Biology subjects

Pouyet, F.

Publications and source records attributed to Pouyet, F..

7 recordsLinked to original sources

bioRxiv2026

DNA:RNA hybrid mutational landscapes reveal a common route to geneticinstability in evolving genomes

Pervasive DNA:RNA hybrids are recognized as pathological sources of genome instability, yet how their genotoxicity shapes mutational landscapes and genome evolution remains poorly understood. Here, we define the mutational footprint of hybrids by integrating genome-wide mapping, long-term mutation accumulation experiments, and analyses of genetic diversity across thousands of natural yeast genomes. We uncover signatures for embedded ribonucleotides and genic R-loops, together with a composite mutational pattern shared across natural populations and experimental evolution. Using reporters designed to dissect the mechanisms underlying genetic alterations, we find that they arise primarily from targeting by MutL{gamma}-dependent mismatch repair followed by Rad52-mediated recombination. Although hybrids form dynamically across the genome, their genotoxicity is strongly skewed toward repetitive regions susceptible to these error-prone pathways, including microsatellites and retroelements. Our findings reveal a common mechanism of hybrid-associated mutagenesis that can shape genetic variation in evolving genomes.

molecular biology↗

bioRxiv2025

Transcription-induced mutation and gBGC at the Transcriptional Start Site impact the evolution of human protein-coding genes

In the human genome, mutation rates vary along genes, yet how their fine-scale structure contributes to gene evolution has remained largely unexplored. Here, we map inherited mutations at single-nucleotide resolution and uncover a striking hypermutation peak at transcription start sites (TSSs). This pattern is observed both in population polymorphisms and in de novo mutations from parent-offspring trios, and is dependent on transcriptional activity in testes. We also find similar hypermutation peaks at TSSs used to produce long noncoding RNAs and at intergenic RNA Polymerase II pause sites. In addition, we identify distinct mutational signatures at exon-intron boundaries and in introns. By comparing the current nucleotide content to predicted equilibrium levels, inferred from mutation and fixation rates, and by analyzing derived ancestral frequency spectrums, we detect signals that are compatible with a low level of ongoing background GC-biased gene conversion (gBGC) throughout the region and ancestral elevated gBGC activity downstream from the TSS. Using a forward-in-time simulation algorithm, we show that the current nucleotide composition surrounding the TSS of protein-coding genes is best explained by local mutation biases coupled to ongoing and ancestral patterns of gene conversions. Our simulations allow us to infer several features of these gBGC events. Overall, these findings indicate that the nucleotide composition around TSSs is largely shaped by non-adaptive forces, particularly mutation bias and gBGC.

evolutionary biology↗

bioRxiv2025

Beyond Recombination: Exploring the Impact of Meiotic Frequency on Genome-wide Genetic Diversity

An important aim of population genetics is to elucidate the processes affecting genetic diversity across regions of the genome and across species. Canonical population genetic models of sexually reproducing species define the rate of meiotic recombination in terms of the frequency of recombination events per site per sexual generation. This paper studies the interplay of several factors with respect to their effects on neutral genetic diversity in a facultatively sexual, diploid, unicellular species such as yeast. The relevant factors are the prevalence of meiosis versus mitosis, the recombination rate, and the selection and dominance coefficients at loci under positive selection. We assume that many generations of mitotic cell divisions are interspersed with episodes of sexual reproduction, in which all individuals in the population undergo meiosis, followed by random matings among the resulting gametes. Our findings reveal that a single hard selective sweep can reduce neutral nucleotide site diversity across the entire genome, provided that the frequency of meiotic events is sufficiently low, and that the effects of a selective sweep on levels of neutral diversity at sites linked to the target of selection can be markedly different from those predicted by standard models of sweeps based on obligate sexuality. Species that reproduce by facultative sex are thus likely to exhibit unusual patterns of genetic diversity. Author summaryIn this study, we explored how different sexual strategies influence genetic diversity. Specifically, we looked at how the balance between sexual reproduction (which involves meiosis) and asexual reproduction (which involves mitosis) affect genetic variation in a species like yeast. Our research focused on the effects of recombination rates and the role of selective sweeps -- when a beneficial genetic variant spreads rapidly through a population -- on genetic diversity. We found that, in species with facultative sex, a selective sweep can dramatically reduce genetic diversity across the genome, but only if sexual reproduction occurs infrequently. We compared our findings to existing models and also developed a new mathematical framework for understanding the effects of sweeps when sexual reproduction is rare. The fact that facultative sex can reduce genetic diversity over the entire genome is likely to complicate inferences about population size and evolutionary dynamics in species with mixed reproductive strategies.

genetics↗

bioRxiv2024

The GC-content at the 5'ends of human protein-coding genes is undergoing mutational decay

