Biology subjects

Wagner, N.

Publications and source records attributed to Wagner, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Brainstem premotor circuits transform dental sensory input into coordinated jaw opening

Protective actions require the rapid transformation of damage into coordinated activity of motor pools, yet the brainstem circuits implementing this operation remain poorly defined. Here, we use the tooth-trigeminal system to identify molecularly specified pathways linking intradental sensory input to opposing jaw motor pools. Optogenetic activation of tooth-associated sensory afferents evoked rapid, stimulus-locked jaw-opening. Intradental afferents formed functional monosynaptic connections with Pdyn+ neurons in the 5Sol transition zone and Calb2+ neurons in the 5Tr transition zone, identifying these regions as sensory-recipient premotor interfaces. Predominantly excitatory Pdyn+ 5Sol neurons provided monosynaptic input to anterior digastric motor neurons, whereas predominantly inhibitory Calb2+ 5Tr neurons provided bilateral monosynaptic input to masseter motor neurons. Activation of Pdyn+ 5Sol neurons was sufficient to evoke jaw opening. Together, these findings define complementary brainstem pathways positioned to couple jaw-opening drive with inhibition of antagonistic jaw-closing output, revealing a withdrawal-like sensorimotor computation adapted to cranial biomechanics.

neuroscience↗

bioRxiv2026

A DNA-scaffolded Retron Ring Mediates Antiphage Immunity

Retrons are a diverse family of bacterial defence systems that couple reverse transcriptase (RT) activity to antiphage immunity by producing multicopy single-stranded DNA (msDNA). Yet, the molecular mechanisms by which most systems detect infection and execute immunity remain unknown. Here, we define the structure, immune sensing and effector mechanisms of retron type IX, composed of an RT, a non-coding RNA, a tandem KH-HTH subunit and a HEPN RNase effector. Retron IX confers robust protection against diverse bacteriophages. Cryo-EM and biochemical analyses reveal a supramolecular ring assembly composed of 8-10 repeating modules, spanning up to 230 [A] in diameter. Within this assembly, the msDNA scaffolds the outer rim inhibiting the HEPN ribonuclease in a catalytically poised state, with the active site occluded within the inner layer. We identify a phage-encoded PD-(D/E)XK nuclease as the immune trigger that cleaves the exposed msDNA stem-loop, leading to ring disassembly and HEPN effector release. Upon activation, the HEPN ribonucleases cleave tRNAs indiscriminately, inducing dormancy and blocking phage propagation. Our findings unveil how ring-shaped higher-order assembly controls enzymatic activities while allowing signal-specific activation and establish the ncRNA as an evolvable scaffold underlying the remarkable structural and defensive diversity of bacterial retron immune complexes.

microbiology↗

bioRxiv2026

Generation of three induced pluripotent stem cell lines from an immune checkpoint inhibitor-induced myocarditis patient and controls

Immune checkpoint inhibitor-associated myocarditis (ICIM) is an uncommon but potentially fatal inflammatory heart disease triggered by cancer immunotherapy, with up to 40% mortality. The underlying mechanisms are still elusive, partly due to the lack of appropriate human disease models. Here, we report the generation of three induced pluripotent stem cell (iPSC) lines derived from an ICIM patient, an ICI-treated patient without myocarditis, and a healthy donor. These lines exhibit typical pluripotent stem cell morphology, express pluripotency markers, maintain normal karyotypes, and differentiate into derivatives of the three germ layers, providing a valuable platform for mechanistic studies and therapeutic discovery.

Developmental Biology↗

bioRxiv2026

Identification of protein secretion systems and type III effectors in wood-associated bacteria of the genus Xylophilus

