Biology subjects

Martin, G.

Publications and source records attributed to Martin, G..

54 records · Page 3Linked to original sources

bioRxiv2020

A wolf in another wolf's clothing. Post-genomic regulation dictates venom profiles of medically-important cryptic kraits in India

The Common Krait (Bungarus caeruleus) shares a distribution range with many other phenotypically-similar kraits across the Indian subcontinent. Despite several reports of fatal envenoming by other Bungarus species, commercial Indian antivenoms are only manufactured against B. caeruleus. It is, therefore, imperative to understand the distribution of genetically-distinct lineages of kraits, compositional differences in their venoms, and the consequent impact of venom variation on the (pre)clinical effectiveness of antivenom therapy. To address this knowledge gap, we conducted phylogenetic and comparative venomics investigations of kraits in Southern and Western India. Phylogenetic reconstructions using mitochondrial markers revealed a new species of krait, Romulus krait (B. romulusi), in Southern India. Additionally, we find that kraits with 17 mid-body dorsal scale rows in Western India do not represent a subspecies of the Sind Krait (B. sindanus walli) as previously believed, but are genetically very similar to B. sindanus in Pakistan. Furthermore, venom proteomics and comparative transcriptomics revealed completely contrasting venom profiles. While the venom gland transcriptomes of all three species were highly similar, venom proteomes and toxicity profiles differed significantly, suggesting the prominent role of post-genomic regulatory mechanisms in shaping the venoms of these cryptic kraits. In vitro venom recognition and in vivo neutralisation experiments revealed a strong negative impact of venom variability on the preclinical performance of commercial antivenoms. While the venom of B. caeruleus was neutralised as per the manufacturers claim, performance against the venoms of B. sindanus and B. romulusi was alarming, highlighting the need for regionally-effective antivenoms in India.

evolutionary biology↗

bioRxiv2020

Genetics of nodulation in Aeschynomene evenia uncovers new mechanisms of the rhizobium-legume symbiosis

Among legumes (Fabaceae) capable of nitrogen-fixing nodulation, several Aeschynomene spp. use a unique symbiotic process that is independent of Nod factors and infection threads. They are also distinctive in developing root and stem nodules with photosynthetic bradyrhizobia. Despite the significance of these symbiotic features, their understanding remains limited. To overcome such limitations, we conducted genetic studies of nodulation in Aeschynomene evenia, supported by the development of a genome sequence for A. evenia and transcriptomic resources for 10 additional Aeschynomene spp. Comparative analysis of symbiotic genes substantiated singular mechanisms in the early and late nodulation steps. A forward genetic screen also showed that AeCRK, coding a novel receptor-like kinase, and the symbiotic signaling genes AePOLLUX, AeCCamK, AeCYCLOPS, AeNSP2 and AeNIN, are required to trigger both root and stem nodulation. This work demonstrates the utility of the A. evenia model and provides a cornerstone to unravel new mechanisms underlying the rhizobium-legume symbiosis.

plant biology↗

bioRxiv2020

Comprehensive dataset of shotgun metagenomes from stratified freshwater lakes and ponds

Stratified lakes and ponds featuring steep oxygen gradients are significant net sources of greenhouse gases and hotspots in the carbon cycle. Despite their significant biogeochemical roles, the microbial communities, especially in the oxygen depleted compartments, are poorly known. Here, we present a comprehensive dataset including 267 shotgun metagenomes from 41 stratified lakes and ponds mainly located in the boreal and subarctic regions, but also including one tropical reservoir and one temperate lake. For most lakes and ponds, the data includes a vertical sample set spanning from the oxic surface to the anoxic bottom layer. The majority of the samples were collected during the open water period, but also a total of 29 samples were collected from under the ice. In addition to the metagenomic sequences, the dataset includes environmental variables for the samples, such as oxygen, nutrient and organic carbon concentrations. The dataset is ideal for further exploring the microbial taxonomic and functional diversity in freshwater environments and potential climate change impacts on the functioning of these ecosystems.

