Biology subjects

Berthelot, C.

Publications and source records attributed to Berthelot, C..

16 recordsLinked to original sources

bioRxiv2026

Evolution of the genetic architecture of uterine disorders

Uterine disorders and menstrual abnormalities are prevalent reproductive conditions with significant clinical consequences. Recent genome-wide association studies have identified hundreds of variants contributing to different uterine disorders, while epidemiological evidence suggests that these disorders co-occur more frequently than expected, implying shared genetic mechanisms. However, the specific genetic variants and biological pathways underlying this shared architecture remain poorly characterized. Here, we conducted a uterus-centric, multi-trait genome-wide association analysis across ten uterine disorders in a European cohort to elucidate this shared genetic architecture. Further, we embedded this architecture in a functional and population genomics framework to investigate its plausible biological mechanisms and its evolutionary history in humans. We confirm strong positive genetic correlations between major uterine disorders and identify 31 independent susceptibility loci jointly affecting the genetic risk of multiple uterine pathologies, substantiating an intertwined biological basis. Populational analyses demonstrated that several of these susceptibility variants exhibit pronounced allele frequency differentiation across global populations suggestive of recent polygenic selection, including variants with well-supported regulatory functions at the ESR1-CCDC170, WNT4, SFR1, FOXO1, ITPR1, DMRT1 and CDKN2B loci. Notably, we show that most derived alleles acquired during recent human evolution increase risk across multiple uterine disorders and may evolve under antagonistic selection. These findings provide functional annotation and population-level prioritization of genetic variants influencing multiple uterine disorders. They also highlight how past evolutionary histories may contribute to population differences in uterine disease prevalence and pathogenesis.

genetics↗

bioRxiv2025

Salmonids reveal principles of regulatory evolution following autotetraploidization

Early vertebrate autotetraploidization events may have enabled major innovations by expanding the genetic material for functional diversification, yet their ancient timing obscures how genome doubling reshaped gene regulatory evolution. Salmonids provide a unique window to these mechanisms, because they experienced a comparatively recent autotetraploidization and are earlier in the rediploidization process - which creates new genes and regulatory elements during evolution. Here, using large-scale multiomics spanning embryonic and adult tissues in two salmonids, we investigate gene regulatory evolution following genome doubling and rediploidization, which we show is governed by developmental and tissue-specific context, with a period of maximal constraint at advanced stages of embryogenesis. This work advances understanding of vertebrate genome evolution, while providing an open resource supporting salmonid aquaculture and conservation.

evolutionary biology↗

bioRxiv2025

Alignment-free integration of single-nucleus ATAC-seq across species with sPYce

Changes in gene regulation largely contribute to differences in cellular identities and phenotypes between species. Single-nucleus assays for transposase-accessible chromatin with sequencing (snATAC-seq) are an efficient strategy to identify putative gene regulatory elements active in a given tissue at single-cell resolution, and have unprecedented potential to provide new insight into evolutionary divergence of regulatory programs. However, no dedicated framework exists to integrate and compare snATAC-seq data across species, whilst methods designed for single-cell gene expression data have serious limitations. Here, we present sPYce, a cross-species snATAC-seq integration method that relies on sequence composition similarities through k-mer histograms. In contrast to other approaches, sPYce does not require orthologous genes or genome alignments to anchor data from different species. Instead, it uses similarity in non-coding regulatory sequence motifs to uncover conserved cellular identities. sPYce can embed datasets from multiple species into the same mathematical space and permits further downstream analysis steps, such as dimensionality reduction, visualisation, clustering, cell type annotation transfer, and motif enrichment. We benchmarked sPYce against existing approaches on two publicly available datasets spanning more than 160 million years of evolution, demonstrating that it successfully uncovers conserved cellular programs whilst preserving biologically relevant species-specific differences. sPYce also implements a significance test for divergence of regulatory motifs between species. By comparing cerebellar development in mouse and opossum, we discovered regulatory divergence in granule cell differentiation programs, particularly driven by Nuclear Factor 1 (NF1). Our extensive evaluation suggests that sPYce is the first easy-to-use, alignment-free cross-species snATAC-seq integration approach, opening novel perspectives to compare gene regulatory evolution across species.

