Biology subjects

Collins, R.

Publications and source records attributed to Collins, R..

14 recordsLinked to original sources

bioRxiv2026

Persistent Malignant Stem Cells Drive Relapse After Transplantation in the Myelodysplastic Neoplasms

The myelodysplastic neoplasms (MDS) are initiated in hematopoietic stem cells (HSCs). Allogeneic transplantation is the only curative treatment, but relapse remains common. To detect rare MDS HSCs, we developed an ultra-low-input DNA sequencing assay and applied it to a multicenter post-transplant cohort. HSC mutation detection preceded relapse by a mean of 98 days and strongly predicted relapse (95.7% vs. 30.3%; hazard ratio, 8.8; P=1.5e-7). Mutations detected only in unfractionated marrow did not predict relapse. We developed methods to measure donor-host HSC chimerism, improving relapse prediction sensitivity. Single-cell protein, DNA, and RNA analyses with mitochondrial lineage tracing confirmed MDS cell enrichment within immunophenotypically- and transcriptionally-defined HSCs, identifying shared ribosomal gene downregulation and candidate mechanisms of venetoclax sensitivity. Venetoclax/azacytidine depleted detectable MDS HSCs in longitudinally evaluated patients. These findings establish that HSC mutation detection predicts post-transplant relapse, provide a rationale for preemptive intervention, and define shared biological features of transplant-resistant MDS HSCs.

cancer biology↗

bioRxiv2026

Giant viruses encode vitamin K-based redox modules for lipid modification

Viruses with large DNA genomes often carry auxiliary metabolic genes that reprogram host physiology, yet their contributions to host redox and membrane homeostasis remains poorly understood. Here we report the discovery and functional reconstitution of viral homologs of vitamin K epoxide reductase (VKOR) encoded by giant viruses. Using phylogenetic and genomic context analysis, we find that viral VKOR genes are frequently located adjacent to {gamma}-carboxylase-like epoxidase and fatty acid desaturase domains, consistent with a putative modular redox pathway for membrane lipid modification. To investigate their function, we expressed viral VKORs in an Escherichia coli strain lacking disulfide bond-forming enzymes and examined both their membrane topology and activity. Remarkably, a minimal set of residue substitutions enabled proper membrane insertion and restored bacterial motility, demonstrating that viral VKORs are catalytically competent electron shuttles. Structural modeling supports their integration into the endoplasmic reticulum-like environment in the host. Finally, we show that VKORs and {gamma}-carboxylase-like epoxidase-desaturases from Fadolivirus and Yasminevirus giant viruses are expressed during infection of Vermamoeba vermiformis, where they may couple vitamin K epoxidation to desaturation-driven lipid remodeling. These findings expand the known functional repertoire of giant viruses and uncover a previously unrecognized viral strategy for manipulating host redox metabolism and membrane composition. Significance statementViruses with large DNA genomes often encode metabolic enzymes that reshape host physiology, yet their ability to control host redox and membrane composition has remained unclear. We discovered that giant viruses encode a vitamin K epoxide reductase and associated enzymes that together form a putative redox module for lipid remodeling. We reconstituted viral VKOR activity in E. coli, demonstrating that these enzymes are catalytically active. We also detected their expression, at the RNA and protein levels, during amoebal infection by two giant viruses. Our findings reveal a previously unrecognized viral strategy for coupling vitamin K redox cycling to fatty acid desaturation. This work broadens our understanding of how giant viruses manipulate host redox homeostasis and membrane architecture during infection.