ecology↗

bioRxiv2020

Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

BackgroundAlternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing. ResultsWe generated a massive resource for A. thaliana (PastDB; pastdb.crg.eu), comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets revealed that A. thaliana shows high levels of AS (similar to fruitflies) and that, compared to animals, disproportionately uses AS for stress responses. We identified core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that was tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, were overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion. ConclusionsNon-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

plant biology↗

bioRxiv2020

A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice

Activated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression, and a transient increase in M1 marker TNF, which resolves over a 24hr period. To elucidate the antifibrotic effect of RP-832c, we used a murine model of bleomycin (BLM) -induced early-stage pulmonary fibrosis. RP-832c significantly reduced bleomycin-induced fibrosis in a dosage dependent manner, as well as decreased CD206, TGF-{beta}1 and -SMA expression in mouse lungs. Interestingly we did not observe any changes in the resident alveolar macrophage marker CD170 expression. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased fibrosis in the lung, as well as significantly decreased inflammatory cytokines TNF, IL-6, IL-10, INF-{gamma}, CXCL1/2, and fibrosis markers TGF-{beta}1 and MMP-13. In comparison with FDA approved drugs, Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed on body weight or blood chemistry. In summary, RP-832c is a potential agent to mitigate the overactivity of M2 macrophages in pathogenesis several pulmonary fibrotic diseases, including SARS-CoV-2 induced lung fibrosis.

pathology↗

bioRxiv2020

Genome of Solanum pimpinellifolium provides insights into structural variants during tomato breeding

Solanum pimpinellifolium (SP) is the wild progenitor of cultivated tomato. Because of its remarkable stress tolerance and intense flavor, SP has been used as an important germplasm donor in modern breeding of tomato. Here we present a high-quality chromosome-scale genome sequence of SP LA2093. Genome comparison identifies more than 92,000 high-confidence structural variants (SVs) between LA2093 and the modern cultivar, Heinz 1706. Genotyping these SVs in ~600 representative tomato accessions unravels alleles under selection during tomato domestication, improvement and modern breeding, and discovers numerous novel SVs underlying genes known to regulate important breeding traits such as fruit weight and lycopene content. Expression quantitative trait locus (eQTL) analysis detects hotspots harboring master regulators controlling important fruit quality traits, including cuticular wax accumulation and flavonoid biosynthesis, and novel SVs contributing to these complex regulatory networks. The LA2093 genome sequence and the identified SVs provide rich resources for future research and biodiversity-based breeding.

genomics↗

bioRxiv2019

Unraveling the complex story of intergenomic recombination in ABB allotriploid bananas

Background and AimsBananas (Musa spp.) are a major staple food for hundreds of millions of people in developing countries. The cultivated varieties are seedless and parthenocarpic clones of which the ancestral origin remains to be clarified. The most important cultivars are triploids with an AAA, AAB, or ABB genome constitution, with A and B genomes provided by M. acuminata and M. balbisiana, respectively. Previous studies suggested that inter-genome recombinations were relatively common in banana cultivars and that triploids were more likely to have passed through an intermediate hybrid. In this study, we investigated the chromosome structure within the ABB group, composed of starchy cooking bananas that play an important role in food security.\n\nMethodsUsing SNP markers called from RAD-Seq data, we studied the chromosome structure of 36 ABB genotypes spanning defined taxonomic subgroups. To complement our understanding, we search for similar events within nine AB hybrid genotypes.\n\nKey ResultsRecurrent Homoeologous Exchanges (HEs), i.e. chromatin exchanges between A and B subgenomes were unraveled with at least 9 founding events at the origin of the ABB bananas prior to the clonal diversification. The discovery of this nine founding events allows discussing the possible routes that led to the creation of the different subgroups and formulate new hypotheses. Based on our observations, we suggest different routes that gave rise to the current diversity in the ABB cultivars. Routes involving primary AB hybrids, routes leading to shared HEs and routes leading to a B excess ratio. Genetic fluxes took place between M. acuminata and M. balbisiana, particularly in India, where these unbalanced AB hybrids and ABB allotriploid originated and where cultivated M. balbisiana are abundant.\n\nConclusionsThe result of this study clarifies the classification of ABB cultivars and leading possibly to the revision of the classification of this subgroup. This is an important step to unravel the origin of polyploid bananas, and contributes to possible scenarios on the origin. ABB bananas are hypothesized to be more drought tolerant. Knowing the origin of our current cultivars and so their potential parents will help breeders to make the right choices for future crosses. The M. balbisiana genome is a good source to create new cultivars able to answer the numerous challenges of banana breeding.

genomics↗

bioRxiv2019

Tracking the global supply chain of herbal medicines with novel genomic DNA barcodes

