Biology subjects

Fellay, J.

Publications and source records attributed to Fellay, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Multi-omics integration identifies a reproducible inflammatory host-response axis in pediatric sepsis

Sepsis is a major cause of morbidity and mortality in children, yet biological heterogeneity in host responses has limited progress toward targeted therapies and patient stratification. Multiomics integration can combine complementary molecular layers to identify coordinated disease programs not captured by individual assays. Here, we integrated genomic, bulk transcriptomic, proteomic and metabolomic data from blood samples of 22 children with culture-confirmed bacterial sepsis enrolled in the Swiss Pediatric Sepsis Study. Multi-Omics Factor Analysis identified a dominant host-response axis reflecting systemic inflammation. This axis was driven primarily by transcriptomic variation and supported by coordinated proteomic and metabolomic signals, including circulating inflammatory mediators and altered amino-acid metabolism. It was associated with C-reactive protein and a severity score proxy. Projection into an independent pediatric sepsis cohort (n = 22) reproduced the inflammatory and severity-related interpretation of this axis. Single-omic projections showed that the integrated signal could be approximated from individual layers, particularly transcriptomics. In three external pediatric whole-blood transcriptomic datasets, the RNA-derived projection separated septic shock from healthy controls and increased across clinical inflammatory syndromes. These findings define a reproducible inflammatory host-response axis in pediatric sepsis and support multi-omics-guided selection of molecular readouts suitable for clinical translation.

immunology↗

bioRxiv2026

Mutational bias shapes protein evolution across RNA viruses

Mutational biases can influence genome composition, but their contribution to protein evolution remains difficult to quantify. Here we utilize a nearly neutral framework that translates nucleotide mutational spectra into expected amino acid substitution patterns and equilibrium amino acid compositions. Using SARS-CoV-2 as a model system, we show that the viral mutational spectrum explains more than 50% of the variation in observed single-nucleotide amino acid substitutions and predicts the overall direction of proteome-wide amino acid composition change during the COVID-19 pandemic. The predictive power of the model varies with selection regime: effectively neutral and weakly deleterious substitutions conform most closely to the mutational expectation, whereas strongly constrained sites and mutational hotspots show larger deviations. This indicates that departures from the nearly neutral baseline provide a quantitative proxy for purifying and positive selection. Extending the analysis across 34 RNA virus species, we find that positive-sense, negative-sense and double-stranded RNA viruses differ systematically in their mutational spectra, and that these differences are associated with predictable shifts in proteome composition. The same relationship is detectable in RNA-dependent RNA polymerase sequences from more than 77,000 viral species. These results indicate that taxon-specific mutational bias contributes persistently to protein evolution across evolutionary scales.

bioinformatics↗

bioRxiv2025

Zygosity-Aware DNA Language Modeling Improves Ancestry and Gene Expression Prediction

AO_SCPLOWBSTRACTC_SCPLOWDNA language models (DNA-LMs) are transforming how genomic sequence information is represented and interpreted. Yet most current approaches treat DNA as a single sequence, overlooking the diploid structure and zygosity information that distinguish the two parental copies of the genome. Here, we systematically evaluate explicit diploid, zygosity-aware representations in DNA-LMs for two downstream tasks: ancestry classification and gene expression prediction. For ancestry, we use HyenaDNA embeddings of the extended MHC region and show that concatenating maternal and paternal haplotype embeddings consistently improves predictive performance across five superpopulations compared to single-haplotype inputs. For gene expression, we compare convolutional neural networks (CNNs) trained from scratch with Nucleotide Transformer models using reference-only, single-copy, and two-copy (zygosity-aware) sequence encodings. CNNs showed increased performance by incorporating genetic variation and zygosity via simple additive genotype encoding, whereas naively injecting variation into pretrained Nucleotide Transformer models yields mixed effects, highlighting a mismatch between current pretraining objectives and variation-sensitive prediction. Together, our results demonstrate that zygosity-aware representations can capture biologically meaningful information beyond reference-only views and underscore the need for diploid- and population-aware pretraining strategies in future DNA-LMs for variant interpretation and precision medicine.

bioinformatics↗

bioRxiv2025

Interdependent Dynamics of mRNA Expression and HIV-1 Viral Load: Insights from Transcriptomics and Mendelian Randomization