bioinformatics↗

bioRxiv2024

Convergent gene expression in epithelial cells illuminates the evolution of uterine receptivity

The epithelium of the uterine endometrium is the first maternal interface encountered by the embryo, and plays crucial roles in the maternal-embryonic crosstalk necessary to embryo implantation. Mechanisms of embryo implantation are highly variable between mammals: humans and mice have convergently evolved similar embryo implantation phenotypes, where the embryo embeds in the maternal mucosa, which differs from the ancestral mammalian and primate phenotypes. This phenomenon is thought to be partly controlled by maternal epithelial receptivity signals during the window of implantation. Here, we combined endometrial epithelial organoid models and single-cell transcriptomics to investigate how gene expression has evolved in endometrial epithelial cells between human, non-human primates and mouse at key time points in the hormonal cycle. We discovered that many maternal genes involved in uterine receptivity and embryo implantation exhibit more similar expression patterns between human and mouse compared to macaque and marmoset. In particular, we show that the endometrial expression of LIF, a crucial actor of endometrial receptivity in both human and mouse, is likely an evolutionary convergence rather than a conserved feature as previously hypothesised.

evolutionary biology↗

bioRxiv2023

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

cancer biology↗

bioRxiv2023

Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits

Changes in gene regulation have long been thought to underlie most phenotypic differences between species. Subterranean rodents, and in particular the naked mole-rat, have attracted substantial attention due to their proposed phenotypic adaptations, which include hypoxia tolerance, metabolic changes and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade or also present in other mammals. Here, we investigate regulatory evolution in heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements, and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptation in metabolic and functional pathways, and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny, and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats - such as the insulin and hypoxia response pathways. Third, we report non-orthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state-of-the-art by addressing known limitations of inter-species comparisons of epigenomic profiles, and has broad implications in the field of comparative functional genomics.

genomics↗

bioRxiv2022

Genome structures resolve the early diversification of teleost fishes

Accurate species phylogenies are a prerequisite for evolutionary research. Teleosts are by far the largest and the most diversified group of extant vertebrates, but relationships among the three oldest lineages of extant teleosts remain unresolved. Based on seven high-quality new genome assemblies in Elopomorpha (tarpons, eels), we revisited the topology of the deepest branches of the teleost phylogeny using independent gene sequence and chromosomal rearrangement phylogenomic approaches. These analyses converged to a single scenario that unambiguously places the Elopomorpha and Osteoglossomorpha (bony-tongues) in a monophyletic group sister to all other teleosts, i.e., the Clupeocephala lineage. This finding resolves over 50 years of controversy on the evolutionary relationships of these lineages and highlights the power of combining different levels of genome-wide information to solve complex phylogenies. One-Sentence SummaryWhole-genome analyses place Elopomorpha (tarpons, eels) and Osteoglossomorpha (bony-tongues) as sister groups at the deepest branching of crown teleosts.

evolutionary biology↗

bioRxiv2022

Reconstruction of hundreds of reference ancestral genomes across the eukaryotic kingdom

Ancestral sequence reconstruction is a fundamental aspect of molecular evolution studies, and can trace small-scale sequence modifications through the evolution of genomes and species. In contrast, fine-grained reconstructions of ancestral genome organisations are still in their infancy, limiting our ability to draw comprehensive views of genome and karyotype evolution. Here we reconstruct the detailed gene contents and organisations of 624 ancestral vertebrate, plant, fungi, metazoan and protist genomes, 183 of which are near-complete chromosomal reconstructions. Reconstructed ancestral genomes are similar to their descendants in terms of gene content as expected and agree precisely with reference cytogenetic and in silico reconstructions when available. By comparing successive ancestral genomes along the phylogenetic tree, we estimate the intra- and inter-chromosomal rearrangement history of all major vertebrate clades at high resolution. This freely available resource introduces the possibility to follow evolutionary processes at genomic scales in chronological order, across multiple clades and without relying on a single extant species as reference.

evolutionary biology↗

bioRxiv2022

A high-resolution comparative atlas across 74 fish genomes illuminates teleost evolution after whole-genome duplication

