Biology subjects

Lauterbur, M. E.

Publications and source records attributed to Lauterbur, M. E..

11 recordsLinked to original sources

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↗

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

Expanding the stdpopsim species catalog, and lessons learned forrealistic genome simulations

Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic data sets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and to the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than three-fold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone.

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

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

Species tree disequilibrium positively misleads models of gene family evolution

Gene duplication is a key source of evolutionary innovation, and multigene families evolve in a birth-death process, continuously duplicating and pseudogenizing through time. To empirically test hypotheses about adaptive expansion and contraction of multigene families across species, models infer gene gain and loss in light of speciation events and these inferred gene family expansions may lead to interpretations of adaptations in particular lineages. While the relative abundance of a gene subfamily in the subgenome may reflect its functional importance, tests based on this expectation can be confounded by the complex relationship between the birth-death process of gene subfamily evolution and the species phylogeny. Using simulations, we confirmed tree heterogeneity as a confounding factor in inferring multi-gene adaptation, causing spurious associations between shifts in birth-death rate and lineages with higher branching rates. We then used the olfactory receptor (OR) repertoire, the largest gene family in the mammalian genome, of different bat species with divergent diets to test whether expansions in olfactory receptors are associated with shifts to frugivorous diets. After accounting for tree heterogeneity, we robustly inferred that certain OR subfamilies exhibited expansions associated with dietary shifts to frugivory. Taken together, these results suggest ecological correlates of individual OR gene subfamilies can be identified, setting the stage for detailed inquiry into within-subfamily functional differences.

evolutionary biology↗

bioRxiv2019

orthoCapture: Facilitating Gene Capture Probe Design for Non-Model Species

In non-model species, targeted gene capture (selective enrichment of specific genomic regions of interest) applications in molecular ecology have been limited by the practicalities of capture design. Currently, the minimal requirement for designing capture probes is a transcriptome, or established reference genome for the species of interest. When an established, annotated reference genome is unavailable, one common approach is to design probes from annotated reference genomes (or transcriptomes) of related species. Unfortunately, as divergence between probes and the genome of interest increases, such as occurs during directional selection, capture performance decreases. Here I introduce orthoCapture, a tool to overcome such limitations by mining unannotated whole-genome sequence (WGS) data from non-model species and/or their close relatives to allow probe design using multiple genomic sources. orthoCapture finds orthologs in WGS data from multiple related species to create a set of exon sequences that encompasses the diversity of the exons of interest. These \"design sequences\" can then be used to design capture probes for the species of interest. orthoCapture thus eliminates the need for transcriptome or whole-genome sequencing for bait capture experiments, making this technique accessible for molecular ecology and conservation studies. Use of orthoCapture is via command-line interface on Unix systems, and requires the input of a gene sequence from an unrelated annotated genome and a fasta database from a target, unannotated genome (e.g., whole-genome shotgun contigs). The output, sequence templates from the nonannotated genomic data, allows probe creation by any commercial company providing gene capture services.

bioinformatics↗

bioRxiv2019

Coalescent models at small effective population sizes and population declines are positively misleading

Population genetics employs two major models for conceptualizing genetic relationships among individuals - outcome-driven (coalescent) and process-driven (forward). These models are complementary, but the basic Kingman coalescent and its extensions make fundamental assumptions to allow analytical approximations: a constant effective population size much larger than the sample size. These make the probability of multiple coalescent events per generation negligible. Although these assumptions are often violated in species of conservation concern, conservation genetics often uses coalescent models of effective population sizes and trajectories in endangered species. Despite this, the effect of very small effective population sizes, and their interaction with bottlenecks and sample sizes, on such analyses of genetic diversity remains unexplored. Here, I use simulations to analyze the influence of small effective population size, population decline, and their relationship with sample size, on coalescent-based estimates of genetic diversity. Compared to forward process-based estimates, coalescent models significantly overestimate genetic diversity in oversampled populations with very small effective sizes. When sampled soon after a decline, coalescent models overestimate genetic diversity in small populations regardless of sample size. Such overestimates artificially inflate estimates of both bottleneck and population split times. For conservation applications with small effective population sizes, forward simulations that do not make population size assumptions are computationally tractable and should be considered instead of coalescent-based models. These findings underscore the importance of the theoretical basis of analytical techniques as applied to conservation questions.

genetics↗

bioRxiv2019

A fruitful endeavor: scent cues and echolocation behavior used by Carollia castanea to find fruit

Frugivores have evolved sensory and behavioral adaptations that allow them to find ripe fruit effectively, but the relative importance of different senses in varying foraging scenarios is poorly known. Within Neotropical ecosystems, short-tailed fruit bats (Carollia: Phyllostomidae) are abundant nocturnal frugivores, relying primarily on plants of the genus Piper as a food resource. Previous research has demonstrated Carollia employ olfaction and echolocation to locate Piper fruit, but it is unknown how their sensory use and foraging decisions are influenced by the complex diversity of chemical cues that fruiting plants produce. Using wild C. castanea and their preferred food, Piper scintillans, we conducted behavioral experiments to test two main hypotheses: (1) foraging decisions in C. castanea are primarily driven by ripe fruit scent and secondarily by vegetation scent, and (2) C. castanea re-weight their sensory inputs to account for available environmental cues, such that bats rely more heavily on echolocation in the absence of adequate scent cues. Our results suggest that C. castanea requires olfactory information and relies almost exclusively on ripe fruit scent to make foraging attempts. Ripe fruit scent is chemically distinct from vegetation scent in P. scintillans, with a greater abundance of {beta}-caryophyllene, germacrene D and {beta}-elemene, and a few unique compounds. Although variation in echolocation call parameters was independent of scent cue presence, bats emitted longer and more frequent echolocation calls in trials where no fruit scent was present. Altogether, these results highlight the adaptations, plasticity, and potential constraints in the sensory system of neotropical fruit bats. SIGNIFICANCE STATEMENTLittle is known about the relative importance of different senses and which plant cues are most important for fruit location by frugivores. We conducted behavioral experiments on short-tailed fruit bats (Carollia castanea), which use a combination of olfaction and echolocation to find ripe fruit, and their preferred food source (Piper scintillans) to test (1) which plant scent cues drive food selection and (2) if bats alter their echolocation behaviors based on which scent cues are present. We find that C. castanea rely almost exclusively on ripe fruit scent to forage, and echolocate more frequently when fruit scent is absent. Ripe fruit scent is chemically different from vegetation scent in P. scintillans, potentially providing a clear signal of food availability to mutualistic bats. These results highlight the sensory adaptations and behavioral flexibility of fruit bats as they navigate the cues provided by fruiting plants.

ecology↗