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Moreau, C.

Publications and source records attributed to Moreau, C..

At least 19 recordsLinked to original sources

Functional remodeling of the parasubthalamic nucleus drives alcohol drinking escalation in dependence

The neurocircuitry changes mediating the development and maintenance of an alcohol use disorder are complex and dynamic. The parasubthalamic nucleus (PSTN), a small nucleus of the posterior lateral hypothalamus best known for suppressing appetite, is interconnected with brain regions disrupted in addiction; yet its potential role in the regulation of alcohol consumption had never been examined. Here we show that the PSTN exerts potent control over alcohol drinking in mice. Remarkably, the influence of endogenous PSTN activity on voluntary alcohol consumption switches from inhibitory to stimulatory upon induction of alcohol dependence. Among PSTN cells, Crh neurons represent a unique subpopulation that promotes alcohol drinking and fires more in dependent mice. Alcohol intake escalation driven by PSTN Crh neurons involves thalamic output and behavioral disinhibition. Based on our results, PSTN Crh neurons could represent a critical node in the brain circuitry overactive in alcohol addiction driven by reward seeking in humans.

neuroscience↗

Aligning gene trees with family trees

Relatedness between individuals can be measured at the genealogical level (by describing shared ancestors in a pedigree) or at a genetic level (by describing shared haplotypes across the genome). The shared haplotype structure can be conveniently summarized as a sequence of trees along the genome, where each tree describes the last shared genetic ancestors between individuals at a locus. While many tools exist to infer tree sequences from genetic data, and many large pedigree datasets are available, few tools exist to identify the relationship between the two - finding which genetic ancestor corresponds to which pedigree ancestor, and conversely. In this paper, we propose an algorithm to solve this problem by providing, for each genetic tree, the list of all consistent ancestry paths within a genealogical tree. We also provide variants of the algorithm with moderate robustness to both tree sequence and pedigree errors. We demonstrate the scalability of our approach on the BALSAC genealogical dataset, which includes millions of individuals in Quebec, Canada. We find that 20 carriers usually provide enough information to reliably identify a common ancestor 15 generations ago or find the parent of origin of alleles among probands, but the number of possible ancestry paths within the pedigree can remain large. We apply the method to reconstruct the inheritance of a causal allele for type 1 myotonic dystrophy.

bioinformatics↗

Fine-scale structure of a whole regional population through genetics and genealogies

The Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec, Canada, a population shaped by a prominent founder effect, has long been considered genetically homogeneous. This study comprehensively investigates the fine-scale population structure within SLSJ by integrating genotype data from the CARTaGENE cohort with extensive genealogical records from the BALSAC population register. A time-efficient algorithm was developed to compute billions of kinship coefficients from genealogies in order to analyse an entire generation. We demonstrate a striking concordance between realised (genetic) and expected (genealogical) kinship (r = 0.78). From both kinship measures, we reveal fine-scale population structure at the municipal level within SLSJ, challenging the notion of regional homogeneity. Our analysis highlights an east-west genetic gradient and uncovers migratory streams and differential founders genetic contributions that shaped the genetic landscape of this population. This research provides insights into the interplay of genetics, demography, and historical events, underscoring the importance of fine-scale population structure in genetic studies and reaffirming the power of large-scale genealogical data.

genetics↗

Single cell transcriptomics reveals that air-liquid interface culture promotes goblet cell differentiation and inhibits glycolysis in cell monolayers derived from rabbit caecum organoids

Faithfully recapitulating the cellular heterogeneity of the intestinal epithelium is essential when using organoid models. Air-liquid interface (ALI) culture has been shown to promote secretory cell differentiation but its impact on gene expression in each epithelial cell type remains unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of rabbit caecum-derived organoid monolayers grown under immerged or ALI conditions. We then compared these organoid cell type-specific gene expression profiles to a scRNA-seq atlas of the rabbit caecal epithelium in vivo. We selected the rabbit model notably because, unlike mice, it possesses BEST4+ epithelial cells, a newly discovered subset of mature absorptive cells. Our analysis revealed a high degree of transcriptomic similarity between in vivo and organoid-derived stem and transit-amplifying cells. ALI culture markedly enhanced the differentiation of the secretory lineage, especially goblet cells, which transcriptome closely resembled that of in vivo goblet cells. Furthermore, ALI was the only condition allowing the detection of enteroendocrine cells. BEST4+ cells, however, were absent from organoids in immerged or ALI conditions despite their presence in vivo. In addition, ALI culture led to a consistent downregulation of hypoxia and glycolysis-associated genes across all cell types, which suggests a metabolic shift likely driven by increased oxygen availability in ALI conditions. Cell-cell communication analyses further indicated that bone morphogenic protein (BMP) and fibroblast growth factor (FGF) signaling under ALI more closely mirrored in vivo patterns than under immerged condition. Altogether, these results demonstrate that ALI culture allows to better recapitulate the in vivo cellular heterogeneity and molecular signatures of the rabbit intestinal epithelium. Future optimization of culture conditions could enhance the physiological relevance of this organoid model, for instance by delivering oxygen exclusively to the basal side, as occurs in vivo.

