Biology subjects

Wilkinson, M.

Publications and source records attributed to Wilkinson, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Statistical analysis provides new insights into patterns and mechanisms of the WANCY hotspot on vertebrate mitochondrial genomes

The vertebrate mitochondrial genomes are commonly composed of 37 genes, and the order of these genes act as useful indicator of phylogenetic relationships. Tandem duplication and random loss (TDRL) is considered to be one of the most important mechanisms leading to mitochondrial gene order rearrangement in vertebrates. The WANCY region has been widely recognized as a TDRL hotspot. In the past, the lack of data limited the in-depth exploration of rearrangement patterns and mechanisms in hotspots. Through statistical analysis of a large amount of available NCBI sequencing data, combined with phylogenetic and bioinformatics methods, we obtained statistically significant data from the four classes of Amphibians, Reptiles, Mammalia and Osteichthyes. These data demonstrate three new convergent rearrangements in the WANCY region of vertebrates, which suggests that the frequency of convergent rearrangements in hotspots is higher than previously thought. We also compared the frequency of TDRL rearrangement in the WANCY region with two other similar small gene clusters (the IQM region and the HSL region). The results to a certain extent support the hypothesis that the WANCY region may be a mechanism hotspot. However, more molecular evidence and larger data volumes are needed to confirm the existence of mechanisms that cause rearrangement hotspots.

genomics↗

bioRxiv2026

Distinct mechanistic pathways of early tauopathy revealed by MAPT mutations

Tau pathology underlies a broad spectrum of neurodegenerative disorders, collectively termed tauopathies, yet these diseases exhibit striking heterogeneity in their biological mechanisms and clinical outcomes. The basis for this heterogeneity remains poorly understood. Here, we address this question using knock-in mouse models expressing two distinct frontotemporal dementia-associated tau mutations to define how different tau variants drive divergent pathogenic programs in vivo. We find that the two mutations give rise to fundamentally different trajectories of tau pathogenesis. One trajectory is marked by progressive tau hyperphosphorylation and cytoskeletal destabilization occurring in the absence of detectable tau seed formation. In contrast, an alternative trajectory is characterized by tau hypophosphorylation, early seed formation, and alterations in nucleotide metabolism and chromatin organization, without overt cytoskeletal disruption. With aging, tau in this latter pathway transitions to a hyperphosphorylated state and forms mature fibrillar aggregates. Genetic enhancement of {beta}-amyloid selectively accelerates fibril formation, particularly in the model exhibiting early seeding. Together, these findings demonstrate that distinct tau mutations can engage separable pathogenic mechanisms, providing a biological framework for the heterogeneity observed across tauopathies, and highlighting the need for mechanism-informed therapeutic strategies and patient stratification. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/705716v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@11eb652org.highwire.dtl.DTLVardef@153cc53org.highwire.dtl.DTLVardef@8b670eorg.highwire.dtl.DTLVardef@1afaad_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractSchematic representation comparing two trajectories of tau pathology. The S305N mutation promotes a 4R isoform shift, cytoskeletal damage and synapse loss, and accumulation of soluble hyperphosphorylated tau. Tau remains soluble even at old ages. In contrast, the P301S mutation generates hypophosphorylated, seed-competent tau that forms fibrils. The effect of amyloid is slow in the S305N, but results in accelerated acceleration of pathology in the P301S. Figure made with Biorender.com.

neuroscience↗

bioRxiv2025

Bayesian Inference Framework to Identify Skin Material Properties \textit{in vivo} from Active Membranes

Accurate in vivo characterization of skin mechanical properties is essential for diagnostics and treatment planning across dermatological and surgical applications. Existing noninvasive techniques are limited in capturing the nonlinear and anisotropic behavior of skin. In this work, we propose a Bayesian inference framework that leverages active membranes to induce desired deformations and infer patient-specific skin properties from a measured strain field. A finite element model of skin-membrane interaction, parameterized using the Holzapfel-Gasser-Ogden model, is used to generate strain field data under various membrane actuation conditions. To overcome the computational cost of repeated simulations required for Bayesian sampling, we construct a data-driven surrogate using principal component analysis for dimensionality reduction and Gaussian process regression for rapid evaluation. Our approach enables probabilistic inference of key skin parameters, including shear modulus, fiber stiffness, dispersion, and orientation. An advatange of the proposed method is that inference of skin biomechanics does not require direct force measurements. Rather, the method relies on known properties of active membranes (which can be tested ahead of time). The method does require strain field measurements. Through synthetic studies, we demonstrate that our method accurately recovers most model parameters even under moderate levels of spatially correlated noise, and that multi-frame or multi-membrane observations significantly enhance identifiability. These results establish the potential of active membranes as a viable platform for noninvasive, in vivo skin biomechanics assessment.