The interaction between HIV-1 and the host immune system plays a crucial role in the natural control and progression of the infection. Previous studies have identified APOBEC3G, Tetherin, SAMHD1, and SERINC5 as HIV-1 host restriction factors, which are counteracted by the viral proteins Vif, Vpu, and Nef, respectively. The blood expression levels of some of these host proteins are correlated with HIV load, suggesting that interindividual differences in the spontaneous control of HIV infection might lead to the identification of novel HIV restriction factors. Our study enrolled 150 participants from the Swiss HIV Cohort Study with human genome-wide genotyping data, pre-antiretroviral treatment peripheral blood mononuclear cells (PBMC) aliquots and HIV load measurements. Using BrB-seq, we quantified mRNA expression of all protein-coding genes and found significant associations between 792 genes and HIV load. Pathway analysis revealed that higher viral load associated with the upregulation of innate immune response, proteasome complex, mitochondrial and cell-cycle related activity, and with the downregulation of ribosomal transcripts and genes involved in cytokine-cytokine receptor interaction, including IL4R, IL7R, and TCF7. Mendelian Randomization confirmed the viral restriction activity of TRABD2A and identified new candidates as potential restriction factors. These findings provide novel insights into the host-virus interplay and suggest additional genes that may contribute to the natural control of HIV-1 infection.

immunology↗

bioRxiv2024

Granulysin antimicrobial activity promotes dormancy in Mycobacterium tuberculosis

Human tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain or exacerbate an infection. Containment is exploited by Mtb as a hideout to persist in a dormant, antibiotic-tolerant state only to resuscitate upon immunosuppression. The immune determinants of a granulomatous response driving Mtb persistence remain elusive. We here combined an ex vivo granuloma model with peripheral blood mononuclear cell (PBMC) specimens from TB patients and a high-dimensional mass cytometry (CyTOF) approach to shed light on the immune factors prompting Mtb dormancy. Compared to healthy controls, patient-derived ex vivo granulomas rapidly force Mtb to adopt a dormant-like state; an observation that correlates with the presence of activated innate (-like) cytotoxic lymphocytes. We further demonstrate that Mtb dormancy is induced by direct exposure to granulysin, thereby unravelling an immune escape mechanism to cytotoxic lymphocyte activity.

immunology↗

bioRxiv2024

Mitochondrial direct repeat reduction as a strategy for enhancing human longevity: the case of the common repeat

Aging, characterized by a series of functional declines correlated with advancing chronological age, has a significant mitochondrial DNA (mtDNA) component, with somatic mtDNA deletions playing a central role. In post-mitotic or slow-dividing cells like neurons and skeletal muscles, selfish mtDNA deletions clonally expand within a cell, ultimately leading to the deterioration and death of host cells and appearence of age-related phenotypes. Thus reducing the burden of somatic deletions could have far- reaching systemic benefits for the entire human body. Given the crucial role of direct nucleotide repeats in the formation of mitochondrial deletions, we hypothesize that minimizing these repeats in the human mitochondrial genome could enhance healthspan by decreasing somatic deletions. To investigate this hypothesis, we focus on the "common repeat", a 13-base pair perfect direct repeat sequence (ACCTCCCTCACCA) located at positions 8470-8482 and 13447-13459, respectively. This perfect repeat: (i) is highly prevalent, with its potential deleterious consequences affecting the majority of humans; (ii) represents one of the most fragile sites, highly prone to forming deletions; (iii) when disrupted, is associated with a decreased somatic deletion load and enhanced human healthspan; (iv) is likely to experience positive selection in the present or near future due to indirect fitness effects, such as the "grandmother effect", and direct fitness effects, such as (v) a decreased mutation rate. These observations support the argument that reducing the mtDNA somatic deletion load through targeted disruption of these repeats, or by using naturally occurring polymorphisms with disrupted repeats in mitochondrial medicine, could be an effective approach to increasing human longevity.

genetics↗

bioRxiv2024

Human genetic ancestry, Mycobacterium tuberculosis diversity and tuberculosis disease severity in Dar es Salaam, Tanzania