AO_SCPLOWBSTRACTC_SCPLOWThe promotion of responsible and sustainable trade in biological resources is widely proposed as one solution to mitigate currently high levels of global biodiversity loss. Various molecular identification methods have been proposed as appropriate tools for monitoring global supply chains of commercialized animals and plants. We demonstrate the efficacy of target capture genomic barcoding in identifying and establishing the geographic origin of samples traded as Anacyclus pyrethrum, a medicinal plant assessed as globally vulnerable in the IUCN Red List of Threatened Species. Samples collected from national and international supply chains were identified through target capture sequencing of 443 low-copy nuclear makers and compared to results derived from genome skimming of plastome, standard plastid barcoding regions and ITS. Both target capture and genome skimming provided approximately 3.4 million reads per sample, but target capture largely outperformed standard plant DNA barcodes and entire plastid genome sequences. Despite the difficulty of distinguishing among closely related species and infraspecific taxa of Anacyclus using conventional taxonomic methods, we succeeded in identifying 89 of 110 analysed samples to subspecies level without ambiguity through target capture. Of the remaining samples, we determined that eleven contained plant material from other genera and families and ten were unidentifiable regardless of the method used. Furthermore, we were able to discern the geographical origin of Anacyclus samples collected in Moroccan, Indian and Sri Lankan markets, differentiating between plant materials originally harvested from diverse populations in Algeria and Morocco. With a recent drop in the cost of analysing samples, target capture offers the potential to routinely identify commercialized plant species and determine their geographic origin. It promises to play an important role in monitoring and regulation of plant species in trade, supporting biodiversity conservation efforts, and in ensuring that plant products are unadulterated, contributing to consumer protection.

genetics↗

bioRxiv2019

Genetic paths to evolutionary rescue and the distribution of fitness effects along them

The past century has seen substantial theoretical and empirical progress on the genetic basis of adaptation. Over this same period a pressing need to prevent the evolution of drug resistance has uncovered much about the potential genetic basis of persistence in declining populations. However, we have little theory to predict and generalize how persistence - by sufficiently rapid adaptation - might be realized in this explicitly demographic scenario. Here we use Fishers geometric model with absolute fitness to begin a line of theoretical inquiry into the genetic basis of evolutionary rescue, focusing here on asexual populations that adapt through de novo mutations. We show how the dominant genetic path to rescue switches from a single mutation to multiple as mutation rates and the severity of the environmental change increase. In multi-step rescue, intermediate genotypes that themselves go extinct provide a springboard to rescue genotypes. Comparing to a scenario where persistence is assured, our approach allows us to quantify how a race between evolution and extinction leads to a genetic basis of adaptation that is composed of fewer loci of larger effect. We hope this work brings awareness to the impact of demography on the genetic basis of adaptation.

evolutionary biology↗

bioRxiv2019

Dynamics of adaptation in an anisotropic phenotype-fitness landscape

We study the dynamics of adaptation of a large asexual population in a n-dimensional phenotypic space, under anisotropic mutation and selection effects. When n = 1 or under isotropy assumptions, the replicator-mutator equation is a standard model to describe these dynamics. However, the n-dimensional anisotropic case remained largely unexplored. We prove here that the equation admits a unique solution, which is interpreted as the phenotype distribution, and we propose a new and general framework to the study of the quantitative behavior of this solution. Our method builds upon a degenerate nonlocal parabolic equation satisfied by the distribution of the fitness components, and a nonlocal transport equation satisfied by the cumulant generating function of the joint distribution of these components. This last equation can be solved analytically and we then get a general formula for the trajectory of the mean fitness and all higher cumulants of the fitness distribution, over time. Such mean fitness trajectory is the typical outcome of empirical studies of adaptation by experimental evolution, and can thus be compared to empirical data. In sharp contrast with the known results based on isotropic models, our results show that the trajectory of mean fitness may exhibit (n - 1) plateaus before it converges. It may thus appear non-saturating for a transient but possibly long time, even though a phenotypic optimum exists. To illustrate the empirical relevance of these results, we show that the anisotropic model leads to a very good fit of Escherichia coli long-term evolution experiment, one of the most famous experimental dataset in experimental evolution. The two evolutionary epochs that have been observed in this experiment have long puzzled the community: we propose that the pattern may simply stem form a climbing hill process, but in an anisotropic fitness landscape.

evolutionary biology↗

bioRxiv2019

Population persistence under high mutation rate: from evolutionary rescue to lethal mutagenesis