biophysics↗

bioRxiv2025

Clumps: A Sequential Clustering Approach to Partitioning Sets of Phylogenies with Non-Identical Leaf Sets

Post-processing of sets of inferred phylogenetic trees often focuses on the canonical case of consensus of (multi)sets of phylogenetic trees on the same leaf set. However, with growing numbers of phylogenomic studies resorting to summary and/or supertree methods to obtain a phylogeny, the amount of (multi)sets of trees with non-identical leaf sets also increases. In an attempt identify trees with non-identical leaf sets that are topologically similar, we define a new sequential subsetting approach, "clumps of trees", based on the distance between any tree in a set and the sets supertree. While clumps were developed with trees with non-identical leaf sets in mind, they can be applied to (multi)sets of trees with identical taxonomic sampling. Unlike islands of trees, clumps will not always be mutually exclusive, thus making them more similar to families of trees.

bioinformatics↗

bioRxiv2024

Decreased BOLD signal variability in middle-aged and older adults on the Autism Spectrum

PurposeAutism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder. Preliminary evidence suggests an increased risk for accelerated or early-onset cognitive and neurological decline in ASD. While it is well established that brain development in children, adolescents and young adults with ASD diverges from neurotypical (NT) peers, it is unknown how brain function is impacted in older adults with ASD. Understanding age-related changes of brain function in ASD is crucial to establish best practices for cognitive and health screenings in adults with ASD and develop interventions that might reduce the risk of accelerated decline. Decreases in blood-oxygenation-level-dependent (BOLD) signal variability (BSV) in typical aging have been shown across multiple studies, likely reflecting declining Gamma-Aminobutyric Acid (GABA) activity, and is associated with poorer cognitive performance. We hypothesized that adults with ASD would show reduced BSV compared to the NT group, with steeper negative age associations in the ASD than NT group. MethodsThe study assessed BSV in a cohort of adults (40-70 years), 28 with ASD and 39 age-matched NT. General linear models tested for main effects of diagnostic group (ASD, NT), age and group-by-age interactions (controlling for RMSD). LimitationsOur cross-sectional data and small sample size highlight the need for longitudinal analyses in larger cohorts, alongside exploring links to cognitive function. Additionally, psychotropic medications used by our cohort of adults on the autism spectrum may have affected BSV. ResultsSignificant group-by-age interactions were observed for the right insular, left temporal occipital fusiform, right frontal orbital and right inferior lateral occipital cortex, with BSV showing strong negative associations with age in the ASD but not NT group. ConclusionThese findings suggest that BSV decreases may occur earlier in adults on the autism spectrum compared to their neurotypical peers, possibly indicating accelerated aging. However, given limited prior research, additional longitudinal analyses will be necessary to determine if the results presented truly reflect accelerated aging or arise from lifelong persistent differences in brain function.

neuroscience↗

bioRxiv2024

Large-scale genomic analysis of SARS-CoV-2 Omicron BA.5 emergence in the United States

The COVID-19 pandemic is marked by the continuing emergence of novel SARS-CoV-2 variants. Questions remain about the mechanisms with which these lineages establish themselves in new geographical areas. In this study, we performed a discrete phylogeographic analysis on [~]19,000 SARS-CoV-2 sequences of Omicron BA.5 lineages between February and June 2022 to better understand how it emerged in different regions of the United States (U.S.). We found that the earliest introductions came from Africa, the putative origin of the variant, but the majority were from Europe, correlating with the high volume of air travelers. Additionally, the analysis revealed extensive domestic transmission between different regions of the U.S. driven by population size and cross-country transmission. Results suggest that most of the within-U.S. spread was between three regions that include California, New York, and Florida. Our results form a framework for understanding novel SARS-CoV-2 variant emergence in the U.S.