To shed light into the biology of bacteria belonging to the genus Xylophilus, including the grapevine pathogen Xylophilus ampelinus, we scrutinized all available genomes of the genus for the presence of type III secretion and flagellar systems. We found three different flagellar systems in the genus, one of which was present in all twelve strains with good-quality genome sequences were available. The other two flagellar systems were only detected in one or two strains. We also identified two types of type III secretion systems, likely under control of the AraC-type transcriptional activator HrpX. One system with resemblance to systems from plant-pathogenic bacteria was only found in the grapevine pathogen. The other system was found in three strains of Xylophilus, all isolated from plant material. We predicted genes that are co-regulated with the type III secretion systems, as supported by the presence of strongly conserved HrpX-binding promoter elements. We identified about 40 type III effectors in the grapevine pathogen with homologs in plant pathogenic bacteria. In contrast, a rhododendron flower isolate had only two type III effector gene candidates with conserved HrpX-binding promoter elements but many genes without homologs beyond the species. Finally, we predicted and confirmed three novel effector candidates from X. ampelinus to contain a functional type III secretion signal using an AvrBs1 reporter approach. The presence of type III effectors suggests that effector-triggered immunity may exist in grapevine or non-host plants and that strategies targeting type III effectors for resistance engineering may contribute to suitable control measures.

microbiology↗

bioRxiv2026

MicroRNA regulatory targets of VO2peak in older adult participants of the Study of Muscle Mobility and Aging (SOMMA)

Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA-gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70-79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA-gene interactions to uncover therapeutic targets for preserving muscle function with age.

molecular biology↗

bioRxiv2025

The adhesion molecules β7 integrin and L-selectin contribute to cholestatic liver disease in male mice

Background & AimsPrimary sclerosing cholangitis (PSC) is a long-term progressive disease, often occurring in conjunction with inflammatory bowel disease (IBD). Dysregulated immune cell migration and gut microbiota alterations are implicated in disease progression. Livers of PSC patients show upregulation of the endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1). Here we examined the role of the leukocytic adhesion molecules (AM) {beta}7 integrin and L-selectin, both binding partners of MAdCAM-1, in an experimental mouse model resembling aspects of human PSC. MethodsWild type (WT), {beta}7 integrin-deficient ({beta}7-/-), L-selectin-deficient (L-sel-/-), and L-selectin/{beta}7 integrin double-deficient (L-sel-/-/{beta}7-/-) male mice were compared in the model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy. The extent of pathology was evaluated by serum parameters, histology, flow cytometry, and expression of inflammatory mediators. Fecal microbiota changes were assessed by 16S rRNA amplicon sequencing and intestinal permeability was measured by FITC-dextran assay. ResultsAM-deficient mice were markedly protected from DDC-induced cholangiopathy. Hepatic immune cell populations of AM-deficient mice differed significantly from those of WT mice. Adoptively transferred {beta}7-/- CD8+ T cells caused significantly less liver damage than CD8+ WT T cells in DDC-treated {beta}7-/- mice. DDC-feeding caused substantial changes in fecal microbiota profiles, which differed between the mouse strains, and a strong increase in intestinal permeability that was significantly lower in {beta}7-/- than WT mice. Conclusions{beta}7 integrin and L-selectin contribute to DDC-induced cholangiopathy with {beta}7 integrin-expressing CD8+ T cells playing a crucial role in promoting pathogenesis. In addition, AM-expressing immune cells may contribute to the inflammatory process by causing unfavorable gut microbiota shifts and destabilizing the gut barrier. Synopsis{beta}7 integrin- and/or L-selectin-deficient mice are less susceptible to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced experimental cholangiopathy. {beta}7 integrin-expressing CD8+ T cells contribute to DDC-induced pathogenesis. {beta}7 integrin promotes DDC-induced gut barrier dysfunction and microbiota shifts, potentially exacerbating hepatic injury.

immunology↗

bioRxiv2025

Fluctuations in AAV genome quantification via digital PCR affected by heat-based virion lysis

Adeno-associated virus (AAV) vectors are central to gene therapy, making precise genome quantification essential for product quality and dose determination. We systematically assessed digital PCR (dPCR) on the QIAcuity platform to quantify recombinant AAV2 and AAV8 genomes, examining how assay design, amplicon length, and heat-based sample preparation affect results. Across multiple genomic targets, shorter amplicons consistently yielded higher copy numbers than longer ones leading to a quantification deviation of up to [~]48%. The results point to heat-induced genomic fragmentation as the main cause of the observed effect. These findings highlight that dPCR-based AAV quantification is highly sensitive to amplicon length and sample preparation. We propose the use of the employed multitarget assay set to evaluate AAV genome extraction procedures, the quality of AAV genomic DNA extracts, and ultimately the AAV genome integrity.

