Biology subjects

Idaghdour, Y.

Publications and source records attributed to Idaghdour, Y..

15 recordsLinked to original sources

bioRxiv2026

Genomic Architecture, Differentiation, and Adaptation in Three Large Falcons

Recent chromosomal rearrangements and divergence in large falcon species make them excellent foci for studies on evolution and genomic architecture. Here, we use high-coverage (44-74X) whole genome resequencing with 10X Genomics Linked-Reads to assess patterns of genomic divergence in peregrine, saker, and gyrfalcons and we link these to chromosomal type and chromosomal rearrangements. We first use admixture analysis and cross-coalescent MSMC2 to demonstrate distinct species boundaries between the large falcons and retrace their demography. We assessed genomic landscapes in terms of recombination rate, nucleotide diversity ({pi}), Tajimas D, autozygosity and Fst between saker and gyrfalcons: {pi} had higher values on smaller chromosomes and Fst had higher values on larger chromosomes. Recombination rate concealed other chromosome type effects on {pi} and Tajimas D but largely explained variation in Fst. We find 39 selective sweeps--some shared--across the falcons. However, only five candidate genes--mostly housekeeping genes--were implicated as targets of balancing selection across all falcons, with 4 of these shared between Hierofalco and three shared across all the falcons. Occurrence of selective sweeps and balancing selection were not enriched by chromosome type or in the context of chromosome fusions. Overall, our findings provide insights into divergence and adaptation in large falcons, and demonstrate an association of genomic architecture and chromosomal fusions with all population genomic indicators and metrics of differentiation between species. Significance StatementFalcons are culturally and commercially important birds that have undergone recent chromosomal rearrangement, providing a natural system for studies on chromosomal heterogeneities and evolution. By analyzing genomic variation across three large falcon species, we show that chromosome type and chromosomal fusions structure patterns of recombination, diversity, and divergence. Our findings highlight the importance of underlying genomic architecture to common forms of evolutionary inference and call attention to the role of chromosomal fusions in shaping falcon evolution.

genomics↗

bioRxiv2026

Federated single-cell QTL meta-analysis reveals novel disease mechanisms

Genetic effects on gene expression are often cell type-specific and obscured in bulk analyses. To resolve this context-dependent regulation, we performed a federated cis-eQTL meta-analysis across 12 PBMC datasets (2,032 individuals, 2.5 million cells). Across six immune cell types, we identified cis-eQTLs for 6,592 genes and fine-mapped 14,985 independent loci. Notably, the 42% of eQTLs that were undetected in a bulk eQTL study on 43,301 whole blood samples also showed stronger enrichment for disease GWAS loci. We further identified three genome-wide significant and 65 suggestive loci affecting the abundance of (rare) immune cell types and validated these using previously reported hematological GWAS and bulk-derived trans-eQTLs. Integrating single-cell cis-eQTLs with bulk trans-eQTLs enabled us to anchor 6,382 trans-eGenes (37.2% novel) to upstream regulators and reconstruct directed gene regulatory relationships. For example, a hemorrhoidal disease-associated variant showed a CD4+ T cell-specific cis-eQTL on BACH1 that colocalized with 45 immune and metabolic trans-eGenes. These results demonstrate the power of single-cell QTL meta-analysis in interpreting complex trait genetics.

genetics↗

bioRxiv2025

Integrative multi-omic analysis reveals oral microbiome-metabolome signatures of obesity

Obesity is a major global health challenge and a leading risk factor for cardiometabolic disorders. The global surge in obesity, driven by industrialization and the widespread consumption of low-fiber, ultra-processed food, highlights an urgent need for deeper biological insights. While the gut microbiome has been studied in the context of obesity, the contribution of the oral microbiome--the second largest microbial ecosystem in the human body-remains largely underexplored. Here, we report findings from a deeply-phenotyped prospective-cohort of 628 Emirati adults, leveraging amplicon sequencing of mouthwash samples and multi-omics profiling and functional and metabolic activity analysis of 97 obese individuals and 95 matched controls, making this the most comprehensive multi-omics analysis of the oral microbiome. We identified significant differences in oral microbial diversity, composition, functional pathways, and metabolic profiles between obese and non-obese groups. Integrated multi-omics analysis of the 192 matched metagenomes and metabolome samples uncovered significant metabolic reprogramming and altered energy regulation in obesity. Specifically, the oral microbiome of obese participants were enriched for the proinflammatory Streptococcus parasanguinis and Actinomyces oris, and the lactate-producing Oribacterium sinus. Many microbial pathways involved in dietary carbohydrate metabolism, histidine degradation, as well as the production of obesogenic biomolecules were also enriched in obese participants; however, B-vitamin and heme production pathways were depleted. Consequently, metabolites resulting from these pathways such as lactate, histidine derivatives, choline, uridine, and uracil were elevated in obesity. These consistent microbiome-metabolite shifts were strongly associated with prominent obesity-associated cardiometabolic markers, including serum triglycerides and alkaline phosphatases, establishing a robust link between oral microbiome and obesity. These findings provide the most comprehensive insights into how disrupted microbial-metabolic cross-talk in the oral cavity may contribute to obesity and related cardiometabolic disease risk, underscoring the potential of targeting of oral microbiome-host interactions as a novel avenue for obesity prevention and intervention.