In vertebrates, most protein-coding genes have a peak of GC-content near their 5 transcriptional start site (TSS). This feature promotes both the efficient nuclear export and translation of mRNAs. Despite the importance of GC-content for RNA metabolism, its general features, origin, and maintenance remain mysterious. We investigated the evolutionary forces shaping GC-content at the transcriptional start site (TSS) of genes through both comparative genomic analysis of nucleotide substitution rates between different species and by examining human de novo mutations. Our data suggests that GC-peaks at TSSs were present in the last vertebrate common ancestor and are largely dictated by recombination patterns. We observe that in primates and rodents, where recombination is directed away from TSSs by PRDM9, GC-content at protein-coding gene TSSs is currently undergoing mutational decay. In canids, which lack PRDM9 and perform recombination at TSSs, GC-content at protein-coding gene TSSs is increasing. These patterns extend into the open reading frame affecting protein-coding regions, and we show that changes in GC-content due to recombination affect synonymous codon position choices at the start of the open reading frame. Our results indicate that although high GC-content in protein-coding genes may be shaped by selective pressures to enhance expression, the dynamics of GC-content in mammals are largely shaped by patterns of recombination.

genomics↗

bioRxiv2019

Transition from background selection to associative overdominance promotes diversity in regions of low recombination

Linked selection is a major driver of genetic diversity. Selection against deleterious mutations removes linked neutral diversity (background selection, BGS, Charlesworth et al. 1993), creating a positive correlation between recombination rates and genetic diversity. Purifying selection against recessive variants, however, can also lead to associative overdominance (AOD, Ohta 1971, Zhao & Charlesworth, 2016), due to an apparent heterozygote advantage at linked neutral loci that opposes the loss of neutral diversity by BGS. Zhao & Charlesworth (2016) identified the conditions when AOD should dominate over BGS in a single-locus model and suggested that the effect of AOD could become stronger if multiple linked deleterious variants co-segregate. We present a model describing how and under which conditions multi-locus dynamics can amplify the effects of AOD. We derive the conditions for a transition from BGS to AOD due to pseudo-overdominance (Ohta & Kimura 1970), i.e. a form of balancing selection that maintains complementary deleterious haplotypes that mask the effect of recessive deleterious mutations. Simulations confirm these findings and show that multi-locus AOD can increase diversity in low recombination regions much more strongly than previously appreciated. While BGS is known to drive genome-wide diversity in humans (Pouyet et al. 2018), the observation of a resurgence of genetic diversity in regions of very low recombination is indicative of AOD. We identify 21 such regions in the human genome showing clear signals of multi-locus AOD. Our results demonstrate that AOD may play an important role in the evolution of low recombination regions of many species.

evolutionary biology↗

bioRxiv2017

Assigning Function To Natural Allelic Variation Via Dynamic Modeling Of Gene Network Induction

More and more natural DNA variants are being linked to physiological traits. Yet, understanding what differences they make on molecular regulations remains challenging. Important properties of gene regulatory networks can be captured by computational models. If model parameters can be personalized according to the genotype, their variation may then reveal how DNA variants operate in the network. Here, we combined experiments and computations to visualize natural alleles of the yeast GAL3 gene in a space of model parameters describing the galactose response network. Alleles altering the activation of Gal3p by galactose were discriminated from those affecting its activity (production/degradation or efficiency of the activated protein). The approach allowed us to correctly predict that a non-synonymous SNP would change the binding affinity of Gal3p with the Gal80p transcriptional repressor. Our results illustrate how personalizing gene regulatory models can be used for the mechanistic interpretation of genetic variants.

systems biology↗

bioRxiv2016

Biased gene conversion drives codon usage in human and precludes selection on translation efficiency

In humans, as in other mammals, synonymous codon usage (SCU) varies widely among genes. In particular, genes involved in cell differentiation or in proliferation display a distinct codon usage, suggesting that SCU is adaptively constrained to optimize translation efficiency in distinct cellular states. However, in mammals, SCU is known to correlate with large-scale fluctuations of GC-content along chromosomes, caused by meiotic recombination, via the non-adaptive process of GC-biased gene conversion (gBGC). To disentangle and to quantify the different factors driving SCU in humans, we analyzed the relationships between functional categories, base composition, recombination, and gene expression. We first demonstrate that SCU is predominantly driven by large-scale variation in GC-content and is not linked to constraints on tRNA abundance, which excludes an effect of translational selection. In agreement with the gBGC model, we show that differences in SCU among functional categories are explained by variation in intragenic recombination rate, which, in turn, is strongly negatively correlated to gene expression levels during meiosis. Our results indicate that variation in SCU among functional categories (including variation associated to differentiation or proliferation)- result from differences in levels of meiotic transcription, which interferes with the formation of crossovers and thereby affects gBGC intensity within genes. Overall, the gBGC model explains 81.3% of the variance in SCU among genes. We argue that the strong heterogeneity of SCU induced by gBGC in mammalian genomes precludes any optimization of the tRNA pool to the demand in codon usage.

evolutionary biology↗