Teleost fishes are ancient tetraploids stemming from an ancestral whole-genome duplication that may have contributed to the impressive diversification of this clade. Whole-genome duplications can occur via self-doubling (autopolyploidy) or via hybridization between different species (allopolyploidy). The mode of tetraploidization conditions evolutionary processes by which duplicated genomes return to a diploid state through meiosis resolution and subsequent genetic divergence (cytological and genetic rediploidization). How teleosts became tetraploid remains unresolved, leaving a fundamental gap to interpret their functional evolution. As legacy of the whole genome duplication, identifying orthologous and paralogous genomic regions across teleosts is challenging, hindering genome-wide investigations into their polyploid history. Here, we combine tailored gene phylogeny methodology together with a state-of-the-art ancestral karyotype reconstruction to establish the first high-resolution comparative atlas of paleopolyploid regions across 74 teleost genomes. We then leverage this atlas to investigate how rediploidization occurred in teleosts at the genome-wide level. We uncover that some duplicated regions maintained tetraploidy for over 60 million years, with three chromosome pairs diverging genetically only after the separation of major teleost families. This evidence suggests that the teleost ancestor was an autopolyploid. Further, we find evidence for biased gene retention along several duplicated chromosomes, contradicting current paradigms that asymmetrical evolution is specific to allopolyploids. Altogether, our results offer novel insights into genome evolutionary dynamics following ancient polyploidizations in vertebrates.

genomics↗

bioRxiv2021

Classification of non-coding variants with high pathogenic impact

Whole genome sequencing is increasingly used to diagnose medical conditions of genetic origin. While both coding and non-coding DNA variants contribute to a wide range of diseases, most patients who receive a WGS-based diagnosis today harbour a protein-coding mutation. Functional interpretation and prioritization of non-coding variants represents a persistent challenge, and disease-causing non-coding variants remain largely unidentified. Depending on the disease, WGS fails to identify a candidate variant in 20-80% of patients, severely limiting the usefulness of sequencing for personalised medicine. Here we present FINSURF, a machine-learning approach to predict the functional impact of non-coding variants in regulatory regions. FINSURF outperforms state-of-the-art methods, owing to control optimisation during training. In addition to ranking candidate variants, FINSURF also delivers diagnostic information on functional consequences of mutations. We applied FINSURF to a diverse set of 30 diseases with described causative non-coding mutations, and correctly identified the disease-causative non-coding variant within the ten top hits in 22 cases. FINSURF is implemented as an online server to as well as custom browser tracks, and provides a quick and efficient solution to prioritize candidate non-coding variants in realistic clinical settings.

bioinformatics↗

bioRxiv2020

Synteny-guided resolution of gene trees clarifies the functional impact of whole genome duplications

Whole genome duplications (WGD) have major impacts on the evolution of species, as they produce new gene copies contributing substantially to adaptation, isolation, phenotypic robustness, and evolvability. They result in large, complex gene families with recurrent gene losses in descendant species that sequence-based phylogenetic methods fail to reconstruct accurately. As a result, orthologs and paralogs are difficult to identify reliably in WGD-descended species, which hinders the exploration of functional consequences of WGDs. Here we present SCORPiOs, a novel method to reconstruct gene phylogenies in the context of a known WGD event. WGDs generate large duplicated syntenic regions, which SCORPiOs systematically leverages as a complement to sequence evolution to infer the evolutionary history of genes. We applied SCORPiOs to the 320-million-year-old WGD at the origin of teleost fish. We find that almost one in four teleost gene phylogenies in the Ensembl database (3,391) are inconsistent with their syntenic contexts. For 70% of these gene families (2,387), we were able to propose an improved phylogenetic tree consistent with both the molecular substitution distances and the local syntenic information. We show that these synteny-guided phylogenies are more congruent with the species tree, with sequence evolution and with expected expression conservation patterns than those produced by state-of-the-art methods. Finally, we show that synteny-guided gene trees emphasize contributions of WGD paralogs to evolutionary innovations in the teleost clade.

genomics↗

bioRxiv2019

Rare earth element (REE)-dependent growth of Pseudomonas putida KT2440 depends on the ABC-transporter PedA1A2BC and is influenced by iron availability