cell biology↗

Genomic and Genetic Insights into Mendel's Pea Genes

Pea, Pisum sativum, is an excellent model system through which Gregor Mendel established the foundational principles of inheritance. Surprisingly, till today, the molecular nature of the genetic differences underlying the seven pairs of contrasting traits that Mendel studied in detail remains partially understood. Here, we present a genomic and phenotypic variation map, coupled with haplotype-phenotype association analyses across a wide range of traits in a global Pisum diversity panel. We focus on a genomics-enabled genetic dissection of each of the seven traits Mendel studied, revealing many previously undescribed alleles for the four characterized genes, R, Le, I and A, and elucidating the gene identities and mutations for the remaining three uncharacterized traits. Notably, we identify: (1) a ca. 100kb deletion upstream of the Chlorophyll synthase (ChlG) gene, which generates aberrant transcripts and confers the yellow pod phenotype of gp mutants; (2) an in-frame premature stop codon mutation in a Dodeca-CLE41/44 signalling peptide which explains the parchmentless mutant phenotype corresponding to p; and (3) a 5bp in-frame deletion in a CIK-like receptor kinase gene corresponding to the fasciated stem phenotype fa, which Mendel described in terms of flower position, and we postulate the existence of a Modifier of fa (Mfa) locus that masks this meristem defect. Mendel noted the pleiotropy of the a mutation, including inhibition of axil ring anthocyanin pigmentation, a trait we found to be controlled by allelic variants of the gene D within an R2R3-MYB gene cluster. Furthermore, we characterize and validate natural variation of a quantitative genetic locus governing both pod width and seed weight, characters that Mendel deemed were not sufficiently demarcated for his analyses. This study establishes a cornerstone for fundamental research, education in biology and genetics, and pea breeding practices.

genetics↗

Distinct Gene Regulatory Dynamics Drive Skeletogenic Cell Fate Convergence During Vertebrate Embryogenesis

Cell type repertoires have expanded extensively in metazoan animals, with some clade-specific cells being paramount to their evolutionary success. A prime example are the skeletogenic cells of vertebrates that form the basis of their developing endoskeletons. Depending on anatomical location, these cells originate from three different embryonic precursor lineages - the neural crest, the somites, and the lateral plate mesoderm - yet they converge developmentally towards similar cellular phenotypes. Furthermore, these lineages have gained skeletogenic competency at distinct timepoints during vertebrate evolution, thus questioning to what extent different parts of the vertebrate skeleton rely on truly homologous cell types. Here, we investigate how lineage-specific molecular properties of the three precursor pools are integrated at the gene regulatory level, to allow for phenotypic convergence towards a skeletogenic cell fate. Using single-cell transcriptomics and chromatin accessibility profiling along the precursor-to-skeletogenic cell continuum, we examine the gene regulatory dynamics associated with this cell fate convergence. We find that distinct transcription factor profiles are inherited from the three precursor states, and that lineage-specific enhancer elements integrate these different inputs at the cis-regulatory level, to execute a core skeletogenic program. We propose a lineage-specific gene regulatory logic for skeletogenic convergence from three embryonic precursor pools. Early skeletal cells in different body parts thus share only a partial deep homology. This regulatory uncoupling may render them amenable to individualized selection, to help to define distinct morphologies and biomaterial properties in the different parts of the vertebrate skeleton.

developmental biology↗

Fine-scale genetic structure and rare variant frequencies

In response to the current challenge in genetic studies to make new associations, we advocate for a shift toward leveraging population fine-scale structure. Our exploration brings to light distinct fine-structure within populations having undergone a founder effect, challenging the prior perception of homogeneity. This underscores that smaller, but well-defined cohorts, demonstrate an important increase in rare variant frequencies, offering a promising avenue for new genetic variants discovery.

genomics↗

A pectin-binding peptide with a structural and signaling role in the assembly of the plant cell wall

