Biology subjects

Jay, P.

Publications and source records attributed to Jay, P..

18 recordsLinked to original sources

bioRxiv2026

The fate of mutations on Y chromosomes andautosomes: a unified Wright-Fisher frameworkaccounting for segregation time

Understanding how mutations evolve on Y chromosomes is central to explaining the origin, diversity and persistence of sex chromosomes. Mutations occurring on the Y chromosome in sexual populations experience selective dynamics that differ markedly from those on autosomes, due to a reduced effective population size and the presence of large non-recombining regions containing alleles maintained in a permanently heterozygous state. These specific features alter gene transmission in the Y chromosome population compared to autosomes, even within the same pedigree. Here, we provide a two-sex diploid Wright-Fisher model that explicitly incorporates both sex chromosomes and autosomes within a unified population framework, in order to capture the influence of these specificities on the fate of mutations, not only considering fixation probabilities but also segregation times. We use diffusion approximations and provide analytical and numerical tools to compute these quantities across a wide range of parameters and selection regimes. We recover classical results on fixation probabilities in various scenarios, including purely beneficial, deleterious or overdominant mutations, and extend them in the light of mean segregation time, a key but often overlooked determinant of evolutionary outcomes over finite timescales. In particular, our analyses show that overdominant mutations are overall more likely to fix in observable time windows on the Y chromosome than on autosomes. Individual-based simulations corroborate our approximations and highlight parameter regimes where the theoretical approach is particularly useful, especially for parameter values inducing long segregation times or small fixation probabilities, for which simulations are impractical. Our results provide a comprehensive and tractable framework for clarifying how chromosome-specific features shape evolutionary dynamics beyond fixation probabilities alone.

evolutionary biology↗

bioRxiv2026

A crypt-operating DNA repair checkpoint for uncoupling regeneration and tumorigenesis

The rapid turnover of the intestinal epithelium increases its vulnerability to genomic instability and environmental insults such as irradiation. Defects in DNA damage resolution can compromise epithelial regeneration, promote chronic tissue injury, and predispose to colorectal tumorigenesis. However, the intrinsic mechanisms that coordinate DNA repair with epithelial regeneration at the crypt level remain poorly defined. Here, we identify the Nod-like receptor protein 6 (Nlrp6) as a key epithelial regulator of genome surveillance and regenerative control in intestinal crypts. Nlrp6 is strategically expressed in crypt base columnar cells, where it preserves crypt homeostasis by restraining proliferation under genotoxic stress conditions. Loss of Nlrp6 in crypt base columnar cells results in uncontrolled oncogenic stress, defective epithelial regeneration, and accumulation of unrepaired DNA damage, features associated with poor prognosis in colorectal cancer. Conversely, aberrant Nlrp6 overexpression induces cytoplasmic retention of Csnk2 catalytic subunits, limiting their nuclear availability when DNA repair is required. These findings position Nlrp6 as a non-canonical, cell-intrinsic surveillance mechanism that links DNA damage responses to epithelial regeneration through Csnk2-dependent signaling. Collectively, our study reveals a crypt-intrinsic DNA repair pathway that governs epithelial regeneration and disease outcomes, providing new insight into how genome instability and regenerative failure contribute to colorectal cancer progression.

cell biology↗

bioRxiv2025

Stepwise expansion of recombination suppression on sex chromosomes and other supergenes through lower load advantage and deleterious mutation sheltering