genomics↗

bioRxiv2024

Residues 2-7 of alpha-synuclein regulate amyloid formation via lipid-dependent and -independent pathways

Amyloid formation by -synuclein (Syn) occurs in Parkinsons disease, multiple system atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate Syn amyloid fibril formation will not only provide mechanistic insight, but may also reveal new targets to prevent and treat disease. Previous investigations have identified several regions of Syn to be important in the regulation of amyloid formation, including the non-amyloid-{beta} component (NAC), P1 region (residues 36-42), and residues in the C-terminal domain. Recent studies have also indicated the importance of the N-terminal region of Syn for both its physiological and pathological roles. Here, the role of residues 2-7 in the N-terminal region of Syn are investigated in terms of their ability to regulate amyloid fibril formation in vitro and in vivo. Deletion of these residues (Syn{Delta}N7) slows the rate of fibril formation in vitro and reduces the capacity of the protein to be recruited by wild-type (SynWT) fibril seeds, despite cryo-EM showing a fibril structure consistent with those of full-length Syn. Strikingly, fibril formation of Syn{Delta}N7 is not induced by liposomes, despite the protein binding to liposomes with similar affinity to SynWT. A Caenorhabditis elegans model also showed that Syn{Delta}N7::YFP forms few puncta and lacks motility and lifespan defects typified by expression of SynWT::YFP. Together, the results demonstrate the involvement of residues 2-7 of Syn in amyloid formation, revealing a new target for the design of amyloid inhibitors that may leave the functional role of the protein in membrane binding unperturbed. Significance StatementAmyloid formation of -synuclein (Syn) is associated with Parkinsons disease. Attempts to target Syn aggregation to treat synucleinopathies, thus far, have been unsuccessful. A better understanding of residues that regulate amyloid formation may reveal new targets for therapeutics. Here, six residues at the N-terminus of Syn are identified as regulators of amyloid formation. Deletion of these residues slows lipid-independent assembly, ablates lipid-dependent amyloid formation in vitro, and prevents aggregation and its associated cellular toxicity in vivo. Importantly, these residues are not necessary for binding to synthetic membranes. The work reveals a new target for the prevention of synucleinopathies by disfavouring aggregation without perturbing membrane binding, a property considered to be essential for the physiological function of Syn at the synapse.

biophysics↗

bioRxiv2023

Phenology across scales: an intercontinental analysis of leaf-out dates in temperate deciduous tree communities

AimTo quantify the intra-community variability of leaf-out (ICVLo) among dominant trees in temperate deciduous forests, assess its links with specific and phylogenetic diversity, identify its environmental drivers, and deduce its ecological consequences with regard to radiation received and exposure to late frost. LocationEastern North America (ENA) and Europe (EUR). Time period2009-2022 Major taxa studiedTemperate deciduous forest trees. MethodsWe developed an approach to quantify ICVLo through the analysis of RGB images taken from phenological cameras. We related ICVLo to species richness, phylogenetic diversity and environmental conditions. We quantified the intra-community variability of the amount of radiation received and of exposure to late frost. ResultsLeaf-out occurred over a longer time interval in ENA than in EUR. The sensitivity of leaf-out to temperature was identical in both regions (-3.4 days per {degrees}C). The distributions of ICVLo were similar in EUR and ENA forests, despite the latter being more species-rich and phylogenetically diverse. In both regions, cooler conditions and an earlier occurrence of leaf-out resulted in higher ICVLo. ICVLo resulted in a ca. 8% difference of radiation absorption over spring among individual trees. Forest communities in ENA had shorter safety margins as regards the exposure to late frosts, and were actually more frequently exposed to late frosts. Main conclusionsWe conducted the first intercontinental analysis of the variability of leaf-out at the scale of tree communities. North American and European forests showed similar ICVLo, in spite of their differences in terms of species richness and phylogenetic diversity, highlighting the relevance of environmental controls on ICVLo. We quantified two ecological implications of ICVLo (difference in terms of radiation absorption and exposure to late frost), which should be explored in the context of ongoing climate change, which affects trees differently according to their phenological niche.

ecology↗

bioRxiv2022

The in-tissue molecular architecture of β-amyloid pathology in the mammalian brain.