Pressurized cells with strong walls make up the hydrostatic skeleton of plants. Assembly and expansion of such stressed walls depend on a family of secreted RAPID ALKALINIZATION FACTOR (RALF) peptides which, curiously, bind both a membrane receptor complex and wall-localized LEUCINE-RICH REPEAT EXTENSINs (LRXs) in a mutually exclusive way. Here we show that, in root hairs, the RALF22 peptide has a dual structural and signaling role in cell expansion. Together with LRX1, it directs the compaction of charged pectin polymers at the root hair tip into periodic circumferential rings. Free RALF22 induces the formation of a complex with LORELEI-LIKE-GPI-ANCHORED PROTEIN 1 (LLG1) and FERONIA (FER), triggering adaptive cellular responses. These findings show how a peptide simultaneously functions as a structural component organizing cell wall architecture and as a signaling molecule that regulates this process. This mechanism may also underlie wall assembly and expansion in other plant cell types.

plant biology↗

Deciphering the genetic structure of the Quebec founder population using genealogies

Using genealogy to study the demographic history of a population makes it possible to overcome the models and assumptions often used in population genetics. The Quebec founder population is one of the few populations in the World having access to the complete genealogy of the last 400 years. The goal of this paper is to follow the evolution of the Quebec population structure generation per generation from the beginning of European colonization until the present day. To do so, we calculated the kinship coefficients of all ancestors pairs in the ascending genealogy of 665 individuals from eight regional and ethnocultural groups per 25-year period. We show that the Quebec population structure appeared in the St. Lawrence valley as early as 1750. At that time, the ancestors of two groups, the Sagueneans and the Acadians from the Gaspe Peninsula, experienced a marked increase in kinship and inbreeding levels which have shaped the contemporary population structure. Interestingly, this structure arose before the colonization of the Saguenay region and at the very beginning of the Gaspe Peninsula settlement. The resulting regional founder effects in these two groups, but also in the other regional groups, led to differences in the present-day identity-by-descent sharing and are directly linked to the number of most recent common ancestors and their genetic contribution to the studied subjects.

genetics↗

Rationally designed Gla-domainless FXa as TFPI bait in hemophilia

Gla-domainless factor Xa (GD-FXa) was proposed as a trap to the endogenous anticoagulant Tissue Factor Pathway Inhibitor (TFPI) to restore thrombin generation in hemophilia. Using computational chemistry and experimental approaches, we previously showed that S195A GD-FXa also binds TFPI and restores ex vivo coagulation in hemophilia plasmas. To design a GD-FXa variant with improved anti-TFPI activity and identify suitable sites for mutagenesis, we performed molecular dynamics simulations. The calculations identified residues R150FXa and K96FXa as cold-spots of interaction between GD-FXa and the K2 domain of TFPI. In the three-dimensional model, both residues are facing TFPI hydrophobic residues and are thus potential candidates for mutagenesis into hydrophobic residues to favor an improved protein-protein interaction. Catalytically inactive GD-FXa variants containing the S195A mutation and additional mutations as K96Y, R150I, R150G and R150F were produced to experimentally confirm these computational hypotheses. Among these mutants, the R150FFXA showed increased affinity for TFPI as theoretically predicted, and was also more effective than S195A GD-FXa in restoring coagulation in FVIII deficient plasmas. Moreover, the R150 mutants lost interaction with antithrombin, which is favorable to extend their half-life.

bioengineering↗

The secrets to domestic bliss - Partner fidelity and environmental filtering preserve stage-specific turtle ant gut symbioses for over 40 million years