In the soil-dwelling organism Pseudomonas putida KT2440, the rare earth element (REE)-utilizing and pyrroloquinoline quinone (PQQ)-dependent ethanol dehydrogenase PedH is part of a periplasmic oxidation system that is vital for growth on various alcoholic volatiles. Expression of PedH and its Ca2+-dependent counterpart PedE is inversely regulated in response to lanthanide (Ln3+) bioavailability, a mechanism termed the REE-switch. In the present study, we demonstrate that copper, zinc, and in particular, iron availability influences this regulation in a pyoverdine-independent manner by increasing the minimal Ln3+ concentration required for the REE-switch to occur by several orders of magnitude. A combined genetic- and physiological approach reveals that an ABC-type transporter system encoded by the gene cluster pedA1A2BC is essential for efficient growth with low (nanomolar) Ln3+ concentrations. In the absence of pedA1A2BC, a ~100-fold higher La3+ concentration is needed for PedH-dependent growth but not for the ability to repress growth based on PedE activity. From these results, we conclude that cytoplasmic uptake of lanthanides through PedA1A2BC is essential to facilitate REE-dependent growth under environmental conditions with poor REE bioavailability. Our data further suggest that the La3+/Fe3+ ratio impacts the REE-switch through the mismetallation of putative La3+-binding proteins, such as the sensor histidine kinase PedS2, in the presence of high iron concentrations. As such, this study provides an example for the complexity of bacteria-metal interactions and highlights the importance of medium compositions when studying physiological traits in vitro in particular in regards to REE-dependent phenomena.

microbiology↗

bioRxiv2018

Adaptation of proteins to the cold in Antarctic fish: A role for Methionine?

The evolution of antifreeze glycoproteins has enabled notothenioid fish to flourish in the freezing waters of the Southern Ocean. Whilst successful at the biodiversity level to life in the cold, paradoxically at the cellular level these stenothermal animals have problems producing, folding and degrading proteins at their ambient temperatures of down to -1.86{degrees}C. In this first multi-species transcriptome comparison of the amino acid composition of notothenioid proteins with temperate teleost proteins, we show that, unlike psychrophilic bacteria, Antarctic fish provide little evidence for the mass alteration of protein amino acid composition to enhance protein folding and reduce protein denaturation in the cold. The exception was the significant over-representation of positions where leucine in temperate fish proteins was replaced by methionine in the notothenioid orthologues. Although methionine may increase stability in critical proteins, we hypothesise that a more likely explanation for the extra methionines is that they have been preferentially assimilated into the genome because they act as redox sensors. This redox hypothesis is supported by the enrichment of duplicated genes within the notothenioid transcriptomes which centre around Mapk signalling, a major pathway in the cellular cascades associated with responses to environmental stress. Whilst notothenioid fish show cold-associated problems with protein homeostasis, they may have modified only a selected number of biochemical pathways to work efficiently below 0{degrees}C. Even a slight warming of the Southern Ocean might disrupt the critical functions of this handful of key pathways with considerable impacts for the functioning of this ecosystem in the future.

evolutionary biology↗

bioRxiv2018

The PedS2/PedR2 two-component system is crucial for the rare earth element switch in Pseudomonas putida KT2440

