiviral protein (ZAP), a host protein that blocks many different viruses. We found that changing one of the sites from the original amino acid to another dramatically improves ZAPs antiviral activity against Sindbis virus, an alphavirus, due to improved inhibition of viral translation. Our mutation is also better at inhibiting other members in the Alphavirus genus. We observed that our mutant ZAP has reduced ability to bind poly(ADP-ribose), a post-translational modification that is targeted by alphaviruses for productive infection. Our findings help us better understand how viruses have shaped the evolution of broad-spectrum host antiviral proteins, with great implications for the engineering of super restriction factors.

microbiology↗
bioRxiv2023

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic implications of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions, their expression is biased towards male germ cells and are enriched in functions related to meiosis and sperm biology. We tested the role of gorilla relaxed genes previously not implicated in male reproductive function using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.

evolutionary biology↗
bioRxiv2023

Quantifying Adaptive Evolution of the Human Immune Cell Landscape

The human immune system is under constant evolutionary pressure, primarily through its role as first line of defence against pathogens. Accordingly, population genomics studies have shown that immune-related genes have a high rate of adaptive evolution. These studies, however, are mainly based on protein-coding genes without cellular context, leaving the adaptive role of cell types and states uncharted. Inferring the rate of protein-coding genes adaptation in developing and adult immune cells at cellular resolution, we found cell types from both the lymphoid and myeloid compartments to harbour significantly increased adaptation rates. Specific cell states, such as foetal Pre-Pro B cells and adult T resident memory CD8+ cells show highly elevated rates of adaptation. We further analysed activated cell states, specifically, iPSC-derived macrophages responding to various challenges, including pro- and anti-inflammatory cytokines or bacterial and viral infections, the latter simulating the evolutionary arms race between humans and pathogens. Here, we found positive selection to be concentrated in early immune responses, suggesting benefits for the host to adapt to early stages of infection to control pathogen numbers and spread. Together, our study reveals spatio-temporal and functional biases in human immune populations with evidence of rapid adaptive evolution and provides a retrospect of forces that shaped the complexity, architecture, and function of the human body.

immunology↗
bioRxiv2023

An efficient and robust ABC approach to infer the rate and strength of adaptation

Inferring the effects of positive selection on genomes remains a critical step in characterizing the ultimate and proximate causes of adaptation across species, and quantifying positive selection remains a challenge due to the confounding effects of many other evolutionary processes. Robust and efficient approaches for adaptation inference could help characterize the rate and strength of adaptation in non-model species for which demographic history, mutational processes, and recombination patterns are not currently well-described. Here, we introduce an efficient and user-friendly extension of the McDonald-Kreitman test (ABC-MK) for quantifying long-term protein adaptation in specific lineages of interest. We characterize the performance of our approach with forward simulations and find that it is robust to many demographic perturbations and positive selection configurations, demonstrating its suitability for applications to non-model genomes. We apply ABC-MK to the human proteome and a set of known Virus Interacting Proteins (VIPs) to test the long-term adaptation in genes interacting with viruses. We find substantially stronger signatures of positive selection on RNA-VIPs than DNA-VIPs, suggesting that RNA viruses may be an important driver of human adaptation over deep evolutionary time scales.

evolutionary biology↗
bioRxiv2022

Stability evolution as a major mechanism of human protein adaptation in response to viruses

Pathogens were a major driver of genetic adaptation during human evolution. Viruses in particular were a dominant driver of adaptation in the thousands of proteins that physically interact with viruses (VIPs for Virus-Interacting Proteins). This however poses a conundrum. The best understood cases of virus-driven adaptation in specialized immune antiviral factors or in host viral receptors are numerically vastly insufficient to explain abundant adaptations in VIPs. What adaptive mechanisms can then at least partly close this gap? VIPs tend to be broadly conserved proteins with conserved host native molecular functions. Because many amino acid changes in a protein can alter its stability -the balance between the folded and unfolded forms of a protein- without destroying conserved native activities, here we ask if stability evolution was an important mechanism of virus-driven human protein adaptation. Using predictions of protein stability changes based on Alphafold 2 structures and validated by multiple lines of evidence, we find that amino acid changes that altered stability experienced highly elevated adaptative evolution in VIPs, compared to changes with a weaker impact on stability. We further find that RNA viruses, rather DNA viruses, predominantly drove strong adaptation through stability changes in VIPs. We also observe that stability in immune antiviral VIPs preferentially evolved under directional selection. Conversely, stability in proviral VIPs needed by viruses evolved under compensatory evolution following viral epidemics. Together, these results suggest that stability evolution, and thus functional host protein abundance evolution, was a prominent mechanism of host protein adaptation during viral epidemics.