microbiology↗

bioRxiv2025

The tissue specificity of cancer genes

Defining genes that are somatically mutated in different cancers is a central goal of cancer genetics. Nevertheless, traditional definitions of "driver" genes based on pooled mutation frequency are biased toward common cancer types and tend to overlook genes that might be specific to rarer subtypes. As such, our understanding of the compendium of cancer genes is incomplete. In this study, we developed a statistical framework that defines genes enriched for functional somatic mutations in primary cancers to quantify incidence and tissue specificity for each gene. By applying this framework to the AACR GENIE v18.0 dataset, which comprised over 1.15 million mutations identified in 146,394 patients spanning 265 histologic subtypes, we identified a total of 95 genes significantly mutated in at least one subtype. We mined this dataset to derive tissue specificity scores for all 95 genes, demonstrating that tissue specificity in cancer is the norm, not the exception, for nearly all genes. We interrogated these new tissue specificity scores to reveal that oncogenes with restricted expression across normal tissues tend to exhibit higher tissue-specific mutation patterns in cancer. In contrast, tumor suppressors were often ubiquitously expressed irrespective of their underlying tissue specificity, which was partially correlated with differentially expressed compensatory genes and pathways in mutationally permissive tissues. Significance StatementWe present a statistically robust, subtype-aware framework to identify tissue-specific cancer driver genes and uncover their underlying biology. Our findings reveal that tissue-selective oncogenicity arises from expression constraints and tissue-restricted compensatory pathways. These findings provide a systematic, well-powered resource on mutational significance, tissue tropism, and biological consequences for the cancer research community.

cancer biology↗

bioRxiv2025

Disulfide bonds are required for cell division, cell envelope biogenesis and antibiotic resistance proteins in mycobacteria

Mycobacteria, including Mycobacterium tuberculosis--the etiological agent of tuberculosis--have a unique cell envelope critical for their survival and resistance. The cell envelopes assembly and maintenance influence permeability, making it a key target against multidrug-resistant strains. Disulfide bond (DSB) formation is crucial for the folding of cell envelope proteins. The DSB pathway in mycobacteria includes two enzymes, DsbA and VKOR, required for survival. Using bioinformatics and cysteine profiling proteomics, we identified cell envelope proteins dependent on DSBs. We validated via in vivo alkylation that key proteins like LamA (MmpS3), PstP, LpqW, and EmbB rely on DSBs for stability. Furthermore, chemical inhibition of VKOR results in phenotypes similar to those of {Delta}vkor. Thus, targeting DsbA-VKOR systems could compromise both cell division and mycomembrane integrity. These findings emphasize the potential of DSB inhibition as a novel strategy to combat mycobacterial infections.

microbiology↗

bioRxiv2024

The structural organisation of pentraxin-3 and its interactions with heavy chains of inter-alpha-inhibitor regulate crosslinking of the hyaluronan matrix

Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) of the inter--inhibitor (II) family of proteoglycans are covalently attached, playing a key role in the (non-covalent) crosslinking of HC*HA complexes. These interactions stabilise the cumulus matrix, essential for ovulation and fertilisation in mammals, and are also implicated in the formation of pathogenic matrices in the context of viral lung infections. To better understand the physiological and pathological roles of PTX3 we have analysed how its quaternary structure underpins HA crosslinking via its interactions with HCs. A combination of X-ray crystallography, cryo-electron microscopy (cryo-EM) and AlphaFold predictive modelling revealed that the C-terminal pentraxin domains of the PTX3 octamer are arranged in a central cube, with two long extensions on either side, each formed from four protomers assembled into tetrameric coiled-coil regions, essentially as described by (Noone et al., 2022; doi:10.1073/pnas.2208144119). From crystallography and cryo-EM data, we identified a network of inter-protomer salt bridges that facilitate the assembly of the octamer. Small angle X-ray scattering (SAXS) validated our model for the octameric protein, including the analysis of two PTX3 constructs: a tetrameric Half-PTX3 and a construct missing the 24 N-terminal residues ({Delta}1-24-PTX3). SAXS determined a length of [~]520 [A] for PTX3 and, combined with 3D variability analysis of cryo-EM data, defined the flexibility of the N-terminal extensions. Biophysical analyses revealed that the prototypical heavy chain HC1 does not interact with PTX3 at pH 7.4, consistent with our previous studies showing that, at this pH, PTX3 only associates with HC*HA complexes if they are formed in its presence. However, PTX3 binds to HC1 at acidic pH, and can also be incorporated into pre-formed HC*HA complexes under these conditions. This provides a novel mechanism for the regulation of PTX3-mediated HA crosslinking (e.g., during inflammation), likely mediated by a pH-dependent conformational change in HC1. The PTX3 octamer was found to associate simultaneously with up to eight HC1 molecules and, thus, has the potential to form a major crosslinking node within HC*HA matrices, i.e., where the physical and biochemical properties of resulting matrices could be tuned by the HC/PTX3 composition.