Populations may genetically adapt to severe stress that would otherwise cause their extirpation. Recent theoretical work, combining stochastic demography with Fishers geometric model of adaptation, has shown how evolutionary rescue becomes unlikely beyond some critical intensity of stress. Increasing mutation rates may however allow adaptation to more intense stress, raising concerns about the effectiveness of treatments against pathogens. This previous work assumes that populations are rescued by the rise of a single resistance mutation. However, even in asexual organisms, rescue can also stem from the accumulation of multiple mutations in a single genome. Here, we extend previous work to study the rescue process in an asexual population where the mutation rate is sufficiently high so that such events may be common. We predict both the ultimate extinction probability of the population and the distribution of extinction times. We compare the accuracy of different approximations covering a large range of mutation rates. Moderate increase in mutation rates favors evolutionary rescue. However, larger increase leads to extinction by the accumulation of a large mutation load, a process called lethal mutagenesis. We discuss how these results could help design \"evolution-proof\" anti-pathogen treatments that even highly mutable strains could not overcome.

evolutionary biology↗

bioRxiv2018

Dynamics of fitness distributions in the presence of a phenotypic optimum: an integro-differential approach

We propose an integro-differential description of the dynamics of the fitness distribution in an asexual population under mutation and selection, in the presence of a phenotype optimum. Due to the presence of this optimum, the distribution of mutation effects on fitness depends on the parents fitness, leading to a non-standard equation with \"context-dependent\" mutation kernels.\n\nUnder general assumptions on the mutation kernels, which encompass the standard n dimensional Gaussian Fishers geometrical model (FGM), we prove that the equation admits a unique time-global solution. Furthermore, we derive a nonlocal nonlinear transport equation satisfied by the cumulant generating function of the fitness distribution. As this equation is the same as the equation derived by Martin and Roques (2016) while studying stochastic Wright-Fisher-type models, this shows that the solution of the main integro-differential equation can be interpreted as the expected distribution of fitness corresponding to this type of microscopic models, in a deterministic limit. Additionally, we give simple sufficient conditions for the existence/non-existence of a concentration phenomenon at the optimal fitness value, i.e, of a Dirac mass at the optimum in the stationary fitness distribution. We show how it determines a phase transition, as mutation rates increase, in the value of the equilibrium mean fitness at mutation-selection balance. In the particular case of the FGM, consistently with previous studies based on other formalisms (Waxman and Peck, 1998, 2006), the condition for the existence of the concentration phenomenon simply requires that the dimension n of the phenotype space be larger than or equal to 3 and the mutation rate U be smaller than some explicit threshold.\n\nThe accuracy of these deterministic approximations are further checked by stochastic individual-based simulations.

evolutionary biology↗

bioRxiv2018

When sinks become sources: adaptive colonization in asexuals

The successful establishment of a population into a new empty habitat outside of its initial niche is a phenomenon akin to evolutionary rescue in the presence of immigration. It underlies a wide range of processes, such as biological invasions by alien organisms, host shifts in pathogens or the emergence of resistance to pesticides or antibiotics from untreated areas.\n\nIn this study, we derive an analytically tractable framework to describe the coupled evolutionary and demographic dynamics of asexual populations in a source-sink system. In particular, we analyze the influence of several factors -- immigration rate, mutational parameters, and harshness of the stress induced by the change of environment -- on the establishment success in the sink (i.e. the formation of a self-sufficient population in the sink), and on the time until establishment. To this aim, we use a classic phenotype-fitness landscape (Fishers geometrical model in n dimensions) where source and sink habitats determine distinct phenotypic optima. The harshness of stress, in the sink, is determined by the distance between the fitness optimum in the sink and that of the source. The dynamics of the full distribution of fitness and of population size in the sink are analytically predicted under a strong mutation strong immigration limit where the population is always polymorphic.\n\nThe resulting eco-evolutionary dynamics depend on mutation and immigration rates in a non straightforward way. Below some mutation rate threshold, establishment always occurs in the sink, following a typical four-phases trajectory of the mean fitness. The waiting time to this establishment is independent of the immigration rate and decreases with the mutation rate. Beyond the mutation rate threshold, lethal mutagenesis impedes establishment and the sink population remains so, albeit with an equilibrium state that depends on the details of the fitness landscape. We use these results to get some insight into possible effects of several management strategies.

evolutionary biology↗

bioRxiv2018

Three new genome assemblies support a rapid radiation in Musa acuminata (wild banana)