molecular biology↗

bioRxiv2025

Aberrant splicing prediction during human organ development

Developmental disorders constitute a major class of genetic diseases, yet tools to identify splicing-disruptive variants during development are lacking. To address this need we extended the AbSplice framework to incorporate splicing dynamics across developmental stages. Moreover, we introduced several improvements including a refined ground truth from the aberrant splicing caller FRASER2, a continuous representation of splice site usage, and integration of the rich set of predictions from the sequence-based model Pangolin. These advances improve the performance of the original model at predicting aberrant splicing events and enable predictions across embryonic, childhood, and adult tissues. Genome-wide scores for all single-nucleotide variants and a web interface to score indels are available to facilitate the exploration of the predictions. Our genome-wide predictions reveal a class of variants with splicing-disruptive effects confined to early development, particularly abundant in the brain (>18,000 variants). These variants are enriched in loss-of-function intolerant genes and neurodevelopmental disorder genes. Within the rare-disease cohort Solve-RD high-impact brain-specific predictions are significantly enriched in individuals affected by neurodevelopmental disorders (NDD) in NDD-linked genes. Furthermore, the predicted developmental timing of the splicing disruption correlates with the clinical age of onset. Analysis of genomes of individuals with a suspected Mendelian disorder from Genomics England identified 26 unique variants in disease-linked genes, with stronger predicted effects during development than in adulthood, including a candidate new diagnosis in the gene FGFR1. Altogether, these results improve the accuracy of splice-disruptive variant prediction and provide tissue and developmental context to aid interpretation in rare disease diagnostics.

genomics↗

bioRxiv2025

The EPS-I exopolysaccharide transforms Ralstonia wilt pathogen biofilms into viscoelastic fluids for rapid dissemination in planta

Ralstonia solanacearum species complex (RSSC) pathogens cause destructive plant wilt diseases of a wide variety of crops, leading to significant agricultural losses worldwide. These bacteria rapidly spread through the water-transporting xylem where they grow prolifically and produce abundant biofilm that clogs xylem vessels. To understand RSSC biofilm behavior in planta, we examined their complex fluid mechanics. Rheological analyses revealed that unlike all previously analyzed microbial biofilms, RSSC biofilms are shear-thinning, viscoelastic fluids at physiologically relevant shear forces. To determine which factors confer these unique mechanics, we analyzed biofilms of bacterial mutants with altered biofilm components. Genetic analysis demonstrated that development of the viscous-dominant biofilms required production of EPS-I, an amphiphilic exopolysaccharide that is a major virulence factor for all RSSC pathogens. We show that EPS-I confers "biofilm mobility", which allows wildtype RSSC colonies to passively expand when deformed. Despite its high metabolic cost, bioassays demonstrated that EPS-I production conferred a net fitness benefit where biofilm mobility allowed the pathogen to spread and access more nutrients in complex environments like xylem vessels. The RSSC are a monophyletic lineage of aggressive plant wilt pathogens, and our evolutionary hypothesis testing suggests the origin of the eps biosynthetic gene cluster coincides with the emergence of wilt pathogenesis in the RSSC ancestor. Furthermore, comparative physiological assays demonstrated that biofilm mobility is unique to the RSSC within the genus Ralstonia. In summary, EPS-I production is a key evolutionary innovation that enables RSSC dispersal and virulence by conferring unique biofilm mechanics. Significance StatementRalstonia solanacearum species complex (RSSC) pathogens threaten global food security by fatally wilting plants. A soft matter physics lens demystified the cryptic role of a major virulence factor, the EPS-I exopolysaccharide. EPS-I transforms RSSC biofilms into viscoelastic fluids, a mechanical behavior not previously described for other microbial biofilms that are almost always viscoelastic solids. We demonstrate that the development of fluid biofilms was a key evolutionary innovation that enabled pathogenic success of these aggressive pathogens that rapidly wilt plants.

microbiology↗

bioRxiv2025

Tissue resident macrophages innately develop in a human iPSC-derived cardiac organoid model

