Biology subjects

Gueguen, L.

Publications and source records attributed to Gueguen, L..

12 recordsLinked to original sources

bioRxiv2024

Large effect life-history genomic regions are associated with functional morphological traits in Atlantic salmon

Understanding pleiotropic architectures of phenotypes is instrumental for identifying the functional basis of adaptive genetic variation in the wild. Life-history variation may have a morphological basis that mediates resource acquisition allocation pathways, but identifying the underlying genetic basis of such traits is challenging. Using Atlantic salmon juveniles reared in common garden conditions, we test if two life-history associated loci in Atlantic salmon, six6 and vgll3, are also associated with functional morphological traits. These loci had previously shown to exhibit strong signals of adaptation and are highly correlated with sea age at maturity. We show that genetic variation at the vgll3 locus is linked to variation in morphological traits that underlie swimming performance, along a trade-off axis between efficient cruising and maneuvering, while the genetic variation at the six6 locus was linked to variation in body-head proportions suggesting the potential functional importance of these traits for resource acquisition efficiency. However, the direction of changes in morphological traits associated with late-vs. early-maturing alleles was not always consistent with the expected direction of an effect to maturation timing. Our results reveal a complex morphological landscape associated with the genetic variation in these loci, possibly as a result of pleiotropy or linkage across these genomic regions.

ecology↗

bioRxiv2023

Dollo parsimony overestimates ancestral gene content reconstructions

Ancestral reconstruction is a widely-used technique that has been applied to understand the history of gain and loss of gene families over evolutionary time scales, and to produce hypotheses on how these gains and losses may have influenced the evolutionary trajectories of extant organisms. Ancestral gene content can be reconstructed via different phylogenetic methods, such as maximum likelihood or Bayesian inference, but many current and previous studies employ Dollo parsimony. We hypothesize that Dollo parsimony is not appropriate for ancestral gene content reconstruction inferences based on sequence homology, as Dollo parsimony is derived from the assumption that a complex character can only be gained once in evolutionary history. This premise does not accurately model molecular sequence evolution, in which false orthology can result from sequence convergence (including random sequence similarity and parallel gene gains), non-orthologous homology or lateral gene transfer. The aim of this study is to test Dollo parsimonys suitability for ancestral gene content reconstruction and to compare its inferences with a maximum likelihood-based approach which allows a gene family to be gained more than once within a tree. In order to test our hypothesis, we first compared the performance of the two approaches on a series of artificial datasets each of 5,000 genes that were simulated according to a spectrum of evolutionary rates. Next, we reconstructed protein domain evolution on a phylogeny representing known eukaryotic diversity. We observed that Dollo parsimony produced numerous ancestral gene content overestimations, which were more pronounced at nodes closer to the root of the tree. These observations led us to the conclusion that, confirming our hypothesis, Dollo parsimony is not an appropriate method for ancestral reconstruction studies based on sequence homology.

evolutionary biology↗

bioRxiv2023

The inflammatory and tumor suppressor SAMD9L acts through a Schlafen-like box to restrict HIV and inhibit cell translation in SAAD/ATXPC

Sterile alpha motif domain-containing proteins 9 and 9L (SAMD9/9L) are associated with life-threatening genetic diseases and are restriction factors of poxviruses. Yet, their cellular function and the extent of their antiviral role are poorly known. Here, we found that interferon-stimulated SAMD9L, and not SAMD9, restricts HIV-1 replication at the translation step, with a strong inhibition of Transmitted/Founder HIV-1 patient strains. More broadly, SAMD9L restricts primate lentiviruses, but not another retrovirus (MLV) or two ssRNA viruses (MOPV, VSV). Using structural modeling and mutagenesis of SAMD9L, we identified a Schlafen(SLFN)-like active site necessary for HIV-1 restriction. By testing a germline gain-of-function variant from patients with SAMD9L-associated autoinflammatory disease (SAAD) and ataxia-pancytopenia (ATXPC), we determined that SAMD9L cellular and pathogenic functions also depend on the SLFN-like active site. Finally, we propose a model in which SAMD9L translational repression could be dependent on codon-usage, linking its cellular function and the virus-specific innate immunity. The identification of another Achilles heel of HIV, as well as the inflammatory SAMD9L effector and auto-regulatory determinants, provide novel avenues against infectious and genetic diseases. Significance statementThis study identifies SAMD9L as a potent HIV-1 antiviral factor from the interferon immunity and deciphers the host determinants underlying SAMD9L translational repression. The characterization of SAMD9L activity and determinants is also of medical importance for patients with rare genetic diseases bearing deleterious mutations in SAMD9L or with specific cancers. We demonstrate that a pathogenic SAMD9L patients variant is inactivated by the mutation of an identified active site in a SLFN-like box, resulting in an abolished translational shutdown. Furthermore, we describe SAMD9L, but not SAMD9, as an antiviral factor of HIV and lentiviruses, through a translational repression mediated by the SLFN-like box and potentially dependent on codon usage. These findings may have implications to better fight against HIV/AIDS as well as SAAD/ATXPC. Key findings- SAMD9L, but not SAMD9, restricts HIV-1, including Transmitted/Founder patient strains. - SAMD9L broadly restricts primate lentiviruses, but not the retrovirus MLV, nor two ssRNA viruses, the Rhabdovirus VSV and the Arenavirus MOPV. - SAMD9L inhibits viral and cellular translation through an essential E198/D243 active site in a SLFN-like box. - The SAMD9L-associated autoinflammatory disease (SAAD) F886Lfs*11 variant has enhanced HIV translational repression, unveiling an autoregulatory domain of the anti-lentiviral function.