Edible bananas result from interspecific hybridization between Musa acuminata and Musa balbisiana, as well as among subspecies in M. acuminata. Four particular M. acuminata subspecies have been proposed as the main contributors of edible bananas, all of which radiated in a short period of time in southeastern Asia. Clarifying the evolution of these lineages at a whole-genome scale is therefore an important step toward understanding the domestication and diversification of this crop. This study reports the de novo genome assembly and gene annotation of a representative genotype from three different subspecies of M. acuminata. These data are combined with the previously published genome of the fourth subspecies to investigate phylogenetic relationships and genome evolution. Analyses of shared and unique gene families reveal that the four subspecies are quite homogenous, with a core genome representing at least 50% of all genes and very few M. acuminata species-specific gene families. Multiple alignments indicate high sequence identity between homologous single copy-genes, supporting the close relationships of these lineages. Interestingly, phylogenomic analyses demonstrate high levels of gene tree discordance, due to both incomplete lineage sorting and introgression. This pattern suggests rapid radiation within Musa acuminata subspecies that occurred after the divergence with M. balbisiana. Introgression between M. a. ssp. malaccensis and M. a. ssp. burmannica was detected across a substantial portion of the genome, though multiple approaches to resolve the subspecies tree converged on the same topology. To support future evolutionary and functional analyses, we introduce the PanMusa database, which enables researchers to exploration of individual gene families and trees.

evolutionary biology↗

bioRxiv2018

Dental erosion caused by a gastrointestinal disorder in a child from the Late Holocene of Northeastern Brazil

A skeleton of an approximately 3-years-old sub-adult, in an excellent state of conservation, was found at the Pedra do Cachorro rock shelter - Buique, Pernambuco - Brazil, an archaeological site used as funerary place between 3875 and 575 cal years B.P. The skeleton has no signs of pathological bone changes, but its maxillary teeth show strong evidence of enamel and dentin wear caused by acid erosion, suggesting vomiting or gastroesophageal reflux episodes. The aim of this study was to describe the lesions and discuss the aetiology of these dental defects with the emphasis on the cause of the death of this individual.

pathology↗

bioRxiv2017

Evolutionary Rescue Over A Fitness Landscape

Evolutionary rescue describes a situation where adaptive evolution prevents the extinction of a population facing a stressing environment. Models of evolutionary rescue could in principle be used to predict the level of stress beyond which extinction becomes likely for species of conservation concern, or conversely the treatment levels most likely to limit the emergence of resistant pests or pathogens. Stress levels are known to affect both the rate of population decline (demographic effect) and the speed of adaptation (evolutionary effect), but the latter aspect has received less attention. Here, we address this issue using Fishers Geometric Model of adaptation. In this model, the fitness effects of mutations depend both on the genotype and the environment in which they arise. In particular, the model introduces a dependence between the level of stress, the proportion of rescue mutants, and their costs before the onset of stress. We obtain analytic results under a strong-selection-weak-mutation regime, which we compare to simulations. We show that the effect of the environment on evolutionary rescue can be summarized into a single composite parameter quantifying the effective stress level, which is amenable to empirical measurement. We describe a narrow characteristic stress window over which the rescue probability drops from very likely to very unlikely as the level of stress increases. This drop is sharper than in previous models, as a result of the decreasing proportion of stress-resistant mutations as stress increases. We discuss how to test these predictions with rescue experiments across gradients of stress.

evolutionary biology↗

bioRxiv2017

Discovery of global regulators of 3’ untranslated region processing in cancers with KAPAC

3 UTR length is regulated in relation to cellular state. To uncover key regulators of poly(A) site (PAS) use in specific conditions, we have developed PAQR, a method for quantifying PAS use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on PAS choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovered sequence motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular, our analysis points to Polypyrimidine tract binding protein 1 as a regulator of PAS choice in glioblastoma.

systems biology↗

bioRxiv2017

Enrichment of the HIV reservoir in CD32+ CD4 T cells occurs early in blood and tissue

The Fc receptor CD32 has been proposed as a marker for CD4 T cells latently infected with HIV. We demonstrate that enrichment for HIV DNA in CD32+ CD4 T cells can be found early in infection in both tissue and blood. However, we find no evidence for a correlation between CD32 expression on CD4 T cells and either HIV DNA levels or time to rebound viraemia following treatment interruption. CD32+ CD4 T cells have a more differentiated memory phenotype, and high levels of expression of immune checkpoint receptors PD-1, Tim-3 and TIGIT as well as the activation marker, HLA DR. There was no difference in the phenotype or frequency of CD32 expressing cells prior to or after the initiation of antiretroviral therapy, or compared with healthy controls, suggesting that preferential infection or survival, rather than up-regulation, may be responsible for the observed enrichment of proviral HIV DNA in CD32+ CD4 T cells.

immunology↗