The heart is the first functional organ to develop during embryogenesis, forming in parallel with the vasculature and hematopoietic cell lineages. To advance our understanding of human cardiac development and disease, human induced pluripotent stem cell-derived cardiomyocytes offer a promising in vitro model. However, conventional 2D culture systems lack the complexity required to recapitulate the intricate interactions of different cell types leading to fully functional and mature cardiac tissue. Here, we present a cardiac organoid model that mimics several aspects of cardiogenesis. The organoids develop a functional myocardium consisting of cardiomyocytes and fibroblasts capable of spontaneous rhythmic contractions. The myocard is interspersed with a branched endothelial network. Additionally, macrophages develop within the organoids and integrate into the myocardium. In summary, we describe a complex 3D cell culture platform to study human heart tissue development with all the involved cell types (cardiomyocytes, fibroblasts, endothelial cells, macrophages), paving the way for new insights into the role of macrophages in cardiac development and disease.

developmental biology↗

bioRxiv2025

Intercellular adhesion molecule-1 protects against adipose tissue inflammation and insulin resistance but promotes liver inflammation and hepatic fibrosis in mice

Metabolic dysfunction associated steatotic liver disease (MASLD) presents a growing global health problem with a range of manifestations, including steatosis, steatohepatitis, and cirrhosis. It is strongly associated with obesity, disease progression being promoted not only by hepatic leukocyte accumulation but also by inflammatory signals from adipose tissue and an altered gut microbiome. To determine the contribution of intercellular adhesion molecule-1 (ICAM-1) to MASLD pathogenesis, mice with an ICAM-1 mutation (Icam1tmBay) were compared to wild type (WT) mice in a Western-style diet (WD) model. WD-induced MASLD was accompanied by increased ICAM-1 expression in liver, epididymal white adipose tissue (EWAT), and intestine in WT mice. WD-fed Icam1tmBay mice exhibited increased circulating neutrophils, higher frequencies of inflammatory leukocytes in EWAT, and a worsened glucose tolerance when compared to WT mice. In contrast, the mutation resulted in reduced WD-induced liver damage and less accumulation of intrahepatic leukocytes. WD-feeding caused substantial changes in fecal microbiota with decreased microbial diversity that differed between the mouse strains. In conclusion, ICAM-1 positively regulates adipose tissue homeostasis and protects from insulin resistance but promotes liver damage in diet-induced obesity. This points to various organ-specific roles for ICAM-1 and the potential of liver-specific targeting of ICAM-1 for treatment of MASLD.

immunology↗

bioRxiv2025

MicroRNA signatures of VO2peak in older adult participants of the Study of Muscle, Mobility and Aging

BackgroundPeak oxygen consumption during exercise (VO2peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO2peak variation are not clear. Our objective is to understand the miRNA signatures that relate to VO2peak variation, which could provide insights to novel mechanisms that contribute to low VO2peak. MethodsWe used small RNA sequencing to analyze serum samples from 72 participants (70-79 yrs old, 53% female) of the Study of Muscle, Mobility and Aging (SOMMA). We analyzed samples from individuals with low or high VO2peak (N=18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO2peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. We used receiver operating characteristic curve analysis to evaluate the Area Under the Curve (AUC) and sensitivity and specificity rates. ResultsWe identified 1,055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO2peak (p < 0.05). After p-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The five miRNAs had AUC ranging from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70 to 80% and 80 to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO2peak (p < 0.05) and miR-519a-3p remained significant based on adjusted of p-values. ConclusionsWe identified a miRNA signature of VO2peak in older individuals that might provide insights to novel mechanisms that drive low VO2peak. Future studies will validate the findings in a larger, longitudinal study cohort.

molecular biology↗

bioRxiv2024

Characterization of HLA-DR immunopeptidome of bronchoalveolar lavage cells in patients with newly diagnosed rheumatoid arthritis and healthy current-smoker controls