Infectious diseases have affected humanity for millennia and are among the strongest selective forces. Tuberculosis (TB) is an ancient disease, caused by the human-adapted members of the Mycobacterium tuberculosis complex (MTBC). The outcome of TB infection and disease is highly variable, and co-evolution between human populations and MTBC strains may account for some of this variability. Particular human genetic ancestries have been associated with higher susceptibility to TB, but socio-demographic aspects of the disease can confound such associations. Here, we studied 1,000 TB patients from Dar es Salaam, Tanzania, together with their respective MTBC isolates, by combining human and bacterial genomics with clinical data. We found that the genetic background of the TB patient population was strongly influenced by migrationsof Bantu-speaking populations from West Africa, which is in contrast to the corresponding MTBC genotypes that were mainly introduced from outside Africa. These findings suggest a recent evolutionary history of co-existence between the human and MTBC populations in Dar es Salaam. We detected no evidence of an effect of human genetic ancestry, or MTBC phylogenetic diversity alone, nor their interaction, on TB disease severity. There was also no evidence of an association between human variation genome-wide and TB disease severity.Treatment-seeking, social and environmental factors are likely to be the main determinants of disease severity at the point of care in this patient population. Author SummaryTuberculosis (TB) is an ancient infectious disease that continues to challenge global health efforts. Here, we explored the interplay between human and bacterial genetics on TB in Dar es Salaam, Tanzania. We found that neither the genetic ancestry of the patient, nor the bacterial genotype alone, nor their interaction, influenced the severity of TB. Our finding indicate that in this patient population, social and environmental factors may be the main determinants of TB disease severity.

evolutionary biology↗

bioRxiv2023

Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania

The Mycobacterium tuberculosis complex (MTBC) comprises nine human-adapted lineages that differ in their geographical distribution. Local adaptation of specific MTBC genotypes to the respective human host population has been invoked in this context. Here, we generated macrophages from cryopreserved blood mononuclear cells of Tanzanian tuberculosis patients, from which the infecting MTBC strains had previously been phylogenetically characterized. We infected these macrophages ex vivo with a phylogenetically similar MTBC strain ("matched infection") or with strains representative of other MTBC lineages ("mismatched infection"). We found that L1 infections resulted in a significantly lower bacterial burden and that the intra-cellular replication rate of L2 strains was significantly higher compared the other MTBC lineages, irrespective of the MTBC lineage originally infecting the patients. Moreover, L4-infected macrophages released significantly greater amounts of TNF-, IL-6, IL-10, MIP-1{beta}, and IL-1{beta} compared to macrophages infected by all other strains. Taken together, while our results revealed no measurable effect of local adaptation, they further highlight the strong impact of MTBC phylogenetic diversity on the variable outcome of the host-pathogen interaction in human tuberculosis.

microbiology↗

bioRxiv2023

Unravelling the Mitochondrial Mutational Landscape in Chordates: damage-induced versus replication-induced signatures, their Etiologies, and dynamics

To elucidate the primary factors shaping mitochondrial DNA (mtDNA) mutagenesis, we derived a comprehensive 192-component mtDNA mutational spectrum using 86,149 polymorphic synonymous mutations reconstructed from the CytB gene of 967 chordate species. The mtDNA spectrum analysis provided numerous findings on repair and mutation processes, breaking it down into three main signatures: (i) symmetrical, evenly distributed across both strands, mutations, induced by gamma DNA polymerase (about 50% of all mutations); (ii) asymmetrical, heavy-strand-specific, C>T mutations (about 30%); and (iii) asymmetrical, heavy-strand-specific A>G mutations, influenced by metabolic and age-specific factors (about 20%). We propose that both asymmetrical signatures are driven by single-strand specific damage coupled with inefficient base excision repair on the lagging (heavy) strand of mtDNA. Understanding the detailed mechanisms of this damage is crucial for developing strategies to reduce somatic mtDNA mutational load, which is vital for combating age-related diseases.

bioinformatics↗

bioRxiv2023

Transcriptomics and chromatin accessibility in multiple African population samples