Many organisms possess sex chromosomes with non-recombining regions that have expanded progressively. Yet, the causes of this stepwise expansion remain poorly understood. Here, using mathematical modeling and stochastic simulations, we show that the widespread presence of deleterious recessive mutations in genomes can generate several phenomena that can contribute to the evolution of recombination suppression on sex chromosomes. We demonstrate that a significant proportion of new chromosomal inversions, or any other recombination suppressor, are initially advantageous because they carry fewer mutations than average. However, these less-loaded inversions generally fail to fix on autosomes because, as their frequency increases, the recessive deleterious mutations they carry are more likely to occur in a homozygous state, leading to a selective disadvantage. In contrast, the permanent heterozygosity of Y-like sex chromosomes shelters their inversions from this disadvantage, facilitating their fixation and thereby the stepwise expansion of non-recombining regions. Due to this sheltering effect, we show that fixation probabilities are substantially higher on Y-like chromosomes than on autosomes across a wide range of parameters, particularly when segregating deleterious mutations are moderately to strongly recessive, and this is true even after controlling for differences in effective population sizes between those chromosomes. Then, once recombination is suppressed, deleterious mutations accumulate on inversions, which could select for recombination restoration. However, we show that the accumulation of overlapping genomic rearrangements following recombination suppression can prevent its restoration. Overall, our theoretical model proposes a testable framework that may contribute to explaining evolutionary strata on sex and mating-type chromosomes, and other supergenes.

evolutionary biology↗

bioRxiv2025

Loci under balancing selection facilitate the emergence of pseudo-overdominance and recombination suppression

Loci under strong balancing selection, such as sex-determining, mating-type, and self-incompatibility loci, are frequently flanked by regions of suppressed recombination. The reasons why recombination suppression evolves around these loci remain poorly understood. Here, we propose that one reason may be that loci under balancing selection facilitate the emergence of pseudo-overdominance, a phenomenon under which linked partially recessive deleterious mutations in repulsion mimic overdominance. Pseudo-overdominance arises when linkage disequilibrium gradually builds up between recessive deleterious mutations, often due to strong genetic linkage and genetic drift. Once complementary haplotypes form, homozygous and recombinant offspring are selected against because they carry homozygous recessive deleterious mutations. Using individual-based simulations, we demonstrate here that the presence of loci under balancing selection eases the establishment of pseudo-overdominance, by facilitating the maintenance of partially recessive deleterious mutations and linkage disequilibrium in their flanking regions. This occurs particularly in regions with low recombination rates and a high load of partially recessive deleterious mutations, which can be found in specific genomic regions in natural populations. We further show that such resulting pseudo-overdominance can render more likely the evolution of recombination suppression around permanently heterozygous loci, preventing the creation of unfit homozygous recombinant offspring. These results suggest new avenues for understanding the evolution of loci under balancing selection, sex chromosomes and supergenes, and shed new light on the mechanisms driving genome evolution.

evolutionary biology↗

bioRxiv2024

A secreted helminth microRNA suppresses gastrointestinal cell differentiation required for innate immunity

Pathogens have developed multiple strategies to modulate host immune defense mechanisms. Understanding how this is achieved has potential to inform novel therapeutics for diseases caused by immune dysfunction. Parasitic helminths are masters of immune evasion, via release of secreted products, resulting in chronic infection. Helminths secrete small regulatory microRNA (miRNAs), which can interact with host cells. Here we show that a single parasite miRNA (miR-5352), conserved across gastrointestinal (GI) nematodes, suppresses IL-13-induced GI epithelial cell differentiation and cytokine responses, and promotes stem cell maintenance. Mechanistically, this is achieved through targeted repression of critical host factors, including Klf-4 and the IL-22 receptor, together with modulation of Wnt and Notch signalling pathways. Nematode miR-5352 shows seed sequence conservation with mammalian miR-92a family members, indicating that through convergent evolution, GI nematodes exploit a host miRNA regulatory network to suppress host innate responses, promote tissue regeneration and establish a favourable environment for chronic infection.

microbiology↗

bioRxiv2024

Deleterious mutations can contribute to the evolution of recombination suppression between sex chromosomes

