Biology subjects

Necsulea, A.

Publications and source records attributed to Necsulea, A..

10 recordsLinked to original sources

bioRxiv2026

Evolution of regulatory chromatin contacts: insights from duplicated genes

In multicellular organisms, gene expression is controlled by numerous cis-regulatory elements that can be located far away from their target genes on the linear genome. Interactions between gene promoters and distant regulatory elements take place through chromatin contacts or loops. While other aspects of gene expression regulation have been well studied from an evolutionary perspective, regulatory chromatin contact evolution remains largely unexplored, due to a lack of comparable data across species. Here, we study the evolution of regulatory chromatin contacts by focusing on duplicated genes in the mouse genome. We use an extensive collection of high resolution promoter-centered Hi-C data to define promoter-enhancer chromatin contacts for 1,420 pairs of duplicated genes and to study their evolutionary divergence, in conjunction with the evolutionary divergence of their expression patterns. We show that chromatin contacts evolve faster than expression patterns, as previously observed for other gene regulation mechanisms. We show that duplicated gene localisation in cis or in trans is strongly associated with chromatin contact divergence. We find a significant correlation between expression divergence and chromatin contact divergence across duplicated gene pairs. Our results highlight the complex evolutionary dynamics of regulatory chromatin contacts and the association between chromatin contact evolution and gene expression evolution, across a broad time scale.

evolutionary biology↗

bioRxiv2024

Meta-analysis reveals limited reproducibility of lncRNA-related findings in hepatocellular carcinoma research

Background & AimsThe human genome comprises tens of thousands of long non-coding RNAs (lncRNAs), whose functionality is highly debated. In the field of hepatocellular carcinoma (HCC) research, as for other cancer types, lncRNAs are increasingly reported to act as oncogenes or tumor suppressors and are put forward as useful diagnostic or prognostic biomarkers. Here, we investigate the reliability of these claims by performing a meta-analysis of the associations between HCC and lncRNAs reported in the scientific literature, and by assessing lncRNA expression patterns in two HCC patient cohorts. Approach & ResultsWhile nowadays up to 6% of all HCC-related publications cite lncRNAs, we show that most reported associations between HCC and lncRNAs have not been reproduced. In general, lncRNAs are less often differentially expressed between HCC tissues and controls compared to protein-coding genes. However, HCC-associated lncRNAs are frequently up-regulated in tumor samples, consistent with the fact that they are often selected based on transcriptome-wide comparative analyses. We perform a detailed examination of the 25 lncRNAs that are most frequently cited in association with HCC. For 10 out of these 25 lncRNAs, including well known lncRNAs such as MALAT1, NEAT1, H19 and XIST, we identify important conflicts between the biological roles and expression patterns previously reported for them in HCC and the expression patterns that we observe here. Finally, we observe that HCC-associated publications that cite lncRNAs are retracted three times more often than publications that cite protein-coding genes. ConclusionsOur results thus highlight the poor reproducibility of lncRNA-related claims in association with HCC, which is problematic in a context where new biomarkers and molecular targets for therapy are greatly needed.

cancer biology↗

bioRxiv2024

GTDrift: A resource for exploring the interplay between genetic drift, genomic and transcriptomic characteristics in eukaryotes

We present GTDrift, a comprehensive data resource that enables explorations of genomic and transcriptomic characteristics alongside proxies of the intensity of genetic drift in individual species. This resource encompasses data for 1,506 eukaryotic species, including 1,413 animals and 93 green plants, and is organized in three components. The first two components contain approximations of the effective population size, which serve as indicators of the extent of random genetic drift within each species. In the first component, we meticulously investigated public databases to assemble data on life history traits such as longevity, adult body length and body mass for a set of 979 species. The second component includes estimations of the ratio between the rate of non-synonymous substitutions and the rate of synonymous substitutions (dN/dS) in protein-coding sequences for 1,324 species. This ratio provides an estimate of the efficiency of natural selection in purging deleterious substitutions. Additionally, we present polymorphism-derived Ne estimates for 66 species. The third component encompasses various genomic and transcriptomic characteristics. With this component, we aim to facilitate comparative transcriptomics analyses across species, by providing easy-to-use processed data for more than 16,000 RNA-seq samples across 491 species. These data include intron-centered alternative splicing frequencies, gene expression levels and sequencing depth statistics for each species, obtained with a homogeneous analysis protocol. To enable cross-species comparisons, we provide orthology predictions for conserved single-copy genes based on BUSCO gene sets. To illustrate the possible uses of this database, we identify the most frequently used introns for each gene and we assess how the sequencing depth available for each species affects our power to identify major and minor splice variants.