In Pseudomonas putida KT2440, two pyrroloquinoline quinone-dependent ethanol dehydrogenases (PQQ-EDHs) are responsible for the periplasmic oxidation of a broad variety of volatile organic compounds (VOCs). Depending on the availability of rare earth elements (REEs) of the lanthanide series (Ln3+), we have recently described that the transcription of the genes encoding the Ca2+-utilizing enzyme PedE and the Ln3+-utilizing enzyme PedH are inversely regulated. With adaptive evolution experiments, site-specific mutations, transcriptional reporter fusions, and complementation approaches, we herein demonstrate that the PedS2/PedR2 (PP_2671/PP_2672) two-component system (TCS) plays a central role in the observed REE-mediated switch of PQQ-EDHs in P. putida. We provide evidence that in the absence of lanthanum (La3+), the sensor histidine kinase PedS2 phosphorylates its cognate LuxR-type response regulator PedR2, which in turn not only activates pedE gene transcription but is also involved in repression of pedH. Our data further suggests that the presence of La3+ lowers kinase activity of PedS2, either by the direct binding of the metal ions to the periplasmic region of PedS2 or by an uncharacterized indirect interaction, leading to reduced levels of phosphorylated PedR2. Consequently, the fading pedE expression and concomitant alleviation of pedH repression causes - in conjunction with the transcriptional activation of the pedH gene by a yet unknown regulatory module - the Ln3+-dependent transition from PedE to PedH catalysed oxidation of alcoholic VOCs.\n\nIMPORTANCEThe function of lanthanides for methano- and methylotrophic bacteria is gaining increasing attention, while knowledge about the role of rare earth elements (REEs) in non-methylotrophic bacteria is still limited. The present study investigates the recently described differential expression of the two PQQ-EDHs of P. putida in response to lanthanides. We demonstrate that a specific TCS is crucial for their inverse regulation and provide evidence for a dual regulatory function of the LuxR-type response regulator involved. Thus, our study represents the first detailed characterization of the molecular mechanism underlying the REE switch of PQQ-EDHs in a non-methylotrophic bacterium and stimulates subsequent investigations for the identification of additional genes or phenotypic traits that might be co-regulated during REE-dependent niche adaptation.

microbiology↗

bioRxiv2017

Evolution of gene expression after whole-genome duplication: new insights from the spotted gar genome

Whole genome duplications (WGD) are important evolutionary events. Our understanding of underlying mechanisms, including the evolution of duplicated genes after WGD, however remains incomplete. Teleost fish experienced a common WGD (teleost-specific genome duplication, or TGD) followed by a dramatic adaptive radiation leading to more than half of all vertebrate species. The analysis of gene expression patterns following TGD at the genome level has been limited by the lack of suitable genomic resources. The recent concomitant release of the genome sequence of spotted gar (a representative of holosteans, the closest lineage of teleosts that lacks the TGD) and the tissue-specific gene expression repertoires of over 20 holostean and teleostean fish species, including spotted gar, zebrafish and medaka (the PhyloFish project), offered a unique opportunity to study the evolution of gene expression following TGD in teleosts. We show that most TGD duplicates gained their current status (loss of one duplicate gene or retention of both duplicates) relatively rapidly after TGD (i.e. prior to the divergence of medaka and zebrafish lineages). The loss of one duplicate is the most common fate after TGD with a probability of approximately 80%. In addition, the fate of duplicate genes after TGD, including subfunctionalization, neofunctionalization, or retention of two similar copies occurred not only before, but also after the radiation of species tested, in consistency with a role of the TGD in speciation and/or evolution of gene function. Finally, we report novel cases of TGD ohnolog subfunctionalization and neofunctionalization that further illustrate the importance of these processes.

evolutionary biology↗

bioRxiv2017

Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression

To gain insight into how mammalian gene expression is controlled by rapidly evolving regulatory elements, we jointly analysed promoter and enhancer activity with downstream transcription levels in liver samples from twenty species. Genes associated with complex regulatory landscapes generally exhibit high expression levels that remain evolutionarily stable. While the number of regulatory elements is the key driver of transcriptional output and resilience, regulatory conservation matters: elements active across mammals most effectively stabilise gene expression. In contrast, recently-evolved enhancers typically contribute weakly, consistent with their high evolutionary plasticity. These effects are observed across the entire mammalian clade and robust to potential confounders, such as gene expression level. Overall, our results illuminate how the evolutionary stability of gene expression is profoundly entwined with both the number and conservation of surrounding promoters and enhancers.\n\nHighlightsO_LIGene expression levels and stability are linked to the number of elements in the regulatory landscape.\nC_LIO_LIConserved regulatory elements associate with tightly controlled, highly expressed genes.\nC_LIO_LIRecently evolved enhancers weakly influence gene expression, but promoters are similarly active regardless of conservation.\nC_LIO_LIThe interplay between complexity of the regulatory landscape and conservation of individual promoters and enhancers shapes gene expression in mammals.\nC_LI

genomics↗