immunology↗

bioRxiv2022

Distinct evolutionary trajectories of SARS-CoV-2 interacting proteins in bats and primates identify important host determinants of COVID-19

The COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus that spilled from the bat reservoir. Despite numerous clinical trials and vaccines, the burden remains immense, and the host determinants of SARS-CoV-2 susceptibility and COVID-19 severity remain largely unknown. Signatures of positive selection detected by comparative functional-genetic analyses in primate and bat genomes can uncover important and specific adaptations that occurred at virus-host interfaces. Here, we performed high-throughput evolutionary analyses of 334 SARS- CoV-2 interacting proteins to identify SARS-CoV adaptive loci and uncover functional differences between modern humans, primates and bats. Using DGINN (Detection of Genetic INNovation), we identified 38 bat and 81 primate proteins with marks of positive selection. Seventeen genes, including the ACE2 receptor, present adaptive marks in both mammalian orders, suggesting common virus-host interfaces and past epidemics of coronaviruses shaping their genomes. Yet, 84 genes presented distinct adaptations in bats and primates. Notably, residues involved in ubiquitination and phosphorylation of the inflammatory RIPK1 have rapidly evolved in bats but not primates, suggesting different inflammation regulation versus humans. Furthermore, we discovered residues with typical virus-host arms-race marks in primates, such as in the entry factor TMPRSS2 or the autophagy adaptor FYCO1, pointing to host-specific in vivo important interfaces that may be drug targets. Finally, we found that FYCO1 sites under adaptation in primates are those associated with severe COVID-19, supporting their importance in pathogenesis and replication. Overall, we identified functional adaptations involved in SARS- CoV-2 infection in bats and primates, critically enlightening modern genetic determinants of virus susceptibility and severity. Key findingsO_LIEvolutionary history of 334 SARS-CoV-2 interacting proteins (VIPs) in bats and primates identifying how the past has shaped modern viral reservoirs and humans - results publicly-available in an online resource. C_LIO_LIIdentification of 81 primate and 38 bat VIPs with signatures of adaptive evolution. The common ones among species delineate a core adaptive interactome, while the ones displaying distinct evolutionary trajectories enlighten host lineage-specific determinants. C_LIO_LIEvidence of primate specific adaptation of the entry factor TMPRSS2 pointing to its host- specific in vivo importance and predicting molecular interfaces. C_LIO_LIFYCO1 sites associated with severe COVID-19 in human (GWAS) display hallmarks of ancient adaptive evolution in primates, highlighting its importance in SARS-CoV-2 replication or pathogenesis and differences with the bat reservoir. C_LIO_LIIdentification of adaptive evolution in the bats multifunctional RIPK1 at residues that may differentially regulate inflammation. C_LI

evolutionary biology↗

bioRxiv2020

Comparison of developmental genome expression in rodent molars reveals extensive developmental system drift.