BackgroundGut microbiomes can vary across development, a pattern often found for insects with complete metamorphosis. With varying nutritional need and distinct opportunities for microbial acquisition, questions arise as to how such holometabolous insects retain helpful microbes at larval and adult stages. Ants are an intriguing system for such study. In a number of lineages adults digest only liquid food sources, while larvae digest solid foods. Like some other social insects, workers and soldiers of some ant species engage in oral-anal trophallaxes, enabling microbial transfer among siblings. But do queens, the typical colony founding caste, obtain symbionts through such transfer? Does this enable transgenerational symbiont passage? And does the resulting partner fidelity promote the evolution of beneficial symbionts? Furthermore, how might such adult-centric biology shape larval microbiomes? To address these questions, we characterized symbiotic gut bacteria across 13 species of Cephalotes turtle ants, with up to 40-million years of divergence. Adding to the prior focus on workers we, here, study underexplored castes and stages including queens, soldiers, and larvae, by performing 16S rRNA qPCR, amplicon sequencing, and phylogenetic classification. ResultsWe show that adult microbiomes are conserved across species and largely across castes. Nearly 95% of the bacteria in adults have, thus far, been found only in Cephalotes ants. Furthermore, the microbiomes from most adults exhibit phylosymbiosis, a trend in which microbiome community similarity recapitulates patterns of host relatedness. Additionally, an abundant, adult-enriched symbiont cospeciates with some Cephalotes. Evidence here suggests that these partner fidelity patterns extend from transgenerational symbiont transfer through alate gyne dispersal and subsequent colony-founding by queens. Like adults, larvae of Cephalotes species exhibit strong microbiome conservation. Phylosymbiosis patterns are weaker, however, with further evidence elevating environmental filtering as a primary mechanism behind such conservation. Specifically, while adult-enriched symbionts are found in most larvae, symbionts of older larvae are highly related to free-living bacteria from the Enterobacteriaceae, Lactobacillales, and Actinobacteria. ConclusionsOur findings suggest that both partner fidelity and conserved environmental filtering drive stable, stage-specific, social insect symbioses. We discuss the implications for our broader understanding of insect microbiomes, and the means of sustaining a beneficial microbiome.

evolutionary biology↗

Large scale screening discovers clofoctol as an inhibitor of SARS-CoV-2 replication that reduces COVID-19-like pathology

Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients. SummaryAntivirals targeting SARS-CoV-2 are sorely needed. In this study, we screened a library of drug compounds and identified clofoctol as an antiviral against SARS-CoV-2. We further demonstrated that, in vivo, this compound reduces inflammatory gene expression and lowers pulmonary pathology.

microbiology↗

Facilitating population genomics of non-model organisms through optimized experimental design for reduced representation sequencing

Genome-wide data are invaluable to characterize differentiation and adaptation of natural populations. Reduced representation sequencing (RRS) subsamples a genome repeatedly across many individuals. However, RRS requires careful optimization and fine-tuning to deliver high marker density while being cost-efficient. The number of genomic fragments created through restriction enzyme digestion and the sequencing library setup must match to achieve sufficient sequencing coverage per locus. Here, we present a workflow based on published information and computational and experimental procedures to investigate and streamline the applicability of RRS. In an iterative process genome size estimates, restriction enzymes and size selection windows were tested and scaled in six classes of Antarctic animals (Ostracoda, Malacostraca, Bivalvia, Asteroidea, Actinopterygii, Aves). Achieving high marker density would be expensive in amphipods, the malacostracan target taxon, due to the large genome size. We propose alternative approaches such as mitogenome or target capture sequencing for this group. Pilot libraries were sequenced for all other target taxa. Ostracods, bivalves, sea stars, and fish showed overall good coverage and marker numbers for downstream population genomic analyses. In contrast, the bird test library produced low coverage and few polymorphic loci, likely due to degraded DNA. Prior testing and optimization are important to identify which groups are amenable for RRS and where alternative methods may currently offer better cost-benefit ratios. The steps outlined here are easy to follow for other non-model taxa with little genomic resources, thus stimulating efficient resource use for the many pressing research questions in molecular ecology.

genomics↗

Global prevalence of potentially pathogenic short-tandem repeats in an epilepsy cohort

This study aims to decipher the role of short tandem repeats (STRs) in epilepsy patients. Whole genome short-read sequencing data of 734 epileptic patients was used to look for known STR expansions associated with increased risk of neurodevelopmental diseases or epilepsy using three different software. Results show one hit of particular interest on ARX gene associated with Early Infantile Encephalopathic Epilepsy that could be causal for one patient with developmental and epileptic encephalopathy. However, we show that the different software do not agree on most of the calls above the threshold and that experimental validation is still needed for diagnostic, although these algorithms could prove useful for pre-selection of samples to be validated.

genetics↗

Subtypes of functional connectivity associate robustly with ASD diagnosis

Our understanding of the changes in functional brain organization in autism is hampered by the extensive heterogeneity that characterizes this neurodevelopmental disorder. Data driven clustering offers a straightforward way to decompose this heterogeneity into subtypes of distinguishable connectivity types and promises an unbiased framework to investigate behavioural symptoms and causative genetic factors. Yet the robustness and generalizability of these imaging subtypes is unknown. Here, we show that unsupervised functional connectivity subtypes are moderately associated with the clinical diagnosis of autism, and that these associations generalize to independent replication data. We found that subtypes identified robust patterns of functional connectivity, but that a discrete assignment of individuals to these subtypes was not supported by the data. Our results support the use of data driven subtyping as a data dimensionality reduction technique, rather than to establish clinical categories.