evolutionary biology↗

bioRxiv2023

Transposable element expression with variation in gonosome number supports a toxic Y effect on human longevity

AO_SCPLOWBSTRACTC_SCPLOWWhy women live longer than men is still an open question in human biology. Sex chromosomes have been proposed to play a role in the observed sex gap in longevity, and the Y male chromosome has been suspected of having a potential toxic genomic impact on male longevity. It has been hypothesized that in aging individuals, TE repression is diminished, which could lead to detrimental effects (e.g. somatic mutations, perturbed gene expression) and to an acceleration of the aging process. As the Y chromosome is typically enriched in transposable elements (TE), this could explain why the presence of a Y chromosome is associated with shorter longevity. Using transcriptomic data from humans with atypical karyotypes, we found an association between TE expression and the presence and number of Y chromosomes. These findings are consistent with the existence of a toxic Y effect on men's longevity.

molecular biology↗

bioRxiv2022

Random genetic drift sets an upper limit on mRNA splicing accuracy in metazoans

Most eukaryotic genes undergo alternative splicing (AS), but the overall functional significance of this process remains a controversial issue. It has been noticed that the complexity of organisms (assayed by the number of distinct cell types) correlates positively with their genome-wide AS rate. This has been interpreted as evidence that AS plays an important role in adaptive evolution by increasing the functional repertoires of genomes. However, this observation also fits with a totally opposite interpretation: given that complex organisms tend to have small effective population sizes (Ne), they are expected to be more affected by genetic drift, and hence more prone to accumulate deleterious mutations that decrease splicing accuracy. Thus, according to this "drift barrier" theory, the elevated AS rate in complex organisms might simply result from a higher splicing error rate. To test this hypothesis, we analyzed 3,496 transcriptome sequencing samples to quantify AS in 53 metazoan species spanning a wide range of Ne values. Our results show a negative correlation between Ne proxies and the genome-wide AS rates among species, consistent with the drift barrier hypothesis. This pattern is dominated by low abundance isoforms, which represent the vast majority of the splice variant repertoire. We show that these low abundance isoforms are depleted in functional AS events, and most likely correspond to errors. Conversely, the AS rate of abundant isoforms, which are relatively enriched in functional AS events, tends to be lower in more complex species. All these observations are consistent with the hypothesis that variation in AS rates across metazoans reflects the limits set by drift on the capacity of selection to prevent gene expression errors.

evolutionary biology↗

bioRxiv2022

GOntact: using chromatin contacts to infer Gene1Ontology enrichments for cis-regulatory elements

Cis-regulatory elements (CREs) can be efficiently predicted genome-wide, but identifying their target genes remains challenging. Regulatory interactions between genes and CREs can take place over long genomic distances, often bypassing genes. Inferring CRE targets based on genomic proximity, as traditionally done in genomic studies, can thus be misleading. Thanks to chromosome conformation capture techniques, chromatin contacts between CREs and gene promoters can be assayed at the genome-wide scale, thus permitting more accurate predictions of CRE target genes. Here, we present a standalone computational tool and webserver named GOntact, which infers CRE target genes using chromosome conformation capture data. GOntact can be used to derive Gene Ontology (GO) enrichments for CRE sets, thus providing a basis for functional interpretation. We apply GOntact on enhancers active in several embryonic tissues, using Promoter Capture Hi-C data to infer chromatin contacts between genes and CREs. We show that GOntact predicts functional annotations that are coherent with enhancer activity. Compared to genomic proximity, GOntact predicts consistent but more specific functional annotations. With the increasing availability of high-resolution chromatin contact data, we believe that GOntact can provide better-informed target genes and functional predictions for CREs. GOntact is available at https://gontact.univ-lyon1.fr (webserver) and https://gitlab.in2p3.fr/anamaria.necsulea/GOntact (standalone command-line tool).

genomics↗

bioRxiv2021

LncRNA analyses reveal increased levels of non-coding centromeric transcripts in hepatocellular carcinoma

