Biology subjects

Morris, A.

Publications and source records attributed to Morris, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Intranucleolar Invasion of Cajal Body Remnants Suppresses Ribosomal Biogenesis in cis and Telomerase Functions in trans

Cellular processes are compartmentalized within immiscible heterotypic condensates, yet the functional consequences of losing their physical segregation remain unclear. Here, we show that genetic inactivation of the RNA chaperone SMN forces the aberrant intermixing of the two most prominent nuclear condensates: nucleolus and Cajal Body (CB). Upon SMN depletion, CB components invade the nucleolus and undergo reduced mobility and solubility consistent with a liquid-to-gel-like hardening transition. The CB-scaffold coilin aberrantly enriches at the nucleolar FC/DFC boundary and occupies rDNA chromatin, thereby locally suppressing rRNA production. Concurrently, this sequestration globally impairs coilin targeting to snRNA/snoRNA loci and limits telomerase access to telomeres, reducing telomeric synthesis. Crucially, genetic coilin depletion alone alleviates this mistargeting and rescues these functional impairments across condensates. Our findings reveal an inter-condensate rheostat model in which the loss of CB-nucleolar immiscibility is directly sensed, communicated, and executed by CB remnants, thereby proportionally coupling the functional outputs of otherwise distinct RNPs essential for splicing, translation, and genomic integrity.

molecular biology↗

bioRxiv2026

Patterns of association between mothers and offspring and their outcomes in a polygynous ungulate

Prolonged association between mothers and their offspring is common in ungulates, with the level of maternal investment likely to play a central role in shaping this trait. Here we examined patterns of association between mothers and offspring over time, the apparent benefits of association to offspring, and costs to mothers. We analyzed 40 years worth of census data from an individually-monitored, food-limited population of red deer (Cervus elaphus) on the Isle of Rum, Scotland. Starting from birth, female calves associated more frequently with their mothers than male calves in their first year. Calves also associated less with their mothers if the mother did not conceive a new calf. Association frequency decreased with mothers age and population density, and survival over the first year was not related to mother-calf association. Yearlings, now in their second year, were more often associated with their mothers if they were female, if there was no subsequent calf (or the subsequent calf died as a neonate), and if they were still being suckled. Increased association between mothers and yearlings was associated with increased survival to adulthood at 28 months, but suckling a yearling did not improve its probability of survival. For individuals that reached maturity, increased association in the yearling year was associated with slightly shorter adult life spans. The level of association between a calf and mother was not associated with the mothers immediate survival or fecundity. Our findings suggest that juveniles born to poor-condition mothers benefit from prolonged association through improved yearling survival.

animal behavior and cognition↗

bioRxiv2026

Fitness costs of parasitism depend on fine-scale density and resource availability in a wild ungulate

Resource competition and parasite exposure both present common density-dependent fitness costs for wild animals. Because launching effective immune responses is costly in terms of resources, parasites fitness costs should be further exacerbated in high-density, resource-depleted areas. To disentangle these relationships, we related density, parasitism, and resource availability to survival and fecundity across lifespan in a long-term study of wild red deer. All fitness measures declined with a combination of parasite count, greater density, and reduced resource availability. Beyond these relationships, as expected, local density and resource scarcity exacerbated survival costs of parasitism in calves, effectively undermining tolerance of infection. However, these synergistic relationships faded in yearlings and then reversed in adults, likely through age-structured selection biases. These findings emphasize that the costs of parasites and resource scarcity can be synergistic and intertwined with density in wild populations, accentuating the value of incorporating resource competition when examining parasite-dependent population regulation.

ecology↗

bioRxiv2025

Multi-ancestry fine-mapping accounting for ancestral and environmental heterogeneity improves resolution and interpretation