microbiology↗

bioRxiv2024

Nuclear actin-dependent Meg3 expression suppresses metabolic genes by affecting the chromatin architecture at sites of elevated H3K27 acetylation levels

Three-dimensional organization of the eukaryotic genome is directly affected by the nuclear {beta}-actin pool that regulates enhancer function by affecting H3K27 acetylation levels. This actin-based mechanism, in turn, influences enhancer-dependent transcriptional regulation and plays a crucial role in driving gene expression changes observed upon compartment-switching. Using a combination of bulk RNA-seq and qPCR analyses performed on total RNA from WT mouse embryonic fibroblasts (MEFs), {beta}-actin heterozygous (HET) MEFs, and {beta}-actin KO MEFs, in this study we demonstrate that expression of several lncRNAs is directly affected by {beta}-actin depletion. Among these lncRNAs, Meg3 expression increases in a {beta}-actin dosage-dependent manner. Using ChIRP-seq, ChIRP-MS and f-RIP-qPCR, we show that {beta}-actin depletion leads to alterations in Meg3 genomic association. It also leads to Meg3 enrichment at or close to gene regulatory sites including enhancers and promoters concomitantly with increased H3K27 acetylation levels. At these sites, specific Meg3 association with H3K27 acetylation leads to loss of promoter-enhancer interactions as revealed by the Activity by Contact (ABC) model that builds on RNA-seq, H3K27acetylation ChIP-seq, ATAC-seq and HiC-seq obtained in WT and {beta}-actin KO MEFs. Results from metabolomics experiments in WT, HET and {beta}-actin KO MEFs show these mechanisms contribute to the repression of genes involved in metabolic biosynthetic pathways for chondroitin, heparan, dermatan sulfate, and phospholipases, hence impacting their synthesis. We propose that at sites of actin-dependent increase in H3K27acetylation levels Meg3 interferes with promoter-enhancer interactions, potentially impairing local genome organization (or DNA looping) and negatively regulating gene expression.

molecular biology↗

bioRxiv2024

Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease

Sjogrens disease (SjD) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been involved in the development of SjD. Saliva production is regulated by parasympathetic input into the glands initiating intracellular Ca2+ signals that activate the store operated Ca2+ entry (SOCE) pathway eliciting sustained Ca2+ influx. SOCE is mediated by the STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel. However, there are no studies on the effects of lack of STIM1/2 function in salivary acini in animal models and its impact on SjD. Here we report that male and female mice lacking Stim1 and Stim2 (Stim1/2K14Cre) in salivary glands showed reduced intracellular Ca2+ levels via SOCE in parotid acini and hyposalivate upon pilocarpine stimulation. Bulk RNASeq of the parotid glands of Stim1/2K14Cre mice showed a decrease in the expression of Stim1/2 but no other Ca2+ associated genes mediating saliva fluid secretion. SOCE was however functionally required for the activation of the Ca2+ activated chloride channel ANO1. Despite hyposalivation, ageing Stim1/2K14Cre mice showed no evidence of lymphocytic infiltration in the glands or elevated levels of SSA or SSB autoantibodies in the serum, which may be linked to the downregulation of the toll-like receptor 8 (Tlr8). By contrast, salivary gland biopsies of SjD patients showed increased STIM1 and TLR8 expression, and induction of SOCE in a salivary gland cell line increased the expression of TLR8. Our data demonstrate that SOCE is an important activator of ANO1 function and saliva fluid secretion in salivary glands. They also provide a novel link between SOCE and TLR8 signaling which may explain why loss of SOCE does not result in SjD.