Serial appendages are similar organs found at different places in the body, such as fore/hindlimbs or different teeth. They are bound to develop with the same pleiotropic genes, apart from identity genes. These identity genes have logically been implicated in cases where a single appendage evolved a drastically new shape while the other retained an ancestral shape, by enabling developmental changes specifically in one organ. Here, we showed that independent evolution involved developmental changes happening in both organs, in two well characterized model systems. Mouse upper molars evolved a new dental plan with two more cusps on the lingual side, while the lower molar kept a much more ancestral morphology, as did the molars of hamster, our control species. We obtained quantitative timelines of cusp formation and corresponding transcriptomic timeseries in the 4 molars. We found that a molecular and morphogenetic identity of lower and upper molars predated the mouse and hamster divergence and likely facilitated the independent evolution of molars lingual side in the mouse lineage. We found 3 morphogenetic changes which could combine to cause the supplementary cusps in the upper molar and a candidate gene, Bmper. Unexpectedly given its milder morphological divergence, we observed extensive changes in mouse lower molar development. Its transcriptomic profiles diverged as much as, and co-evolved extensively with, those of the upper molar. Consistent with the transcriptomic quantifications, two out of the three morphogenetic changes also impacted lower molar development. Moving to limbs, we show the drastic evolution of the bat wing also involved gene expression co-evolution and a combination of specific and pleiotropic changes. Independent morphological innovation in one organ therefore involves concerted developmental evolution of the other organ. This is facilitated by evolutionary flexibility of its development, a phenomenon known as Developmental System Drift. AUTHOR SUMMARYSerial organs, such as the different wings of an insect or the different limbs or teeth of a vertebrate, can develop into drastically different shapes due to the position-specific expression of so-called "identity" genes. Often during evolution, one organ evolves a new shape while another retains a conserved shape. It was thought that identity genes were responsible for these cases of independent evolution, by enabling developmental changes specifically in one organ. Here, we showed that developmental changes evolved in both organs to enable the independent evolution of the upper molar in mice and the wing in bats. In the organ with the new shape, several developmental changes combine. In the organ with the conserved shape, part of these developmental changes are seen as well. This modifies the development but is not sufficient to drastically change the phenotype, a phenomenon known as "Developmental System Drift", DSD. Thus, the independent evolution of one organ relies on concerted molecular changes, which will contribute to adaptation in one organ and be no more than DSD in another organ. This concerted evolution could apply more generally to very different body parts and explain previous observations on gene expression evolution.

evolutionary biology↗

bioRxiv2020

A codon model for associating phenotypic traits with altered selective patterns of sequence evolution

Changes in complex phenotypes, such as pathogenicity levels, trophic lifestyle, and habitat shifts are brought on by multiple genomic changes: sub- and neofunctionalization, loss of function, and levels of gene expression. Thus, detecting the signature of selection in coding sequences and associating it with shifts in phenotypic state can unveil the genes underlying complex traits. Phylogenetic branch-site codon models are routinely applied to detect changes in selective patterns along specific branches of the phylogeny. These methods rely on a pre-specified partition of the phylogeny to branch categories, thus treating the course of trait evolution as fully resolved and assuming that transitions in phenotypic states have occurred only at speciation events. Here we present TraitRELAX, a new phylogenetic model that alleviates these strong assumptions by explicitly accounting for the uncertainty in the evolution of both trait and coding sequences. This joint statistical framework enables the detection of changes in selection intensity upon repeated trait transitions. We evaluated the performance of TraitRELAX using simulations and then applied it to two case studies. Using TraitRELAX, we found an intensification of selection in the SEMG2 gene in polygynandrous species of primates compared to species of other mating forms, as well as changes in the intensity of purifying selection operating on sixteen bacterial genes upon transitioning from free-living to an endosymbiotic lifestyle.

evolutionary biology↗

bioRxiv2020

DGINN, an automated and highly-flexible pipeline for the Detection of Genetic INNovations on protein-coding genes

Adaptive evolution has shaped major biological processes. Finding the protein-coding genes and the sites that have been subjected to adaptation during evolutionary time is a major endeavor. However, very few methods fully automate the identification of positively selected genes, and widespread sources of genetic innovations as gene duplication and recombination are absent from most pipelines. Here, we developed DGINN, a highly-flexible and public pipeline to Detect Genetic INNovations and adaptive evolution in protein-coding genes. DGINN automates, from a genes sequence, all steps of the evolutionary analyses necessary to detect the aforementioned innovations, including the search for homologues in databases, assignation of orthology groups, identification of duplication and recombination events, as well as detection of positive selection using five different methods to increase precision and ranking of genes when a large panel is analyzed. DGINN was validated on nineteen genes with previously-characterized evolutionary histories in primates, including some engaged in host-pathogen arms-races. The results obtained with DGINN confirm and also expand results from the literature, establishing DGINN as an efficient tool to automatically detect genetic innovations and adaptive evolution in diverse datasets, from the users gene of interest to a large gene list in any species range.