Many organisms have sex chromosomes with large non-recombining regions that expand in a stepwise manner, although the underlying reasons remain poorly understood. Recently, we proposed that recombination suppression may evolve in sex chromosomes simply because of the presence of recessive deleterious mutations within genomes. Specifically, we demonstrated that chromosomal inversions suppressing recombination and carrying by chance fewer deleterious mutations than average have a selective advantage. In addition, we showed that the permanent heterozygosity of Y-like sex chromosomes facilitates the fixation of these less-loaded inversions by a sheltering effect, i.e., by preventing the expression of recessive deleterious mutations in a homozygous state when they increase in frequency. In contrast, similar less-loaded inversions in autosomes suffer from a disadvantage in the homozygous state as their frequency increases, preventing their fixation. However, the methodology and significance of our previous study have been questioned. Here, we present new analyses that further reinforce our original claims, demonstrating that the lower-load advantage and the sheltering effect can explain the fixation of inversions on sex chromosomes over a broad range of parameter values. We show that these mechanisms promote the fixation of inversions on Y-like chromosomes at rates exceeding those expected under drift alone. We used, as a control, autosomes with a similar population size as the Y chromosome, which, we argue, provides the appropriate neutral control for the sheltering effect. We also address criticisms regarding our focus on inversions surviving the first 20 generations in a figure of our previous study, and show that these criticisms stemmed from a misunderstanding of what this figure was intended to illustrate. Including all inversions, even those that went extinct within 20 generations, does not alter our conclusions. Overall, the present study offers new support for our theory based on the combination of lower-load advantage and sheltering effect, and addresses the questions about its significance and range of applicability.

evolutionary biology↗

bioRxiv2024

Repeated loss of function at HD mating-type genes and of recombination suppression without mating-type locus linkage in anther-smut fungi

A wide diversity of mating systems occur in nature, with frequent evolutionary transitions in mating-compatibility mechanisms. Basidiomycete fungi typically have two mating-type loci controlling mating compatibility, HD and PR, usually residing on different chromosomes. In Microbotryum anther-smut fungi, there have been repeated events of linkage between the two mating-type loci through chromosome fusions, leading to large non-recombining regions. By generating high-quality genome assemblies, we found that two sister Microbotryum species parasitizing Dianthus plants, M. superbum and M. shykoffianum, as well as the distantly related M. scorzonarae, have their HD and PR mating-type loci on different chromosomes, but with the PR mating-type chromosome fused with part of the ancestral HD chromosome. Furthermore, progressive extensions of recombination suppression have generated evolutionary strata. In all three species, rearrangements suggest the existence of a transient stage of HD-PR linkage by whole chromosome fusion, and, unexpectedly, the HD genes lost their function. In M. superbum, multiple natural diploid strains were homozygous, and the disrupted HD2 gene was hardly expressed. Mating tests confirmed that a single genetic factor controlled mating compatibility (i.e. PR) and that haploid strains with identical HD alleles could mate and produce infectious hyphae. The HD genes have therefore lost their function in the control of mating compatibility in these Microbotryum species. While the loss of function of PR genes in mating compatibility has been reported in a few basidiomycete fungi, these are the first documented cases for the loss of mating-type determination by HD genes in heterothallic fungi. The control of mating compatibility by a single genetic factor is beneficial under selfing and can thus be achieved repeatedly, through evolutionary convergence in distant lineages, involving different genomic or similar pathways.

evolutionary biology↗

bioRxiv2023

Tuft cell-derived acetylcholine is an effector of type 2 immunity and directly targets helminth parasites in the gut lumen

Upon parasitic helminth infection, activated intestinal tuft cells secrete IL-25, which initiates a type 2 immune response during which lamina propria ILC2s produce IL-13. This causes epithelial remodelling, including tuft cell hyperplasia with an unknown function. We describe a novel cholinergic effector function of tuft cells, which we show are the only epithelial cells expressing Choline Acetyltransferase (ChAT). During parasite infections, mice with epithelial-specific deletion of ChAT have increased worm burden and faecal egg counts although they are able to mount a comparable type 2 immune response. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. We demonstrate a direct effect of ACh on worms, reducing their viability and fecundity via helminth muscarinic ACh receptors, with effects promoted by inhibition of acetylcholinesterase, an helminth-secreted enzyme. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infections serves an additional type 2 immune response effector function.