Amongst genome-wide association studies (GWAS) across diverse populations, allelic effect heterogeneity may arise due to differences in genetic ancestry and environmental exposures. This heterogeneity impacts the refinement of sets of potential causal variants underlying genetic associations through statistical fine-mapping. We introduce two multi-ancestry fine-mapping methods, MR-MEGAfm and env-MR-MEGAfm, allowing for multiple causal variants in a genomic region. Both methods integrate GWAS summary statistics and differing linkage disequilibrium from multiple cohorts; env-MR-MEGAfm additionally incorporates summary-level environmental covariates. Through simulations, we show that, when allelic heterogeneity is correlated with environmental exposures and ancestry, env-MR-MEGAfm yields improved resolution over MR-MEGAfm and similar resolution to SuSiEx. In twelve sex-stratified African GWAS of low-density lipoprotein cholesterol in 19,589 individuals, MR-MEGAfm and env-MR-MEGAFM (adjusting for urban status) identify five variants with posterior probability > 0.5 within two loci. One variant showed heterogeneity only due to ancestry, while three showed heterogeneity due only to urban status.

genetics↗

bioRxiv2025

Description of Gopheromyces tardescens, gen. nov., sp.nov., Gigasporangiomyces pilosus, gen. nov., sp.nov., Kelyphomyces adhaerens, gen. nov., sp. nov., proposal of Testudinimycetales ord. nov. and Testudinimycetaceae fam. nov., and emended description of the order Neocallimastigales.

Anaerobic gut fungi (AGF, Neocallimastigomycota) represent a phylum of zoospore-producing fungi inhabiting the gastrointestinal tracts of herbivores. Twenty mammalian-affiliated genera (M-AGF) and two tortoise-affiliated genera (T-AGF) have been described so far. Here, we report on three additional novel T-AGF isolates obtained from Texas and sulcata tortoises. Phylogenetic analysis using the D1-D2 regions of the large ribosomal RNA subunit (D1-D2 LSU), RNA polymerase II large subunit (RPB1), internal transcribed spacer-1 region (ITS1), and transcriptomics-enabled phylogenomic analysis clustered these strains into three distinct, deep-branching clades, closely related to previously described T-AGF genus Testudinimyces. All isolates displayed filamentous rhizoidal growth patterns and produced monoflagellated zoospores. Unique morphological characteristics included the production of elongated, thick, nucleated structures in GX isolates, the formation of thin hair-like projections on sporangial walls in SR isolates, and irregularly shaped sporangia in TM isolates. All strains grew optimally at 32-35 {degrees}C and showed distinct substrate utilization capacity (e.g., growth on pectin, chitin, galactose). LSU analyses revealed GX isolates as the first cultured representatives of tortoise-affiliated but previously uncultured lineage NY56, while SR and TM strains have not been encountered in prior culture-independent AGF surveys. We propose to accommodate these isolates in three new genera and species - Gopheromyces tardescens (GXA2), Gigasporangiomyces pilosus (SR0.6), and Kelyphomyces adhaerens (TM0.3). Further, based on the ecological, physiological, and phylogenetic distinctions between T-AGF and M-AGF, we propose to establish a new family (Testudinimycetaceae) to accommodate the genera Testudinimyces, Gopheromyces, Gigasporangiomyces, and Kelyphomyces, within a new order (Testudinimycetales), and amend the description of Neocallimastigales to circumscribe M-AGF genera only.

microbiology↗

bioRxiv2025

Fbxl10/Kdm2b is required for Kmt2b/Mll2 binding across thegenome and regulates H3K4 methylation on bivalent promoters

The presence of histone modifications associated with both transcriptional repression (H3K27me3) and activation (H3K4me3) on key developmental promoters in embryonic stem cells results from the co-localization of repressive Polycomb group (PcG) and activating Trithorax group (TrxG) protein complexes. Functional interactions between PcG and TrxG on these promoters are not fully understood. Here we focus on the relationships between Fbxl10/Kdm2b, a component of a PcG complex PRC1, and Kmt2b/Mll2, an essential component of TrxG at bivalent promoters. Computational analysis of previously published data revealed genome-wide correlation between chromatin occupancies of these two proteins, suggesting potential crosstalk between Kdm2b and Mll2 at both active and repressed promoters. We tested this hypothesis experimentally and found that loss of Kdm2b resulted in depletion of Mll2 at promoters genome-wide, suggesting that Kdm2b is required for Mll2 occupancy at both bivalent and active promoters. Loss of Kdm2b or the core PRC1 component Ring1b also resulted in the reduction of H3K4me3 specifically at bivalent promoters. These findings provide a direct pathway for cooperation between PcG and TrxG at bivalent promoters, suggesting an unexpected modification to the current model of bivalency. In addition, these findings reveal genome-wide role of Kdm2b independent of the full PRC1 complex.