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

genomics↗

bioRxiv2023

G2GSnake: A Snakemake workflow for host-pathogen genomic association studies

SummaryJoint analyses of paired host and pathogen genome sequences have the potential to enhance our understanding of host-pathogen interactions. A systematic approach to conduct such a joint analysis is through a "genome-to-genome" (G2G) association study, which involves testing for associations between all host and pathogen genetic variants. Significant associations reveal host genetic factors that might drive pathogen variation, highlighting biological mechanisms likely to be involved in host control and pathogen escape. Here, we present a Snakemake workflow that allows researchers to conduct G2G studies in a reproducible and scalable manner. In addition, we have developed an intuitive R Shiny application that generates custom summaries of the results, enabling users to derive relevant insights. Availability and implementationG2GSnake is freely available at: https://github.com/zmx21/G2GSnake under the MIT license.

bioinformatics↗

bioRxiv2023

Genetic features and genomic targets of human KRAB-Zinc Finger Proteins

Kruppel-associated box (KRAB) domain-containing zinc finger proteins (KZFPs) are one of the largest groups of transcription factors encoded by tetrapods, with 378 members in human alone. KZFP genes are often grouped in clusters reflecting amplification by gene and segment duplication since the gene family first emerged more than 400 million years ago. Previous work has revealed that many KZFPs recognize transposable element (TE)-embedded sequences as genomic targets, and that KZFPs facilitate the co-option of the regulatory potential of TEs for the benefit of the host. Here, we present a comprehensive survey of the genetic features and genomic targets of human KZFPs, notably completing past analyses by adding data on more than a hundred family members. General principles emerge from our study of the TE-KZFP regulatory system, which point to multipronged evolutionary mechanisms underlaid by highly complex and combinatorial modes of action with strong influences on human speciation.

genomics↗

bioRxiv2022

Buffering role of HSP shapes the molecular evolution of mammalian and human genomes at short and long-term scales

Heat shock proteins in parallel with their main and originally discovered function - maintenance of folded proteins under stressful conditions, can play also background buffering role - by folding proteins with an excess of slightly-deleterious nonsynonymous variants (SDNV). Here we tested several scenarios of this buffering role. On the comparative species scale, we demonstrated that low-Ne species are characterized by a higher expression level of hsp90 which can be explained by the excess of SDNV. On the comparative tissue level, we showed that long-lived tissues have also a higher hsp90 expression level, which can be advantageous to maintain the functionality of proteins. On the comparative gene level, we demonstrated that purifying selection of hsp90 in low-Ne-species did not relax as strongly as it happens for control genes, similar to hsp90. Additionally, we demonstrated that hsp clients versus non-clients are characterised by decreased level of selective constraints; demonstrate stronger relaxation of purifying selection in low-Ne species; have an excess of slightly-deleterious variants associated with complex disease phenotypes in humans; have an excess of pathological variants associated with clinical phenotypes in humans, suggesting that clients, being buffered by hsp90 can degenerate a bit more as compared to non-clients. Altogether, our results show that the secondary role of hsp, buffering of SDNV, is widespread and universal affecting properties of species, tissues and genes. A deep understanding of the buffering role of hsp90 will help to predict the deleterious effect of each variant in the human genome more precisely as well as will extend the application of the effectively-neutral theory of molecular evolution.

evolutionary biology↗

bioRxiv2022

The mitochondrial component of human infertility- an increased mtDNA content and an excess of ultra-rare mtDNA variants in aneuploid versus euploid embryos.

Using low-coverage, whole-genome sequences of trophectoderm biopsies from 11,610 human blastocyst-stage embryos, we analyzed the relationship between chromosomal abnormalities and mitochondrial (mt) DNA dynamics. Comparing 6,208 aneuploid and 5,402 euploid embryos in cohort studies, we found that mtDNA content in aneuploid embryos was significantly higher than that in euploid embryos. This outcome was confirmed through intrafamilial analyses of embryos with matched parents and in vitro fertilization cycles, and it occurred independent of maternal age. Additional human population-based studies uncovered a higher abundance of ultra-rare mtDNA variants located in never-altered positions in the human population in aneuploid compared to euploid embryos in both cohort- and family-based analyses. This maternal age-independent association of increased mtDNA content and aneuploidy in human embryos may reflect a novel mechanism of purifying selection against potentially deleterious mtDNA variants, which arise from germline or early developmental mtDNA damaging events, that occurs in human embryos prior to implantation.

bioinformatics↗

bioRxiv2022

The butterfly effect: mutational bias of SARS-CoV-2 affects its pattern of molecular evolution on synonymous and nonsynonymous levels