evolutionary biology↗

bioRxiv2019

Treerecs: an integrated phylogenetic tool, from sequences to reconciliations

MotivationGene and species tree reconciliation methods are used to interpret gene trees, root them and correct uncertainties that are due to scarcity of signal in multiple sequence alignments. So far, reconciliation tools have not been integrated in standard phylogenetic software and they either lack performance on certain functions, or usability for biologists. ResultsWe present Treerecs, a phylogenetic software based on duplication-loss reconciliation. Treerecs is simple to install and to use. It is fast and versatile, has a graphic output, and can be used along with methods for phylogenetic inference on multiple alignments like PLL and Seaview. AvailabilityTreerecs is open-source. Its source code (C++, AGPLv3) and manuals are available from https://project.inria.fr/treerecs/ Contacteric.tannier@inria.fr or david.parsons@inria.fr

bioinformatics↗

bioRxiv2019

Detecting convergent adaptive amino acid evolution

In evolutionary genomics, researchers have taken an interest in identifying in the genomes substitutions that subtend convergent phenotypic adaptations. This is a difficult question to address, because genomes contain billions of sites, many of which have substituted in the lineages where the adaptations took place, and yet are not linked to them. Those extra substitutions may be linked to other adaptations, may be neutral, or may be linked to mutational biases. Furthermore, one can think of various ways of defining substitutions of interest, and various methods that match those definitions have been used, resulting in different sets of candidate substitutions. In this manuscript we first clarify how adaptation to convergent phenotypic evolution can manifest itself in coding sequences. Second, we review methods that have been proposed to detect convergent adaptive evolution in coding sequences and expose the assumptions that underlie them. Finally, we examine their power on simulations of convergent changes, including in the presence of a confounding factor.

bioinformatics↗

bioRxiv2018

Accurate detection of convergent substitutions

In the history of life, some phenotypes have been acquired several times independently, through convergent evolution. Recently, lots of genome-scale studies have been devoted to identify nucleotides or amino acids that changed in a convergent manner when the convergent phenotypes evolved. These efforts have had mixed results, probably because of differences in the detection methods, and because of conceptual differences about the definition of a convergent substitution. Some methods contend that substitutions are convergent only if they occur on all branches where the phenotype changed towards the exact same state at a given nucleotide or amino acid position. Others are much looser in their requirements and define a convergent substitution as one that leads the site at which they occur to prefer a phylogeny in which species with the convergent phenotype group together. Here we suggest to look for convergent shifts in amino acid preferences instead of convergent substitutions to the exact same amino acid. We define as convergent shifts substitutions that occur on all branches where the phenotype changed and such that they correspond to a change in the type of amino acid preferred at this position. We implement the corresponding model into a method named PCOC. We show on simulations that PCOC better recovers convergent shifts than existing methods in terms of sensitivity and specificity. We test it on a plant protein alignment where convergent evolution has been studied in detail and find that our method recovers several previously identified convergent substitutions and proposes credible new candidates.

evolutionary biology↗

bioRxiv2017

Community-driven data analysis training for biology

The primary problem with the explosion of biomedical datasets is not the data itself, not computational resources, and not the required storage space, but the general lack of trained and skilled researchers to manipulate and analyze these data. Eliminating this problem requires development of comprehensive educational resources. Here we present a community-driven framework that enables modern, interactive teaching of data analytics in life sciences and facilitates the development of training materials. The key feature of our system is that it is not a static but a continuously improved collection of tutorials. By coupling tutorials with a web-based analysis framework, biomedical researchers can learn by performing computation themselves through a web-browser without the need to install software or search for example datasets. Our ultimate goal is to expand the breadth of training materials to include fundamental statistical and data science topics and to precipitate a complete re-engineering of undergraduate and graduate curricula in life sciences.

bioinformatics↗

bioRxiv2017

Unbiased Estimate Of Synonymous And Non-Synonymous Substitution Rates With Non-Stationary Base Composition

The measure of synonymous and non-synonymous substitution rates (dS and dN) is useful for assessing selection operating on protein sequences or for investigating mutational processes affecting genomes. In particular, the ratio [Formula] is expected to be a good proxy of{omega} , the probability of fixation of non-synonymous mutations relative to that of neutral mutations. Standard methods for estimating dN, dS or{omega} rely on the assumption that the base composition of sequences is at the equilibrium of the evolutionary process. In many clades, this assumption of stationarity is in fact incorrect, and we show here through simulations and through analyses of empirical data that non-stationarity biases the estimate of dN, dS and{omega} . We show that the bias in the estimate of{omega} can be fixed by explicitly considering non-stationarity in the modeling of codon evolution, in a maximum likelihood framework. Moreover, we propose an exact method of estimate of dN and dS on branches, based on stochastic mapping, that can take into account non-stationarity. This method can be directly applied to any kind of model of evolution of codons, as long as neutrality is clearly parameterized.

bioinformatics↗