biochemistry↗

bioRxiv2023

A deep catalog of protein-coding variation in 985,830 individuals

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.

genetics↗

bioRxiv2022

Cloud gazing: demonstrating paths for unlocking the value of cloud genomics through cross-cohort analysis

The rapid growth of genomic data has led to a new research paradigm where data are stored centrally in Trusted Research Environments (TREs) such as the All of Us Researcher Workbench (AoU RW) and the UK Biobank Research Analysis Platform (RAP). To characterize the advantages and drawbacks of different TRE attributes in facilitating cross-cohort analysis, we conducted a Genome-Wide Association Study (GWAS) of standard lipid measures on the UKB RAP and AoU RW using two approaches: meta-analysis and pooled analysis. We curated lipid measurements for 37,754 All of Us participants with whole genome sequence (WGS) data and 190,982 UK Biobank participants with whole exome sequence (WES) data. For the meta-analysis, we performed a GWAS of each cohort in their respective platform and meta-analyzed the results. We separately performed a pooled GWAS on both datasets combined. We identified 490 and 464 significant variants in meta-analysis and pooled analysis, respectively. Comparison of full summary data from both meta-analysis and pooled analysis with an external study showed strong correlation of known loci with lipid levels (R2[~]83-97%). Importantly, 90 variants met the significance threshold only in the meta-analysis and 64 variants were significant only in pooled analysis. These method-specific differences may be explained by differences in cohort size, ancestry, and phenotype distributions in All of Us and UK Biobank. We noted approximately 20% of variants significant in only the pooled analysis or significant in only the meta-analysis were most prevalent in non-European, non-Asian ancestry individuals. Pooled analyses included more variants than meta-analyses. Pooled analysis required about half as many computational steps as meta-analysis. These findings have important implications for both platform implementations and researchers undertaking large-scale cross-cohort analyses, as technical and policy choices lead to cross-cohort analyses generating similar, but not identical results, particularly for non-European ancestral populations.

genetics↗

bioRxiv2022

Genotyping, sequencing and analysis of 140,000 adults from the Mexico City Prospective Study

The Mexico City Prospective Study (MCPS) is a prospective cohort of over 150,000 adults recruited two decades ago from the urban districts of Coyoacan and Iztapalapa in Mexico City. We generated genotype and exome sequencing data for all individuals, and whole genome sequencing for 10,000 selected individuals. We uncovered high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Native American, European and African ancestry, with extensive admixture from indigenous groups in Central, Southern and South Eastern Mexico. Native Mexican segments of the genome had lower levels of coding variation, but an excess of homozygous loss of function variants compared with segments of African and European origin. We estimated population specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Native Mexico at exome variants, all available via a public browser. Using whole genome sequencing, we developed an imputation reference panel which outperforms existing panels at common variants in individuals with high proportions of Central, South and South Eastern Native Mexican ancestry. Our work illustrates the value of genetic studies in populations with diverse ancestry and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States where the Hispanic/Latino population is predominantly of Mexican descent.

genetics↗

bioRxiv2022

A genome-wide mutational constraint map quantified from variation in 76,156 human genomes

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders, but attempts to assess constraint for non-protein-coding regions have proven more difficult. Here we aggregate, process, and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD), the largest public open-access human genome reference dataset, and use this dataset to build a mutational constraint map for the whole genome. We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation across the genome. As expected, proteincoding sequences overall are under stronger constraint than non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association, and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, while non-coding constraint captures additional functional information underrecognized by gene constraint metrics. We demonstrate that this genome-wide constraint map provides an effective approach for characterizing the non-coding genome and improving the identification and interpretation of functional human genetic variation.