neuroscience↗

A fast linkage disequilibrium-based statistical test for Genome-Wide Epistatic Selection Scans in structured populations

The quest for genome-wide signatures of selection in populations using SNP data has proven efficient to uncover genes involved in conserved or adaptive molecular functions, but none of the statistical methods were designed to identify interacting genes as targets of selective processes. Here, we propose a straightforward statistical test aimed at detecting epistatic selection, based on a linkage disequilibrium (LD) measure accounting for population structure and heterogeneous relatedness between individuals. SNP-based (Trv) and window-based (TcorPC1v) statistics fit a Student distribution, allowing to easily and quickly test the significance of correlation coefficients in the frame of Genome-Wide Epistatic Selection Scans (GWESS) using candidate genes as baits. As a proof of concept, use of SNP data from the Medicago truncatula symbiotic legume plant uncovered a previously unknown gene coadaptation between the MtSUNN (Super Numeric Nodule) receptor and the MtCLE02 (CLAVATA3-Like) signalling peptide, and experimental evidence accordingly supported a MtSUNN-dependent negative role of MtCLE02 in symbiotic root nodulation. Using human HGDP-CEPH SNP data, our new statistical test uncovered strong LD between SLC24A5 and EDAR worldwide, which persists after correction for population structure and relatedness in Central South Asian populations. This result suggests adaptive genetic interaction or coselection between skin pigmentation and the ectodysplasin pathway involved in the development of ectodermal organs (hairs, teeth, sweat glands), in some human populations. Applying this approach to genome-wide SNP data will foster the identification of evolutionary coadapted gene networks. Author summaryPopulation genomic methods have allowed to identify many genes associated with adaptive processes in populations with complex histories. However, they are not designed to identify gene coadaptation between genes through epistatic selection, in structured populations. To tackle this problem, we developed a straightforward LD-based statistical test accounting for population structure and heterogeneous relatedness between individuals, using SNP-based (Trv) or windows-based (TcorPC1v) statistics. This allows easily and quickly testing for significance of correlation coefficients between polymorphic loci in the frame of Genome Wide Epistatic Selection Scans (GWESS). Following detection of gene coadaptation using SNP data from human and the model plant Medicago truncatula, we report experimental evidence of genetic interaction between two receptors involved in the regulation of root nodule symbiosis in Medicago truncatula. This test opens new avenues for exploring the evolution of genes as interacting units and thus paves the way to infer new networks based on evolutionary coadaptation between genes.

genetics↗

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify dimensions contributing to complex idiopathic conditions. CNVs had large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibited worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.

neuroscience↗

Polygenic risk scores of several subtypes of epilepsies in a founder population

ImportanceEpilepsy is defined as a group of neurological disorders characterized by epileptic seizures, brief episodes of symptoms that are caused by abnormal or excessive neuronal activity in the brain. Epilepsy affects around 3 percent of individuals. In the past 10 years, many groups have been working to better understand the complex genetic mechanisms underlying epilepsy. Together, they studied many different genetic mechanisms, but there is still a substantial missing heritability component in epilepsy genetics.\n\nObjectiveHere, we used polygenic risk scores (PRS) to quantify the cumulative effects of a number of variants, which may individually have a very small effect on susceptibility.\n\nDesignWe calculated PRS in 522 French-Canadian epilepsy patients divided into seven subtypes and French-Canadian controls.\n\nSettingAll study participants (cases and controls) were selected based on their French-Canadian ancestry.\n\nParticipantsThe epilepsy cohort was composed of families of at least three affected individuals with Idiopathic Generalized Epilepsy (IGE) or Non-acquired Focal Epilepsy (NAFE) previously collected and diagnosed by neurologists following the International League Against Epilepsy (ILAE) criteria.\n\nExposuresAll samples were processed on a common genotyping array.\n\nMain outcomes and ResultsWe show that the area under the curve (AUC) is almost always slightly greater than 0.5, especially in patients with IGE and subtypes. We also looked at the association of the PRS with the different phenotypes using a linear mixed effects model estimated by generalized estimating equation (GEE) with the pairwise identity-by-descent (IBD) matrix as a random effect. P-values of GEE were consistent with AUC calculations.\n\nConclusions and RelevanceGlobally, we support the notion that PRS and SNP-based heritability provide reliable measures to rightfully estimate the contribution of genetic factors to the pathophysiological mechanism of epilepsies, but further studies are needed on PRS before they can be used clinically.

genetics↗