physiology↗

bioRxiv2023

Upregulation of steroidogenesis is associated with coma in human cerebral malaria

P. falciparum parasites manipulate host metabolic processes during malaria to ensure their survival and progression, causing the host and parasite metabolic pathways to become intertwined. We analyzed metabolites to evaluate their potential as biomarkers for cerebral malaria (CM). Our analysis of CM (with coma) and CM-like (without coma) patients identified 835 metabolites, including lipids, amino acids, xenobiotics, peptides, nucleotides, carbohydrates, cofactors, and vitamins. Principal component analysis revealed clear segregation between CM-like and CM patients. Metabolite-by-metabolite analysis identified 103 differentially abundant metabolites, 26 of which were significantly lower in CM-like patients (primarily lipids), while 71% of those higher in CM patients were amino acids and xenobiotics. The results revealed significant differences in circulating levels of long chain free fatty acids and catecholamine metabolism and identified steroid biosynthesis as the most enriched lipid metabolism pathway, with eight endogenous steroids showing significantly higher levels in CM patients compared to CM-like patients (FC > 2, B-H FDR-adjusted P < 0.05). These steroids include pregnenolone sulfate, pregnenediol sulfate, pregnenetriol sulfate, androsterone monosulfate, 16-OH-DHEA-S, DHEA-S, cortisol, and cortisone. High levels of pregnenolone and its downstream metabolic derivatives were significantly associated with coma in CM patients. Our findings suggest that monitoring circulating neurosteroid levels in patients could aid in the early identification of those at risk of coma, and may important implications for the clinical management of CM patients.

systems biology↗

bioRxiv2022

Falcon gut microbiome is shaped by diet and enriched in Salmonella

The gut microbiome is increasingly being appreciated as a master regulator of animal health. However, most avian gut microbiome studies have focused on birds of economic importance while the gut microbiomes of raptors remain underexplored. Here we examine the gut microbiota of 29 samples from four Falco species including hybrid birds-- raptors of historic importance --in the context of avian evolution by sequencing the 16S rDNA V4 region. Our results reveal that evolutionary histories and diet are significantly associated with avian gut microbiota in general, whereas diet plays a major role in shaping the falcon gut microbiota. Multiple analyses revealed that gut microbial diversity, composition, and abundance of key diet-discriminating bacterial genera in the falcon gut closely resemble those of carnivorous raptors rather than those of their closest phylogenetic relatives. Furthermore, the falcon microbiota is dominated by Firmicutes and consists of Salmonella at appreciable levels. Salmonella presence may potentially alter the functional capacity of the falcon gut microbiota as its abundance is associated with depletion of multiple predicted metabolic pathways involved in protein mass buildup, muscle maintenance, and enrichment of antimicrobial compound degradation, thus increasing the pathogenic potential of the falcon gut and presents a potential risk to human health. Author Summary in Arabic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/517295v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1440126org.highwire.dtl.DTLVardef@1a76b91org.highwire.dtl.DTLVardef@870bccorg.highwire.dtl.DTLVardef@17ac82_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2022

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Using a combination of multi-omics, here we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. As part of the nutrient-sensing PI3K/Akt/mTOR pathway, NM1 forms a positive feedback loop with mTOR and directly affects mitochondrial oxidative phosphorylation (OXPHOS) via transcriptional regulation of mitochondrial transcription factors TFAM and PGC1. NM1 depletion leads to suppression of PI3K/Akt/mTOR pathway, underdevelopment of mitochondria inner cristae, and redistribution of mitochondria within the cell, which is associated with reduced expression of OXPHOS genes, decreased mitochondrial DNA copy number and deregulated mitochondrial dynamics. This leads to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis and with a metabolomic profile typical for cancer cells, namely, increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. We show that NM1 KO cells form solid tumors in a nude mouse model even though they have suppressed the PI3K/Akt/mTOR signaling pathway suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient signal for carcinogenesis. We suggest that NM1 plays a key role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the early onset of tumorigenesis.

cell biology↗

bioRxiv2022

Linked-Read Sequencing of Eight Falcons Reveals a Unique Genomic Architecture in Flux