evolutionary biology↗
bioRxiv2022

Versatile detection of diverse selective sweeps with Flex-sweep

Understanding the impacts of selection pressures influencing modern-day genomic diversity is a major goal of evolutionary genomics. In particular, the contribution of selective sweeps to adaptation remains an open question, with persistent statistical limitations on the power and specificity of sweep detection methods. Sweeps with subtle genomic signals have been particularly challenging to detect. While many existing methods powerfully detect specific types of sweeps and/or those with strong signals, their power comes at the expense of versatility. We present Flex-sweep, a machine learning-based tool designed to detect sweeps with a variety of subtle signals, including those thousands of generations old. It is especially valuable for non-model organisms, for which we have neither expectations about the overall characteristics of sweeps nor outgroups with population-level sequencing to otherwise facilitate detecting very old sweeps. We show that Flex-sweep has the power to detect sweeps with subtle signals, even in the face of demographic model misspecification, recombination rate heterogeneity, and background selection. Flex-sweep detects sweeps up to 0.125 * 4Ne generations old, including those that are weak, soft, and/or incomplete; it can also detect strong, complete sweeps up to 0.25 * 4Ne generations old. We apply Flex-sweep to the 1000 Genomes Yoruba data set and, in addition to recovering previously identified sweeps, show that sweeps disproportionately occur within genic regions and close to regulatory regions. In addition, we show that virus-interacting proteins (VIPs) are strongly enriched for selective sweeps, recapitulating previous results that demonstrate the importance of viruses as a driver of adaptive evolution in humans.

bioinformatics↗
bioRxiv2022

Adaptive duplication and functional diversification of Protein kinase R contribute to the uniqueness of bat-virus interactions

Several bat species act as asymptomatic reservoirs for many viruses that are instead highly pathogenic in other mammals. Here, we have characterized the functional diversification of the Protein kinase R (PKR), a major antiviral innate defense system. Our data indicate that PKR has evolved under positive selection and has undergone repeated genomic duplications in bats, in contrast to all studied mammals that possess a single copy of the gene. Functional testing of the relationship between PKR and poxvirus antagonists revealed how an evolutionary conflict with ancient pathogenic poxviruses has shaped a specific bat host-virus interface. More importantly, we determined that duplicated PKRs of the Myotis species have undergone functional diversification allowing them to collectively escape from and enhance control of DNA and RNA viruses. These findings suggest that viral-driven adaptations in PKR contribute to modern virus-bat interactions and may account for bat specific immunity.

evolutionary biology↗
bioRxiv2021

Mixture Density Regression reveals frequent recent adaptation in the human genome

How much genome differences between species reflect neutral or adaptive evolution is a central question in evolutionary genomics. In humans and other mammals, the prevalence of adaptive versus neutral genomic evolution has proven particularly difficult to quantify. The difficulty notably stems from the highly heterogeneous organization of mammalian genomes at multiple levels (functional sequence density, recombination, etc.) that complicates the interpretation and distinction of adaptive vs. neutral evolution signals. Here, we introduce Mixture Density Regressions (MDRs) for the study of the determinants of recent adaptation in the human genome. MDRs provide a flexible regression model based on multiple Gaussian distributions. We use MDRs to model the association between recent selection signals and multiple genomic factors likely to affect positive selection, if the latter was common enough in the first place to generate these associations. We find that a MDR model with two Gaussian distributions provides an excellent fit to the genome-wide distribution of a common sweep summary statistic (iHS), with one of the two distributions likely enriched in positive selection. We further find several factors associated with recent adaptation, including the recombination rate, the density of regulatory elements in immune cells, GC-content, gene expression in immune cells, the density of mammal-wide conserved elements, and the distance to the nearest virus-interacting gene. These results support that strong positive selection was relatively common in recent human evolution and highlight MDRs as a powerful tool to make sense of signals of recent genomic adaptation. Author SummaryOver the last 50,000 years, human populations have been exposed to selective pressures that can trigger adaptation in the genome. The search for signals of these selective events is however obscured by the substantial variation of factors that are relevant for the prevalence and detection of adaptation across the genome. Here, we analyze the impact of multiple factors on positive selection using a biologically meaningful approach that considers the influence of adaptative and non-adaptive processes in the human genome. Our results show that this novel approach is better suited to find genomic factors associated with recent positive selection compared to the classic regression or correlation approaches. We find multiple genomic functional elements associated with selection across the genome, including novel associations that emerge only after controlling for multiple confounding factors. This strongly suggests that adaptation was common enough in recent evolutionary times to produce a widespread correlation between functional elements and positive selection in the human genome. Note on the language used in this manuscriptIn this manuscript we use discrete population groups, such as the Yoruba. We want to emphasize that these discrete groups are only used for convenience and clarity when presenting our results, but in fact represent arbitrary human constructions, the same way that the boundaries of countries are arbitrary. There is an unbroken continuum and mixing of geographical ancestries across groups often identified as distinct populations across the world. The discrete groups we use are, as such, by no mean discrete genetic entities. Once grouped together, the grouped individuals only happen to be genetically more similar, with their ancestries coming from specific geographic locations more predominantly than individuals from the other groups. How much more predominantly is completely arbitrary.

evolutionary biology↗
bioRxiv2021

Decreased adaptation at human disease genes as a possible consequence of interference between advantageous and deleterious variants