Evidence suggests that self-tolerance is breached in the lung prior to the clinical onset of rheumatoid arthritis (RA) in the joints. The human leukocyte antigen DR (HLA-DR) shared epitope (SE) represents the strongest genetic risk factor for sero-positive RA. However, to our knowledge, the HLA-DR immunopeptidome of the RA lung and its link to HLA-DR genotype has not been investigated to date. The objective of this study was to optimize the methods for characterizing the HLA-DR immunopeptidome of lung immune cells and apply it to newly diagnosed RA patients versus current-smoker healthy controls, as well as to investigate the connection with the HLA-DR genotype. The HLA-DR immunopeptidome method was improved to facilitate characterization from as few as 6 million bronchoalveolar lavage (BAL) cells per subject, consisting primarily of alveolar macrophages. This method was applied to newly diagnosed RA patients naive to treatment (n=9, LURA cohort), as well as healthy current-smoker controls (n=10, COSMIC cohort). For five of the RA patients, a 6-month follow-up after initiation of the standard-of-care treatment regime was also included. After isolation and purification, peptide samples were separated by nano-flow liquid chromatography coupled to an Orbitrap mass spectrometer equipped with ion mobility device (FAIMS). Mass spectra acquired in data dependent acquisition mode were then searched against a human proteome database. Subsequently, the identified peptides were deconvoluted to their predicted binding HLA-DR allele using MHCMotifDecon based on the sequenced genotype of the individual. An optimized sample preparation and analytic method enabled the detection of over 23,000 peptides from over 3,000 source proteins with between 1,000 and 5,000 peptides identified per sample. Notably, the application of FAIMS with three compensation voltages allowed for efficient transfer of 2+, 3+, and 4+ peptide ions while removing singly charged background ions. Hierarchical clustering revealed that the immunopeptidome was more driven by the HLA-DR genotype than by RA disease or sex. However, since the HLA-DR genotype is a strong risk factor for RA, these results are convoluted. When deconvoluting the peptides to their predicted binding allele, the HLA-DRB1 alleles *01:01, *04:01, *04:04, *04:05, *04:07, and *10:01 were consistently assigned more peptides than other alleles. Except for *04:07 these alleles belong to the SE risk factor alleles, providing a potential explanation between HLA-SE and RA pathogenesis. Native peptides from known citrullinated and non-modified RA autoantigens (such as -enolase and calreticulin) were detected and validated as binders in prediction algorithms. No significant differences were found between base line and follow-up (post-treatment) samples from RA patients. Taken together, this data characterizes the HLA-DR immunopeptidome in the lung of early RA in an unprecedented manner, which together with future immunogenicity studies will help our understanding of the connection between the lung and the pathogenesis of RA. Finally, more peptides predicted to bind to SE alleles and *04:07 compared to other alleles demands further study on the relative expression of HLA-DR alleles and presentation mechanisms to understand the implications for RA.

immunology↗

bioRxiv2024

Micro-RNA 7975 directly regulates MDTH expression and mediates endothelial cell proliferation and migration in the development of early atherosclerosis

Cardiovascular disease (CVD) is commonly due to the development of atherosclerosis. Endothelial integrity is critical in the prevention of pathogenesis of atherosclerosis. The key to prevention of CVD is understanding the molecular mechanisms responsible for initiation of early atherosclerosis. MiRNAs are mediators of endothelial homeostasis, and their dysregulation could lead to early atherosclerotic disorder. We previously revealed the expression of miR-7975 in early atherosclerotic lesions. The aim of this study was to investigate the novel roles of miR-7975 on endothelial cell proliferation and migration, and in the regulation of metadherin (MTDH) expression. We performed proliferation and migration assays coupled with luciferase assay. We show that miR-7975 promotes proliferation and migration of endothelial cells and that miR-7976 directly regulates (MTDH), previously associated with cancer pathogenesis. In conclusion our results show miR-7975 could be a potential mediator of endothelial homeostasis and that MTDH is a novel target of miR-7975.

genomics↗

bioRxiv2024

Nucleotide dependency analysis of DNA language models reveals genomic functional elements