Falcons are diverse birds of cultural and economic importance. They have undergone major lineage-specific chromosomal rearrangements, resulting in greatly-reduced chromosome counts relative to other birds. Here, we use 10X Genomics linked reads to provide new high-contiguity genomes for two gyrfalcons, a saker falcon, a lanner falcon, three subspecies of peregrine falcons, and the common kestrel. Assisted by a transcriptome sequenced from 22 gyrfalcon tissues, we annotate these genomes for a variety of genomic features, estimate historical demography, and then investigate genomic equilibrium in the context of falcon-specific chromosomal rearrangements. We find that falcon genomes are not in AT-GC equilibrium with a bias in mutations towards higher AT content; this bias is predominantly driven by--but not dependent on--hypermutability of CpG sites. Small indels and large structural variants were also biased towards insertions rather than deletions. Patterns of disequilibrium were linked to chromosomal rearrangements: falcons have lost GC content in regions that have fused to larger chromosomes from microchromosomes and gained GC content in regions of macrochromosomes that have translocated to microchromosomes. Inserted bases have accumulated on regions ancestrally belonging to microchromosomes, consistent with insertion-biased gene conversion. We also find an excess of interspersed repeats on regions of microchromosomes that have fused to macrochromosomes. Our results reveal that falcon genomes are in a state of flux. They further suggest that many of the key differences between microchromosomes and macrochromosomes are driven by differences in chromosome size, and indicate a clear role for recombination and biased-gene-conversion in determining genomic equilibrium. SignificanceFalcons are a particularly diverse and widespread genus of birds of particular cultural and economic importance. Falcons have also undergone recent large-scale chromosomal rearrangements to arrive at atypically low chromosome counts relative to other birds. We produced eight new high-quality falcon genomes to support general research on falcons, and we analyze these genomes to assess how chromosome loss has influenced specific aspects of genomic architecture.

genomics↗

bioRxiv2020

Beyond the greenhouse: coupling environmental and salt stress response reveals unexpected global transcriptional regulatory networks in Salicornia bigelovii

Soil salinity is an increasing threat to global food production systems. As such, there is a need for salt tolerant plant model systems in order to understand salt stress regulation and response. Salicornia bigelovii, a succulent obligatory halophyte, is one of the most salt tolerant plant species in the world. It possesses distinctive characteristics that make it a candidate plant model for studying salt stress regulation and tolerance, showing promise as an economical non-crop species that can be used for saline land remediation and for large-scale biofuel production. However, available S. bigelovii genomic and transcriptomic data are insufficient to reveal its molecular mechanism of salt tolerance. We performed transcriptome analysis of S. bigelovii flowers, roots, seeds and shoots tissues cultivated under desert conditions and irrigated with saline aquaculture effluent. We identified a unique set of tissue specific transcripts present in this non-model crop. A total of 66,943 transcripts (72.63%) were successfully annotated through the GO database with 18,321 transcripts (27.38%) having no matches to known transcripts. Excluding non-plant transcripts, differential expression analysis of 49,914 annotated transcripts revealed differentially expressed transcripts (DETs) between the four tissues and identified shoots and flowers as the most transcriptionally similar tissues relative to roots and seeds. The DETs between above and below ground tissues, with the exclusion of seeds, were primarily involved in osmotic regulation and ion transportation. We identified DETs between shoots and roots implicated in salt tolerance including SbSOS1, SbNHX, SbHKT6 upregulated in shoots relative to roots, while aquaporins (AQPs) were up regulated in roots. We also noted that DETs implicated in osmolyte regulation exhibit a different profile among shoots and roots. Our study provides the first report of a highly upregulated HKT6 from S. bigelovii shoot tissue. Furthermore, we identified two BADH transcripts with divergent sequence and tissue specific expression pattern. Overall, expression of the ion transport transcripts suggests Na+ accumulation in S. bigelovii shoots. Our data led to novel insights into transcriptional regulation across the four tissues and identified a core set of salt stress-related transcripts in S. bigelovii.

plant biology↗

bioRxiv2019

Nuclear genetic regulation of human mitochondrial RNA modification

RNA modifications affect the stability and function of RNA species, regulating important downstream processes. Modification levels are often dynamic, varying between tissues and individuals, although it is not always clear what modulates this variation or what impact it has on biological systems. Here, we quantify variation in RNA modification levels at functionally important positions in the mitochondrial genome across 11,552 samples from 39 tissue/cell types and find evidence that modification levels impact mitochondrial transcript processing. We identify novel links between mitochondrial RNA modification levels in whole blood and genetic variants in the nuclear genome, including missense mutations in LONP1 and PNPT1, as well as missense mutations in MRPP3, SLC25A26 and MTPAP that associate with RNA modification levels across multiple tissue types. Genetic variants linked to modification levels are associated with multiple disease phenotypes, including blood pressure, breast cancer and Moyamoya disease, suggesting a role for these processes in complex disease.