The search for new biomarkers and drug targets for hepatocellular carcinoma (HCC) has spurred an interest in long non-coding RNAs (lncRNAs), often proposed as oncogenes or tumor suppressors. Furthermore, lncRNA expression patterns can bring insights into the global de-regulation of cellular machineries in tumors. Here, we examine lncRNAs in a large HCC cohort, comprising RNA-seq data from paired tumor and adjacent tissue biopsies from 114 patients. We find that numerous lncRNAs are differentially expressed between tumors and adjacent tissues and between tumor progression stages. Although we find strong differential expression for most lncRNAs previously associated with HCC, the expression patterns of several prominent HCC-associated lncRNAs disagree with their previously proposed roles. We examine the genomic characteristics of HCC-expressed lncRNAs and reveal an enrichment for repetitive elements among the lncRNAs with the strongest expression increases in advanced-stage tumors. This enrichment is particularly striking for lncRNAs that overlap with satellite repeats, a major component of centromeres. Consistently, we find increased non-coding RNA transcription from centromeres in tumors, in the majority of patients, suggesting that aberrant centromere activation takes place in HCC.

cancer biology↗

bioRxiv2021

Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

Gene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve not only regulatory element sequences but also their chromatin contacts with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory landscapes constrains large-scale genome evolution. We show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is significantly associated with gene expression evolution.

evolutionary biology↗

bioRxiv2019

Comparative transcriptomics analyses across species, organs and developmental stages reveal functionally constrained lncRNAs

BackgroundTranscription of long non-coding RNAs (lncRNAs) is pervasive, but their functionality is disputed. As a class, lncRNAs show little selective constraint and negligible phenotypic effects upon perturbation. However, key biological roles were demonstrated for individual lncRNAs. Most validated lncRNAs were implicated in gene expression regulation, in pathways related to cellular pluripotency, differentiation and organ morphogenesis, suggesting that functional lncRNAs may be more abundant in embryonic development, rather than in adult organs.\n\nResultsHere, we perform a multi-dimensional comparative transcriptomics analysis, across five developmental time-points (two embryonic stages, newborn, adult and aged individuals), four organs (brain, kidney, liver and testes) and three species (mouse, rat and chicken). Overwhelmingly, lncRNAs are preferentially expressed in adult and aged testes, consistent with the presence of permissive transcription during spermatogenesis. LncRNAs are often differentially expressed among developmental stages and are less abundant in embryos and newborns compared to adult individuals, in agreement with a requirement for tighter expression control and less tolerance for noisy transcription early in development. However, lncRNAs expressed during embryonic development show increased levels of evolutionary conservation, both in terms of primary sequence and of expression patterns, and in particular at their promoter regions. We find that species-specific lncRNA transcription is frequent for enhancer-associated loci and occurs in parallel with expression pattern changes for neighboring protein-coding genes.\n\nConclusionsWe show that functionally constrained lncRNA loci are enriched in developing organ transcriptomes, and propose that many of these loci may function in an RNA-independent manner.

evolutionary biology↗

bioRxiv2017

The fitness cost of mis-splicing is the main determinant of alternative splicing patterns

Most eukaryotic genes are subject to alternative splicing (AS), which may contribute to the production of functional protein variants or to the regulation of gene expression, notably via nonsense-mediated mRNA decay (NMD). However, a fraction of splice variants might correspond to spurious transcripts, and the question of the relative proportion of splicing errors vs. functional splice variants remains highly debated. We propose here a test to quantify the fraction of AS events corresponding to errors. This test is based on the fact that the fitness cost of splicing errors increases with the number of introns in a gene and with expression level. We first analyzed the transcriptome of the intron-rich unicellular eukaryote Paramecium tetraurelia. We show that both in normal and in NMD-deficient cells, AS rates (intron retention, alternative splice site usage or cryptic intron splicing) strongly decrease with increasing expression level and with increasing number of introns. This relationship is observed both for AS events that are detectable by NMD or not, which invalidates the hypothesis of a possible link with the regulation of gene expression. Our results indicate that in genes with a median expression level, 92%-98% of observed splice variants correspond to errors. Interestingly, we observed the same patterns in human transcriptomes. These results are consistent with the mutation-selection-drift theory, which predicts that genes under weaker selective pressure should accumulate more maladaptive substitutions, and therefore should be more prone to errors of gene expression.

genomics↗