Amyloid plaques composed of extracellular focal deposition of A{beta} fibrils are a hallmark of Alzheimers disease (AD). Cryo-EM structures of A{beta} fibrils purified from human AD brain tissue post mortem have recently been determined. However, the molecular architecture of amyloid plaques in the context of fresh, unfixed mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report the native, in situ molecular architecture of A{beta} fibrils in the brain of a mouse model containing the Arctic familial AD mutation (AppNL-G-F) and an atomic model of Arctic A{beta} fibril purified from the brains of these animals. We show that in-tissue A{beta} fibrils are arranged in a lattice or in parallel bundles within a plaque, and are interdigitated by subcellular compartments, exosomes, extracellular droplets and extracellular multilamellar bodies. At the atomic level, the Arctic A{beta} fibril differs significantly from earlier structures of A{beta} amyloid extracted from AppNL-F mice models and human AD brain tissue, showing a striking effect of the Arctic mutation (E22G) on fibril structure. Cryo-electron tomography of ex vivo purified and in-tissue amyloid revealed an ensemble of additional fibrillar species, including thin protofilament-like rods and branched fibrils. Together, these results provide a structural model for the dense network architecture that characterises {beta}-amyloid plaque pathology.

neuroscience↗

bioRxiv2022

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

Different tauopathies are characterized by specific amyloid filament folds that are conserved between patients. Disease-specific tau filament folds probably reflect the specific pathological contexts leading to their formation including isoforms or post-translational modifications. Little is known, however, as to whether and how intrinsic conformational tendencies of the tau sequence itself contribute to its polymorphism. Using cryo-EM structure determination we find that a short amyloidogenic C-terminal peptide consisting of residues 350-362 of the tau repeat domain adopts the same polymorphic conformations in isolation as it does in the context of major disease-associated protofilament folds. Biophysical characterisation and molecular modelling show that the amyloid conformations adopted by this peptide constitute core structural motifs stabilizing distinct disease-associated tau filament folds. In accordance this segment also contributes to the efficient propagation of human AD tau seeds in tau reporter cells while it is irrelevant to heparin-induced recombinant seeds. Our findings suggest that tau 350-362 is key to the propagation of disease-associated tau polymorphs and that the conformational preferences of this segment predispose to the topological diversity observed in tau filament folds.

biophysics↗

bioRxiv2022

Structures of RecBCD in complex with phage-encoded inhibitor proteins reveal distinctive strategies for evasion of a bacterial immunity hub

Following infection of bacterial cells, bacteriophage modulate double-stranded DNA break repair pathways to protect themselves from host immunity systems and prioritise their own recombinases. Here we present biochemical and structural analysis of two phage proteins, gp5.9 and Abc2, which target the DNA break resection complex RecBCD. These exemplify two contrasting mechanisms for control of DNA break repair in which the RecBCD complex is either inhibited or co-opted for the benefit of the invading phage. Gp5.9 completely inhibits RecBCD by preventing it from binding to DNA. The RecBCD-gp5.9 structure shows that gp5.9 acts by substrate mimicry, binding predominantly to the RecB arm domain and competing sterically for the DNA binding site. Gp5.9 adopts a parallel coiled-coil architecture that is unprecedented for a natural DNA mimic protein. In contrast, binding of Abc2 does not substantially affect the biochemical activities of isolated RecBCD. The RecBCD-Abc2 structure shows that Abc2 binds to the Chi-recognition domains of the RecC subunit in a position that might enable it to mediate the loading of phage recombinases onto its single-stranded DNA products.

biochemistry↗

bioRxiv2022

Caecilian genomes reveal molecular basis of adaptation and convergent evolution of limblessness in snakes and caecilians.

We present genome sequences for the caecilians Geotrypetes seraphini (3.8Gb) and Microcaecilia unicolor (4.7Gb), representatives of a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. More than 69% of both genomes are composed of repeats, with retrotransposons the most abundant. We identify 1,150 orthogroups which are unique to caecilians and enriched for functions in olfaction and detection of chemical signals. There are 379 orthogroups with signatures of positive selection on caecilian lineages with roles in organ development and morphogenesis, sensory perception and immunity amongst others. We discover that caecilian genomes are missing the ZRS enhancer of Sonic Hedgehog which is also mutated in snakes. In vivo deletions have shown ZRS is required for limb development in mice, thus revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.