molecular biology↗

bioRxiv2025

Parasite-mediated inbreeding depression in wild red deer

Inbreeding depression is the reduction in fitness of inbred individuals relative to their more outbred counterparts. Parasitism also reduces fitness and is a route by which inbreeding depression may operate, yet the complete pathway from inbreeding to parasitism to fitness has almost never been documented in the wild. Using high-quality, individual-level data on fitness in juveniles and adult females, longitudinal infection data for three gastrointestinal helminth parasites, and genomic inbreeding coefficients we test for parasite-mediated inbreeding depression in a wild ungulate population (red deer, Cervus elaphus). We found evidence for parasite-mediated inbreeding depression via strongyle nematodes in juvenile survival, independent of direct adverse effects of inbreeding on survival and indirect effects of inbreeding on survival via birth weight. Inbreeding also reduced fitness in reproductive adults by reducing overwinter survival. Our study reveals three independent pathways by which inbreeding depresses fitness and highlights the rarely-studied route of parasitism.

ecology↗

bioRxiv2024

SenSet, a novel human lung senescence cell gene signature, identifies cell-specific senescence mechanisms

Cellular senescence is a major hallmark of aging. Senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors including DNA damage, oxidative stress, or nutrient deprivation. While senescence is a well-established driver of aging and age-related diseases, it is a highly heterogeneous process with significant variations across organisms, tissues, and cell types. The relatively low abundance of senescence in healthy aged tissues represents a major challenge to studying senescence in a given organ, including the human lung. To overcome this limitation, we developed a Positive-Unlabeled (PU) learning framework to generate a comprehensive senescence marker gene list in human lungs (termed SenSet) using the largest publicly available single-cell lung dataset, the Human Lung Cell Atlas (HLCA). We validated SenSet in a highly complex ex vivo human 3D lung tissue culture model subjected to the senescence inducers bleomycin, doxorubicin, or irradiation, and established its sensitivity and accuracy in characterizing senescence. Using SenSet, we identified and validated cell-type specific senescence signatures in distinct lung cell populations upon aging and environmental exposures. Our study presents the first comprehensive analysis of senescent cells in the healthy aging lung and uncovers cell-specific gene signatures of senescence, presenting fundamental implications for our understanding of major lung diseases, including cancer, fibrosis, chronic obstructive pulmonary disease, or asthma.

genomics↗

bioRxiv2024

Population density drives increased parasitism via greater exposure and reduced resource availability in wild hosts

Exposure to environmental parasites should increase with host population density due to the accumulation of infective parasites in space. However, competition for resources also increases with density, lowering condition and increasing susceptibility, which offers an alternative pathway for density-dependent infection to act. To test how these two processes act independently or together to drive greater parasite counts, we used a long-term study of red deer to examine associations between host density, resource availability, and counts of three common helminth parasites. We found that greater density correlated with reduced resource availability, and while density was positively associated with both strongyle and tissue worm burdens, resource availability was independently and negatively associated with the same burdens, supporting separate roles of density-dependent exposure and susceptibility in driving infection. This study provides evidence that competition for resources is an important driver of infection in higher-density areas, exacerbating the effects of density-dependent increases in exposure.

ecology↗

bioRxiv2024

PITPβ promotes COPI vesicle fission through lipid transfer and membrane contact formation

Intracellular transport among organellar compartments occurs in two general ways, by membrane-bound carriers or membrane contacts. Specific circumstances that involve the coordination of these two modes of transport remain to be defined. Studying Coat Protein I (COPI) transport, we find that phosphatidylcholine with short acyl chains (sPC) is delivered through membrane contact from the endoplasmic reticulum (ER) to sites of COPI vesicle formation at the Golgi to support the fission stage. Phosphatidylinositol transfer protein beta (PITP{beta}) plays a key role in this process, with the elucidation of this role advancing a new understanding of how PITP{beta} acts, providing a mechanistic understanding of a specific circumstance when vesicular transport requires membrane contact, and contributing to a basic understanding of how transport carriers in a model intracellular pathway are formed. SummarySpecific circumstances that membrane contact is needed for vesicular transport remain to be defined. We find that a critical lipid is delivered through membrane contact to support the fission stage of a model intracellular transport pathway.