immunology↗

bioRxiv2022

The genome sequence of the scarce swallowtail, Iphiclides podalirius

The scarce swallowtail, Iphiclides podalirius (Linnaeus, 1758), is a species of butterfly in the family Papilionidae. Here we present a chromosome-level genome assembly for I. podalirius as well as gene and transposable element annotations. We estimate heterozygosity within different partitions of the genome and find a negative correlation between chromosome length and heterozygosity at fourfold-degenerate sites. This high quality genome assembly, the first for any species in the tribe Leptocircini, will be a valuable resource for population genomics in the genus Iphiclides and comparative genomics more generally.

evolutionary biology↗

bioRxiv2022

CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium

CDK8 and CDK19 form a conserved cyclin-dependent kinase subfamily that interacts with the essential transcription complex, Mediator, and also promotes transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II. Cells lacking either CDK8 or CDK19 are viable and have limited transcriptional alterations, but whether the two kinases redundantly control cell differentiation is unknown. Here, we find that CDK8 is dispensable for RNA polII CTD phosphorylation, regulation of gene expression, normal intestinal homeostasis and efficient tumourigenesis in mice. Furthermore, CDK8 is largely redundant with CDK19 in the control of gene expression. Yet, while their combined deletion in intestinal organoids reduces long-term proliferative capacity, it is not lethal and allows differentiation. Nevertheless, in double mutant organoids, the cystic fibrosis transmembrane conductance regulator (CFTR) pathway is transcriptionally and functionally downregulated, leading to mucus accumulation and increased secretion by goblet cells. This phenotype can be recapitulated by pharmacological inhibition of CDK8/19 kinase activity. Thus, the Mediator kinases are not essential for cell proliferation and differentiation, but they cooperate to regulate tissue-specific transcriptional programmes.

cell biology↗

bioRxiv2021

Dissecting supergene: evidence for recombination suppression among multiple functional loci within inversions.

Supergenes are genetic architectures associated with discrete and concerted variation in multiple traits. It has long been suggested that supergenes control these complex polymorphisms by suppressing recombination between set of coadapted genes. However, because recombination suppression hinders the dissociation of the individual effects of genes within supergenes, there is still little evidence that supergenes evolve by tightening linkage between coadapted genes. Here, combining an landmark-free phenotyping algorithm with multivariate genome wide association studies, we dissected the genetic basis of wing pattern variation in the butterfly Heliconius numata. We showed that the supergene controlling the striking wing-pattern polymorphism displayed by this species contains many independent loci associated with different features of wing patterns. The three chromosomal inversions of this supergene suppress recombination between these loci, supporting the hypothesis that they may have evolved because they captured beneficial combinations of alleles. Some of these loci are associated with colour variations only in morphs controlled by inversions, indicating that they were recruited after the formation of these inversions. Our study shows that supergenes and clusters of adaptive loci in general may form via the evolution of chromosomal rearrangements suppressing recombination between co-adapted loci but also via the subsequent recruitment of linked adaptive mutations.

evolutionary biology↗

bioRxiv2021

Supergene formation is associated with a major shift in genome-wide patterns of diversity in a butterfly

Selection shapes genetic diversity around target mutations, yet little is known about how selection on specific loci affects the genetic trajectories of populations, including their genome-wide patterns of diversity and demographic responses. Here we study the patterns of genetic variation and geographic structure in a neotropical butterfly, Heliconius numata, and its closely related allies in the so-called melpomene-silvaniform clade. H. numata is known to have evolved an inversion supergene which controls variation in wing patterns involved in mimicry associations with distinct groups of co-mimics whereas it is associated to disassortative mate preferences and heterozygote advantage at this locus. We contrasted patterns of genetic diversity and structure 1) among extant polymorphic and monomorphic populations of H. numata, 2) between H. numata and its close relatives, and 3) between ancestral lineages. We show that H. numata populations which carry the inversions as a balanced polymorphism show markedly distinct patterns of diversity compared to all other taxa. They show the highest genetic diversity and effective population size estimates in the entire clade, as well as a low level of geographic structure and isolation by distance across the entire Amazon basin. By contrast, monomorphic populations of H. numata as well as its sister species and their ancestral lineages all show lower effective population sizes and genetic diversity, and higher levels of geographical structure across the continent. One hypothesis is that the large effective population size of polymorphic populations could be caused by the shift to a regime of balancing selection due to the genetic load and disassortative preferences associated with inversions. Testing this hypothesis with forward simulations supported the observation of increased diversity in populations with the supergene. Our results are consistent with the hypothesis that the formation of the supergene triggered a change in gene flow, causing a general increase in genetic diversity and the homogenisation of genomes at the continental scale.