genomics↗

bioRxiv2018

Intergenerational epigenetic inheritance in reef-building corals

MainThe notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants 1,2 and metazoans 1,3. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations 1-4. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals) 4. Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.

genetics↗

bioRxiv2017

Genomic and Environmental Contributions to Chronic Diseases in Urban Populations

Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the GxE interactions in humans. We used a system biology approach to comprehensively assess the interactions between 1.6 million environmental exposure data, health, and expression phenotypes, together with whole genome genetic variation, for [~]1000 individuals from a founder-population in Quebec. We reveal a substantial impact of the urbanization gradient on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. In detail, air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits when controlling for genetic ancestry. Finally, we capture 34 clinically associated expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects chronic disease development, and that genetic variation, including rare variants, can modulate individuals response to environmental challenges.\n\nHighlightsO_LIFine scale environmental effects overpower those of ancestry on gene expression\nC_LIO_LIAir pollution (geographic and temporal) is associated with transcriptional response\nC_LIO_LIGene-by-environment interactions with air pollution include asthma associated loci\nC_LIO_LIInflammatory pathways and cardio-respiratory clinical traits are among those affected\nC_LI

genomics↗

bioRxiv2016

Constraints on eQTL fine mapping in the presence of multi-site local regulation of gene expression

Expression QTL (eQTL) detection has emerged as an important tool for unravelling of the relationship between genetic risk factors and disease or clinical phenotypes. Most studies use single marker linear regression to discover primary signals, followed by sequential conditional modeling to detect secondary genetic variants affecting gene expression. However, this approach assumes that functional variants are sparsely distributed and that close linkage between them has little impact on estimation of their precise location and magnitude of effects. In this study, we address the prevalence of secondary signals and bias in estimation of their effects by performing multi-site linear regression on two large human cohort peripheral blood gene expression datasets (each greater than 2,500 samples) with accompanying whole genome genotypes, namely the CAGE compendium of Illumina microarray studies, and the Framingham Heart Study Affymetrix data. Stepwise conditional modeling demonstrates that multiple eQTL signals are present for ~40% of over 3500 eGenes in both datasets, and the number of loci with additional signals reduces by approximately two-thirds with each conditioning step. However, the concordance of specific signals between the two studies is only ~30%, indicating that expression profiling platform is a large source of variance in effect estimation. Furthermore, a series of simulation studies imply that in the presence of multi-site regulation, up to 10% of the secondary signals could be artefacts of incomplete tagging, and at least 5% but up to one quarter of credible intervals may not even include the causal site, which is thus mis-localized. Joint multi-site effect estimation recalibrates effect size estimates by just a small amount on average. Presumably similar conclusions apply to most types of quantitative trait. Given the strong empirical evidence that gene expression is commonly regulated by more than one variant, we conclude that the fine-mapping of causal variants needs to be adjusted for multi-site influences, as conditional estimates can be highly biased by interference among linked sites.

genetics↗

bioRxiv2016

Integrated Genomic Analysis of Mitochondrial RNA Processing in Human Cancers

Alterations to mitochondrial function and mutations in mitochondrial genes have been reported for a wide variety of cancers, however the mitochondrial transcriptome remains largely unexplored in cancer despite an emerging appreciation of the role that post-transcriptional regulation plays in the etiology of these diseases. Here, we quantify and assess changes to mitochondrial RNA processing in human cancers using integrated genomic analysis of RNA Sequencing and genotyping data from 1226 samples across 12 different cancer types. We find significant changes to m1A and m1G post-transcriptional methylation rates at functionally important positions in mitochondrial tRNAs in tumor tissues across all cancers. Pathways of RNA processing are strongly associated with methylation rates in normal tissues (P=2.85x10-27), yet these associations are lost in tumors. Furthermore, we report 18 gene-by-disease-state interactions where altered methylation rates occur under cancer status conditional on genotype, implicating genes associated with mitochondrial function or cancer (e.g. CACNA2D2, LMO2 and FLT3) and suggesting that nuclear genetic variation can potentially modulate an individuals ability to maintain unaltered rates of mitochondrial RNA processing under cancer status. Finally, we report a significant association between the magnitude of methylation rate changes in tumors and patient survival outcomes. These results highlight mitochondrial post-transcriptional events as a clinically relevant mechanism and as a theme for the further investigation of cancer processes, biomarkers and therapeutic interventions.

genomics↗