genetics↗

bioRxiv2021

Citizen-science surveillance of triazole-resistant Aspergillus fumigatus in UK residential garden soils

Compost is an ecological niche for Aspergillus fumigatus due to its role as a decomposer of organic matter and its ability to survive the high temperatures associated with the composting process. Subsequently, composting facilities are associated with high levels of A. fumigatus spores that are aerosolised from compost and cause respiratory illness in workers. In the UK, gardening is an activity enjoyed by individuals of all ages and it is likely that they are being exposed to A. fumigatus spores when handling commercial compost or compost they have produced themselves. In this study, 246 citizen scientists collected 509 soil samples from locations in their garden in the UK, from which were cultured 5,174 A. fumigatus isolates. Of these isolates, 736 (14%) were resistant to tebuconazole: the third most-sprayed triazole fungicide in the UK, which confers cross-resistance to the medical triazoles used to treat A. fumigatus lung infections in humans. These isolates were found to contain the common resistance mechanisms in the A. fumigatus cyp51A gene TR34/L98H or TR46/Y121F/T289A, and less common resistance mechanisms TR34, TR53, TR46/Y121F/T289A/S363P/I364V/G448S and (TR46)2/Y121F/M172I/T289A/G448S. Regression analyses found that soil samples containing compost were significantly more likely to grow susceptible and tebuconazole-resistant A. fumigatus than those that did not, and that compost samples grew significantly higher numbers of A. fumigatus than other samples. ImportanceThese findings highlight compost as a potential health hazard to individuals with pre-disposing factors to A. fumigatus lung infections, and a potential health hazard to immunocompetent individuals who could be exposed to sufficiently high numbers of spores to develop infection. This raises the question of whether compost bags should carry additional health warnings regarding inhalation of A. fumigatus spores, whether individuals should be advised to wear facemasks whilst handling compost or whether commercial producers should be responsible for sterilising compost before shipping. The findings support increasing public awareness of the hazard posed by compost and investigating measures that can be taken to reduce the exposure risk.

microbiology↗

bioRxiv2020

Wasp controls oriented migration of endothelial cells to achieve functional vascular patterning

Endothelial cell migration and proliferation are essential for the establishment of a hierarchical organization of blood vessels and optimal distribution of blood. However, how these cellular processes are coordinated remains unknown. Here, using the zebrafish trunk vasculature we show that in future veins endothelial cells proliferate more than in future arteries and migrate preferentially towards neighboring arteries. In future arteries endothelial cells show a biphasic migration profile. During sprouting cells move away from the dorsal aorta, during remodelling cells stop or move towards the feeding aorta. The final morphology of blood vessels is thus established by local proliferation and oriented cell migration to and from neighboring vessels. Additionally, we identify WASp to be essential for this differential migration. Loss of WASp leads to irregular distribution of endothelial cells, substantially enlarged veins and persistent arteriovenous shunting. Mechanistically, we report that WASp drives the assembly of junctional associated actin filaments and is required for junctional expression of PECAM-1. Together, our data identify that functional vascular patterning in the zebrafish trunk utilizes differential cell movement regulated by junctional actin, and that interruption of differential migration may represent a pathomechanism in vascular malformations.

developmental biology↗

bioRxiv2019

Avian influenza virus (A/H3N8) with a putative mammalian-adaptive mutation found in a stranded grey seal pup (Halichoerus grypus) rescued on the Cornwall coast, UK