evolutionary biology↗

bioRxiv2021

A deleterious mutation-sheltering theory for the evolution of sex chromosomes and supergenes

Many organisms have sex chromosomes with large non-recombining regions that have expanded stepwise, generating "evolutionary strata" of differentiation. The reasons for this remain poorly understood, but the principal hypotheses proposed to date are based on antagonistic selection due to differences between sexes. However, it has proved difficult to obtain empirical evidence of a role for sexually antagonistic selection in extending recombination suppression, and antagonistic selection has been shown to be unlikely to account for the evolutionary strata observed on fungal mating-type chromosomes. There may, therefore, be other mechanisms involved in the extension of non-recombining regions. We show here, by mathematical modeling and stochastic simulation, that recombination suppression on sex chromosomes and around supergenes can expand in a stepwise manner under a wide range of parameter values simply because it shelters recessive deleterious mutations, which are ubiquitous in genomes. Permanently heterozygous alleles, such as the maledetermining allele in XY systems, protect linked chromosomal inversions against the expression of their recessive mutation load, leading to the successive accumulation of inversions around these alleles without the need for antagonistic selection. Similar results were obtained with models assuming recombination-suppressing mechanisms other than chromosomal inversions, and for supergenes other than sex chromosomes, including those without XY-like asymmetry, such as fungal mating-type chromosomes. However, inversions capturing a permanently heterozygous allele were found to be less likely to spread when the mutation load was lower (e.g. under conditions of large effective population size, low mutation rates and high dominance coefficients). This may explain why sex chromosomes remain homomorphic in some organisms but are highly divergent in others. Here, we explicitly state and model a simple and testable hypothesis explaining the existence of stepwise extensions of recombination suppression on sex chromosomes, which can also be applied to mating-type chromosomes and supergenes in general.

evolutionary biology↗

bioRxiv2020

Admixture can readily lead to the formation of supergenes

Supergenes are genetic architectures allowing the segregation of alternative combinations of alleles underlying complex phenotypes. The co-segregation of sets of alleles at linked loci is determined by polymorphic chromosomal rearrangements suppressing recombination locally. Supergenes are involved in many complex polymorphisms, including sexual, color or behavioral polymorphisms in numerous plants, fungi, mammals, fish, and insects. Despite a long history of empirical and theoretical research, the genetic origin of supergenes remains poorly understood. Here, using a population genetic two-island model, we explore how the evolution of overdominant chromosomal inversions may lead to the formation of supergenes. We show that the evolution of inversions in differentiated populations connected by gene flow leads to an increase in frequency of poorly adapted, immigrant haplotypes. When inversions are associated with recessive fitness cost hampering their fixation (such as a mutational load), this results in the formation of supergenes. These results provide a realistic scenario for the evolution of supergenes and inversion polymorphisms in general, and bring new light into the importance of admixture in the formation of new genetic architectures.

evolutionary biology↗

bioRxiv2020

A semi-automated intestinal organoid screening method demonstrates epigenetic control of epithelial maturation