Deciphering how nucleotides in genomes encode regulatory instructions and molecular machines is a long-standing goal in biology. DNA language models (LMs) implicitly capture functional elements and their organization from genomic sequences alone by modeling probabilities of each nucleotide given its sequence context. However, using DNA LMs for discovering functional genomic elements has been challenging due to the lack of interpretable methods. Here, we introduce nucleotide dependencies which quantify how nucleotide substitutions at one genomic position affect the probabilities of nucleotides at other positions. We generated genome-wide maps of pairwise nucleotide dependencies within kilobase ranges for animal, fungal, and bacterial species. We show that nucleotide dependencies indicate deleteriousness of human genetic variants more effectively than sequence alignment and DNA LM reconstruction. Regulatory elements appear as dense blocks in dependency maps, enabling the systematic identification of transcription factor binding sites as accurately as models trained on experimental binding data. Nucleotide dependencies also highlight bases in contact within RNA structures, including pseudoknots and tertiary structure contacts, with remarkable accuracy. This led to the discovery of four novel, experimentally validated RNA structures in Escherichia coli. Finally, using dependency maps, we reveal critical limitations of several DNA LM architectures and training sequence selection strategies by benchmarking and visual diagnosis. Altogether, nucleotide dependency analysis opens a new avenue for discovering and studying functional elements and their interactions in genomes.

genomics↗

bioRxiv2024

CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses

Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, enhanced numbers of Tregs are found in vivo in spleen, lung and colon. These Tregs display a reduced Foxp3 expression, but enhanced expression of the IL-33 receptor (ST-2), IL-10, IL-13, and CREM. CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in CD4 T cell mediated transfer colitis in an IL-10 dependent way. Mechanistically CREB fulfils dual roles in Tregs. First it downregulates Foxp3 expression, however in cooperation with CREM, CREB expression in Tregs alters chromatin accessibility to the ST-2 region and thereby influences T cell specific immune responses mediated by IL-10. Brief summary: Mice with a Foxp3-specific knockout of CREB display enhanced expression of IL-13, IL-10, ST-2 and CREM, which prevents gut inflammation GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/601312v2_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@a2d341org.highwire.dtl.DTLVardef@1db6852org.highwire.dtl.DTLVardef@19e024borg.highwire.dtl.DTLVardef@a8c84d_HPS_FORMAT_FIGEXP M_FIG C_FIG Created by Biorender

immunology↗

bioRxiv2023

Aberrant expression prediction across human tissues

Despite the frequent implication of aberrant gene expression in diseases, algorithms predicting aberrantly expressed genes of an individual are lacking. To address this need, we compiled an aberrant expression prediction benchmark covering 8.2 million rare variants from 633 individuals across 49 tissues. While not geared toward aberrant expression, the deleteriousness score CADD and the loss-of-function predictor LOFTEE showed mild predictive ability (1-1.6% average precision). Leveraging these and further variant annotations, we next trained AbExp, a model that yielded 12% average precision by combining in a tissue-specific fashion expression variability with variant effects on isoforms and on aberrant splicing. Integrating expression measurements from clinically accessible tissues led to another two-fold improvement. Furthermore, we show on UK Biobank blood traits that performing rare variant association testing using the continuous and tissue-specific AbExp variant scores instead of LOFTEE variant burden increases gene discovery sensitivity and enables improved phenotype predictions.

genetics↗

bioRxiv2023

Genetic and functional diversity help explain pathogenic, weakly pathogenic, and commensal lifestyles in the genus Xanthomonas

The genus Xanthomonas has been primarily studied for pathogenic interactions with plants. However, besides host and tissue specific pathogenic strains, this genus also comprises nonpathogenic strains isolated from a broad range of hosts, sometimes in association with pathogenic strains, and other environments, including rainwater. Based on their incapacity or limited capacity to cause symptoms on the host of isolation, nonpathogenic xanthomonads can be further characterized as commensal and weakly pathogenic. This study aimed to understand the diversity and evolution of nonpathogenic xanthomonads compared to their pathogenic counterparts based on their co-occurrence and phylogenetic relationship and to identify genomic traits that form the basis of a life-history framework that groups xanthomonads by ecological strategies. We sequenced genomes of 83 strains spanning the genus phylogeny and identified eight novel species, indicating unexplored diversity. While some nonpathogenic species have experienced a recent loss of a type III secretion system, specifically, the hrp2 cluster, we observed an apparent lack of association of the hrp2 cluster with lifestyles of diverse species. We gathered evidence for gene flow among co-occurring pathogenic and nonpathogenic strains, suggesting the potential of nonpathogenic strains to act as a reservoir of adaptive traits for pathogenic strains and vice versa. We further identified traits enriched in nonpathogens that suggest a strategy of stress tolerance, rather than avoidance, during their association with a broad range of host plants.

ecology↗