evolutionary biology↗

bioRxiv2021

Polymorphism of Genetic Ambigrams

Double synonyms in the genetic code can be used as a tool to test competing hypotheses regarding ambigrammatic narnavirus genomes. Applying the analysis to recent observations of Culex narnavirus 1 and Zhejiang mosquito virus 3 ambigrammatic viruses indicates that the open reading frame on the complementary strand of the segment coding for RNA-dependent RNA polymerase does not code for a functional protein. Culex narnavirus 1 has been shown to possess a second segment, also ambigrammatic, termed Robin. We find a comparable segment for Zhejiang mosquito virus 3, a moderately diverged relative of Culex narnavirus 1. Our analysis of Robin polymorphisms suggests that its reverse open reading frame also does not code for a functional protein. We make a hypothesis about its role.

genomics↗

bioRxiv2021

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

immunology↗

bioRxiv2020

Towards complete and error-free genome assemblies of all vertebrate species

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are only available for a few non-microbial species1-4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling the most accurate and complete reference genomes to date. Here we summarize these developments, introduce a set of quality standards, and present lessons learned from sequencing and assembling 16 species representing major vertebrate lineages (mammals, birds, reptiles, amphibians, teleost fishes and cartilaginous fishes). We confirm that long-read sequencing technologies are essential for maximizing genome quality and that unresolved complex repeats and haplotype heterozygosity are major sources of error in assemblies. Our new assemblies identify and correct substantial errors in some of the best historical reference genomes. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an effort to generate high-quality, complete reference genomes for all ~70,000 extant vertebrate species and help enable a new era of discovery across the life sciences.

genomics↗

bioRxiv2019

An exploration of ambigrammatic sequences in narnaviruses

Narnaviruses have been described as positive-sense RNA viruses with a remarkably simple genome of [~] 3 kb, encoding only a highly conserved RNA-dependent RNA polymerase (RdRp). Many narnaviruses, however, are ambigrammatic and harbour an additional uninterrupted open reading frame (ORF) covering almost the entire length of the reverse complement strand. No function has been described for this ORF, yet the absence of stops is conserved across diverse narnaviruses, and in every case the codons in the reverse ORF and the RdRp are aligned. The > 3 kb ORF overlap on opposite strands, unprecedented among RNA viruses, motivates an exploration of the constraints imposed or alleviated by the codon alignment. Here, we show that only when the codon frames are aligned can all stop codons be eliminated from the reverse strand by synonymous single-nucleotide substitutions in the RdRp gene, suggesting a mechanism for de novo gene creation within a strongly conserved amino-acid sequence. It will be fascinating to explore what implications this coding strategy has for other aspects of narnavirus biology. Beyond narnaviruses, our rapidly expanding catalogue of viral diversity may yet reveal additional examples of this broadly-extensible principle for ambigrammatic-sequence development.

genomics↗

bioRxiv2019

Terasaki Spiral Ramps and Intracellular Diffusion

The sheet-like endoplasmic reticulum (ER) of eukaryotic cells has been found to be riddled with spiral dislocations, known as Terasaki ramps, in the vicinity of which the doubled bilayer membranes which make up ER sheets can be approximately modeled by helicoids. Here we analyze diffusion on a surface with locally helicoidal topological dislocations, and use the results to argue that the Terasaki ramps facilitate a highly efficient transport of water-soluble molecules within the lumen of the endoplasmic reticulum.

biophysics↗

bioRxiv2019

Persistent Features of Intermittent Transcription

Here we report statistical studies of single-cell mRNA counts from cells derived from different tissues of adult mice. By examining correlations between mRNA gene counts we find strong evidence that when genes are only observed in a small fraction of cells, this is as a consequence of intermittent transcription rather than of expression only in specialized cell types. Count statistics are used to estimate a peak transcription level for each gene, and a probability for the gene to be active in any given cell. We find that the peak transcription levels are approximately constant across different tissue types, but the gene expression probabilities may be markedly different. Both these quantities have very wide ranges of values, with a probability density function well approximated by a power law.\n\nAuthor summaryUsing evidence from single-cell mRNA counts, we argue that the expression of many genes in individual mouse cells is highly intermittent. Comparing cells from different tissues, we find that the peak activity of a given gene is approximately the same in all tissue types, whereas the probability of a gene being active can differ markedly.

genomics↗