Intestinal organoids are an excellent model to study epithelial biology. Yet, the selection of analytical tools to accurately quantify heterogeneous organoid cultures remains limited. Here, we developed a semi-automated organoid screening method, which we applied to a library of highly specific chemical probes to identify epigenetic regulators of intestinal epithelial biology. The role of epigenetic modifiers in adult stem cell systems, such as the intestinal epithelium, is still undefined. Based on this resource data, we identified several targets that affected epithelial cell differentiation, including HDACs, EP300/CREBBP, LSD1, and type I PRMTs, which were verified by complementary methods. For example, we show that inhibiting type I PRMTs, which leads enhanced epithelial differentiation, blocks the growth of adenoma but not normal organoid cultures. Thus, epigenetic probes are powerful tools to study intestinal epithelial biology and may have therapeutic potential.

cell biology↗

bioRxiv2019

The R2TP chaperone assembles cellular machineries in intestinal CBC stem cells and progenitors

The R2TP chaperone cooperates with HSP90 to integrate newly synthesized proteins into multi-subunit complexes, yet its role in tissue homeostasis is unknown. Here, we generated conditional, inducible knock-out mice for Rpap3 to inactivate this core component of R2TP in the intestinal epithelium. In adult mice, Rpap3 invalidation caused destruction of the small intestinal epithelium, and death within 10 days. Levels of R2TP substrates were decreased, with strong effects on mTOR, ATM and ATR. Rpap3-deficient CBC stem cells and progenitors also failed to import RNA polymerase II in the nucleus. This correlated with p53 activation, cell cycle arrest and apoptosis. Interestingly, post-mitotic, differentiated cells did not display any of those alterations, indicating that R2TP clients are built in actively proliferating cells. Analyses of tissues from colorectal cancer patients revealed that high RPAP3 levels correlate with bad cancer prognosis. Thus, in the intestine, the R2TP chaperone functions in physiologic and pathologic proliferation.

developmental biology↗

bioRxiv2019

Mutation accumulation in chromosomal inversions maintains wing pattern polymorphism in a butterfly

While natural selection favours the fittest genotype, polymorphisms are maintained over evolutionary timescales in numerous species. Why these long-lived polymorphisms are often associated with chromosomal rearrangements remains obscure. Combining genome assemblies, population genomic analyses, and fitness assays, we studied the factors maintaining multiple mimetic morphs in the butterfly Heliconius numata. We show that the polymorphism is maintained because three chromosomal inversions controlling wing patterns express a recessive mutational load, which prevents their fixation despite their ecological advantage. Since inversions suppress recombination and hamper genetic purging, their formation fostered the capture and accumulation of deleterious variants. This suggests that many complex polymorphisms, instead of representing adaptations to the existence of alternative ecological optima, could be maintained primarily because chromosomal rearrangements are prone to carrying recessive harmful mutations.

evolutionary biology↗

bioRxiv2017

Supergene evolution triggered by the introgression of a chromosomal inversion

Supergenes are groups of tightly linked loci whose variation is inherited as a single Mendelian locus and are a common genetic architecture for complex traits under balancing selection1. Supergene alleles are long-range haplotypes with numerous mutations underlying distinct adaptive strategies, often maintained in linkage disequilibrium through the suppression of recombination by chromosomal rearrangements2-5. However, the mechanism governing the formation of supergenes is not well understood, and poses the paradox of establishing divergent functional haplotypes in face of recombination1,6. Here, we show that the formation of the supergene alleles encoding mimicry polymorphism in the butterfly Heliconius numata is associated with the introgression of a divergent, inverted chromosomal segment. Haplotype divergence and linkage disequilibrium indicate that supergene alleles, each allowing precise wing-pattern resemblance to distinct butterfly models, originate from over a million years of independent chromosomal evolution in separate lineages. These \"superalleles\" have evolved from a chromosomal inversion captured by introgression and maintained in balanced polymorphism, triggering supergene inheritance. This mode of evolution is likely to be a common feature of complex structural polymorphisms associated with the coexistence of distinct adaptive syndromes, and shows that the reticulation of genealogies may have a powerful influence on the evolution of genetic architectures in nature.

evolutionary biology↗