Evolution is a function of mutagenesis and selection. To analyse the role of mutagenesis on the structure of the SARS-CoV-2 genome, we reconstructed the mutational spectrum, which was highly C>U and G>U biased. This bias forces the SARS-CoV-2 genome to become increasingly U-rich unless selection cancels it. We analysed the consequences of this bias on the composition of the most neutral (four-fold degenerate synonymous substitutions) and the least neutral positions (nonsynonymous substitutions). The neutral nucleotide composition is already highly saturated by U and, according to our model, it is at equilibrium, suggesting that in the future, we dont expect any more increase in U. However, nonsynonymous changes continue slowly evolve towards equilibrium substituting CG-rich amino-acids ("losers") with U-rich ones ("gainers"). This process is universal for all genes of SARS-CoV-2 as well as for other coronaviridae species. In line with the direction mutation pressure hypothesis, we show that viral-specific amino acid content is associated with the viral-specific mutational spectrum due to the accumulation of effectively neutral slightly deleterious variants (losers to gainers) during the molecular evolution. The tuning of a protein space by the mutational process is expected to be typical for species with relaxed purifying selection, suggesting that the purging of slightly-deleterious variants in the SARS-CoV-2 population is not very effective, probably due to the fast expansion of the viral population during the pandemic. Understanding the mutational process can help to design more robust vaccines, based on gainer-rich motifs, close to the mutation-selection equilibrium.

evolutionary biology↗

bioRxiv2022

Is competition for cellular resources a driver of complex trait heritability?

Most human complex traits are enormously polygenic, with thousands of contributing variants with small effects, spread across much of the genome. These observations raise questions about why so many variants-and so many genes-impact any given phenotype. Here we consider a possible model in which variant effects are due to competition among genes for pools of shared intracellular resources such as RNA polymerases. To this end, we describe a simple theoretical model of resource competition for polymerases during transcription. We show that as long as a gene uses only a small fraction of the overall supply of polymerases, competition with other genes for this supply will only have a negligible effect on variation in the genes expression. In particular, although resource competition increases the proportion of heritability explained by trans-eQTLs, this effect is far too small to account for the roughly 70% of expression heritability thought to be due to trans-regulation. Similarly, we find that competition will only have an appreciable effect on complex traits under very limited conditions: that core genes collectively use a large fraction of the cellular pool of polymerases and their overall expression level is strongly correlated (or anti-correlated) with trait values. Our qualitative results should hold for a wide family of models relating to cellular resource limitations. We conclude that, for most traits, resource competition is not a major source of complex trait heritability.

genetics↗

bioRxiv2021

Mitochondrial mutational spectrum is associated with mammalian longevity: a novel signature of oxidative damage.

The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra is affected by the oxidative damage. Assuming that oxidative damage increases with age, we analyze mtDNA mutagenesis of different species. Analysing (i) dozens thousands of somatic mtDNA mutations in samples of different age (ii) 70053 polymorphic synonymous mtDNA substitutions, reconstructed in 424 mammalian species with different generation length and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH>GH substitutions (H - heavy chain notation) is twice higher in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH>GH substitutions are also sensitive to the time spent single stranded (TSSS) during asynchroniuos mtDNA replication we demonstrated that AH>GH substitution rate is a function of both species-specific generation length and position specific TSSS. We propose that AH>GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.

bioinformatics↗

bioRxiv2021

A base-line cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913

Upon recognition of aberrantly located DNA, the innate immune sensor cGAS activates STING/IRF-3-driven antiviral responses. Here we characterized the ability of a specific variant of the cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted towards the possibility for an additional binding site for a potential cellular co-factor in cGAS dimers. However, cGAS(WT) or cGAS(P261H)-reconstituted THP-1 cGAS KO cells shared steady-state expression of interferon-stimulated genes (ISGs), as opposed to cells expressing the enzymatically inactive cGAS(G212A/S213A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared to cGAS KO- or cGAS(G212A/S213A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared to cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend towards a slightly reduced type I IFN response as compared to PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a base-line antiviral state rendering cells more refractory to ISG-sensitive viral infections. Even though rs610913 failed to grossly differ phenotypically from the wild-type gene, its expression potentially results in a slightly altered susceptibility to viral infections in vivo.

immunology↗