Advances in genome sequencing have dramatically improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Despite our expanding knowledge of gene-disease associations, and despite the medical importance of disease genes, their evolution has not been thoroughly studied across diverse human populations. In particular, recent genomic adaptation at disease genes has not been well characterized, even though multiple evolutionary processes are expected to connect disease and adaptation at the gene level. Understanding the relationship between disease and adaptation at the gene level in the human genome is severely hampered by the fact that we dont even know whether disease genes have experienced more, less, or as much adaptation as non-disease genes during recent human evolution. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between disease genes and non-disease genes across 26 distinct human populations from the 1,000 Genomes Project. We find that disease genes have experienced far less selective sweeps compared to non-disease genes during recent human evolution. This sweep deficit at disease genes is particularly visible in Africa, and less visible in East Asia or Europe, likely due to more intense genetic drift in the latter populations creating more spurious selective sweeps signals. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is inexistant at disease genes with higher recombination rates or lower numbers of associated disease variants. Because recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. These results clarify the evolutionary relationship between disease genes and recent genomic adaptation, and suggest that disease genes suffer not only from a higher load of segregating deleterious mutations, but also an inability to adapt as much, and/or as fast as the rest of the genome.

evolutionary biology↗
bioRxiv2020

An ancient coronavirus-like epidemic drove adaptation in East Asians from 25,000 to 5,000 years ago

The current SARS-CoV-2 pandemic has emphasized the vulnerability of human populations to novel viral pressures, despite the vast array of epidemiological and biomedical tools now available. Notably, modern human genomes contain evolutionary information tracing back tens of thousands of years, which may help identify the viruses that have impacted our ancestors - pointing to which viruses have future pandemic potential. Here, we apply evolutionary analyses to human genomic datasets to recover selection events involving tens of human genes that interact with coronaviruses, including SARS-CoV-2, that likely started more than 20,000 years ago. These adaptive events were limited to the population ancestral to East Asian populations. Multiple lines of functional evidence support an ancient viral selective pressure, and East Asia is the geographical origin of several modern coronavirus epidemics. An arms race with an ancient coronavirus, or with a different virus that happened to use similar interactions as coronaviruses with human hosts, may thus have taken place in ancestral East Asian populations. By learning more about our ancient viral foes, our study highlights the promise of evolutionary information to better predict the pandemics of the future. Importantly, adaptation to ancient viral epidemics in specific human populations does not necessarily imply any difference in genetic susceptibility between different human populations, and the current evidence points toward an overwhelming impact of socioeconomic factors in the case of COVID-19.

evolutionary biology↗
bioRxiv2020

Exceptional diversity and selection pressure on SARS-CoV and SARS-CoV-2 host receptor in bats compared to other mammals

Pandemics originating from pathogen transmission between animals and humans highlight the broader need to understand how natural hosts have evolved in response to emerging human pathogens and which groups may be susceptible to infection. Here, we investigate angiotensin-converting enzyme 2 (ACE2), the host protein bound by SARS-CoV and SARS-CoV-2. We find that the ACE2 gene is under strong selection pressure in bats, the group in which the progenitors of SARS-CoV and SARS-CoV-2 are hypothesized to have evolved, particularly in residues that contact SARS-CoV and SARS-CoV-2. We detect positive selection in non-bat mammals in ACE2 but in a smaller proportion of branches than in bats, without enrichment of selection in residues that contact SARS-CoV or SARS-CoV-2. Additionally, we evaluate similarity between humans and other species in residues that contact SARS-CoV or SARS-CoV-2, revealing potential susceptible species but also highlighting the difficulties of predicting spillover events. This work increases our understanding of the relationship between mammals, particularly bats, and coronaviruses, and provides data that can be used in functional studies of how host proteins are bound by SARS-CoV and SARS-CoV-2 strains.

evolutionary biology↗
bioRxiv2020

Ancient RNA virus epidemics through the lens of recent adaptation in human genomes

Over the course of the last several million years of evolution, humans likely have been plagued by hundreds or perhaps thousands of epidemics. Little is known about such ancient epidemics and a deep evolutionary perspective on current pathogenic threats is lacking. The study of past epidemics has typically been limited in temporal scope to recorded history, and in physical scope to pathogens that left sufficient DNA behind, such as Yersinia pestis during the Great Plague. Host genomes however offer an indirect way to detect ancient epidemics beyond the current temporal and physical limits. Arms races with pathogens have shaped the genomes of the hosts by driving a large number of adaptations at many genes, and these signals can be used to detect and further characterize ancient epidemics. Here, we detect the genomic footprints left by ancient viral epidemics that took place in the past ~50,000 years in the 26 human populations represented in the 1,000 Genomes Project. By using the enrichment in signals of adaptation at ~4,500 host loci that interact with specific types of viruses, we provide evidence that RNA viruses have driven a particularly large number of adaptive events across diverse human populations. These results suggest that different types of viruses may have exerted different selective pressures during human evolution. Knowledge of these past selective pressures will provide a deeper evolutionary perspective on current pathogenic threats.

evolutionary biology↗