Avian Influenza A Viruses (IAV) in different species of seals display a spectrum of pathogenicity, from subclinical infection to mass mortality events. Here we present an investigation of avian IAV infection in a 3-4 month old Grey seal (Halichoerus grypus) pup, rescued from St Michaels Mount, Cornwall in 2017. The pup underwent medical treatment but died after two weeks; post-mortem examination and histology indicated sepsis as the cause of death. IAV NP antigen was detected by immunohistochemistry in the nasal mucosa, and sensitive real-time reverse transcription polymerase chain reaction assays detected trace amounts of viral RNA within the lower respiratory tract, suggesting that the infection may have been cleared naturally. IAV prevalence among Grey seals may therefore be underestimated. Moreover, contact with humans during the rescue raised concerns about potential zoonotic risk. Nucleotide sequencing revealed the virus to be of subtype H3N8. Combining a GISAID database BLAST search and time-scaled phylogenetic analyses, we inferred that the seal virus originated from an unsampled, locally circulating (in Northern Europe) viruses, likely from wild Anseriformes. From examining the protein alignments, we found several residue changes in the seal virus that did not occur in the bird viruses, including D701N in the PB2 segment, a rare mutation, and a hallmark of mammalian adaptation of bird viruses. IAVs of H3N8 subtype have been noted for their particular ability to cross the species barrier and cause productive infections, including historical records suggesting that they may have caused the 1889 pandemic. Therefore, infections such as the one we report here may be of interest to pandemic surveillance and risk and may help us better understand the determinants and drivers of mammalian adaptation in influenza.

microbiology↗

bioRxiv2019

Functional annotation of rare structural variation in the human brain

Structural variants (SVs) contribute substantially to risk of many brain related disorders including autism and schizophrenia. However, annotating the potential contribution of SVs to disease remains a major challenge. Here, we integrated high resolution SV calling from genome-sequencing in 755 human post-mortem brains with dorsal lateral prefrontal cortex RNA-sequencing from a subset of 629 samples to quantify the dosage and regulatory effects of SVs. We show that genic (p = 5.44x10-9) and regulatory SVs (enhancer p = 3.22x10-23, CTCF p = 3.86x10-18) are present at significantly lower frequencies than intergenic SVs after correcting for SV length. Copy number variants (CNVs)--deletions and duplications--exhibit a significant quantitative and directional relationship between the proportion of genic and regulatory content altered and gene expression, and the size of the effect is inversely correlated with the loss-of-function intolerance of the gene. We trained a joint linear model that leverages genic and regulatory annotations to predict expression effects of rare CNVs in independent samples (R2 = 0.21-0.41). We further developed a regulatory disruption score for each CNV that aggregates the predicted expression across all affected genes weighted by the genes intolerance score and applied it to an independent set of SVs from 14,891 genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders by ClinGen had significantly more extreme regulatory disruption scores than the rest of the SVs. Rank ordering based on the most extreme regulatory disruption scores prioritized pathogenic deletions that would not have been prioritized by frequency or length alone. This work points to the deleteriousness of regulatory SVs, particularly those altering CTCF sites. We further provide a simple approach for functionally annotating the regulatory effects of SVs in the human brain that has potential to be useful in larger SV studies and should improve as more regulatory annotation data is generated.

genomics↗

bioRxiv2019

Revised subunit order of mammalian septin complexes explains their in vitro polymerization properties

Septins are conserved GTP-binding cytoskeletal proteins that polymerize into filaments by end-to-end joining of heterooligomeric complexes. In human cells, both hexamers and octamers exist, and crystallography studies predicted the order of the hexamers to be SEPT7-SEPT6-SEPT2-SEPT2-SEPT6-SEPT7, while octamers are thought to have the same core, but with SEPT9 at the ends. However, based on this septin organization, octamers and hexamers would not be expected to co-polymerize due to incompatible ends. Here we isolated hexamers and octamers of specific composition from human cells and show that hexamers and octamers polymerize individually and, surprisingly, with each other. Binding of Borg3 results in distinctive clustering of each filament type. Moreover, we show that the organization of hexameric and octameric complexes is inverted compared to its original prediction. This revised septin organization is congruent with the organization and behavior of yeast septins suggesting that their properties are more conserved than was previously thought.

cell biology↗