cell biology↗

bioRxiv2024

Accounting for heterogeneity due to environmental sources in meta-analysis of genome-wide association studies

Meta-analysis of genome-wide association studies (GWAS) across diverse populations offers power gains to identify loci associated with complex traits and diseases. Often heterogeneity in effect sizes across populations will be correlated with genetic ancestry and environmental exposures (e.g. lifestyle factors). We present an environment-adjusted meta-regression model (env-MR-MEGA) to detect genetic associations by adjusting for and quantifying environmental and ancestral heterogeneity between populations. In simulations, env-MR-MEGA had similar or greater association power than MR-MEGA, with notable gains when the environmental factor had a greater correlation with the trait than ancestry. In our analysis of low-density lipoprotein cholesterol in [~]19,000 individuals across twelve sex-stratified GWAS from Africa, adjusting for sex, BMI, and urban status, we identified additional heterogeneity beyond ancestral effects for nine variants. Env-MR-MEGA provides an approach to account for environmental effects using summary-level data, making it a useful tool for meta-analyses without the need to share individual-level data.

genetics↗

bioRxiv2024

Oral bioavailability of a noncoding RNA drug, TY1, that acts on macrophages

All approved RNA therapeutics require parenteral delivery. Here we demonstrate an orally bioavailable formulation wherein synthetic noncoding (nc) RNA, packaged into lipid nanoparticles, is loaded into casein-chitosan (C2) micelles. We used the C2 formulation to deliver TY1, a 24-nucleotide synthetic ncRNA which targets the DNA damage response pathway in macrophages. C2-formulated TY1 (TY1C2) efficiently packages and protects TY1 against degradative enzymes. In healthy mice, oral TY1C2 was well-tolerated and nontoxic. Oral TY1C2 exhibited disease-modifying bioactivity in 2 models of tissue injury: 1) rat myocardial infarction, where a single oral dose of TY1C2 was cardioprotective, on par with intravenously-delivered TY1; and 2) mouse acute lung injury, where a single dose of TY1C2 attenuated pulmonary inflammation. Mechanistic dissection revealed that TY1C2 is not absorbed into the systemic circulation but is, instead, taken up by intestinal macrophages, namely those of the lamina propria and Peyers patches. This route of absorption may rationalize why an antisense oligonucleotide against Factor VII, which acts on hepatocytes, is not effective when administered in the C2 formulation. Thus, some (but not all) ncRNA drugs are bioavailable when delivered by mouth. Oral RNA delivery and uptake, relying on uptake via the gastrointestinal immune system, has broad-ranging therapeutic implications. Graphical AbstractOral TY1C2 is taken up in the small intestine mainly by macrophages of the lamina propria and the Peyers patches. Macrophages that have taken up oral TY1C2 mediate disease-modifying bioactivity in 2 animal models of acute tissue injury. The blue + denotes the as-yet-uncertain mechanisms/mediators linking TY1 gut uptake to the drugs systemic therapeutic benefits. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/591474v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@8bfffdorg.highwire.dtl.DTLVardef@15379e5org.highwire.dtl.DTLVardef@167e9aaorg.highwire.dtl.DTLVardef@11dd317_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

FLASH Irradiation Regulates IFN-β induction by mtDNA via Cytochrome c Leakage

Ultrahigh dose rate radiotherapy (FLASH-RT) is under intensive investigation for its biological benefits. The mechanisms underlying its ability to spare normal tissues while suppress tumor growth still remain controversial. Here we reveal that compared to the low dose rate electron irradiation (0.36 Gy/s), FLASH electron irradiation at 61 or 610 Gy/s enhances the cytochrome c leakage from mitochondria in human breast cells MCF-10A, which elicits substantial caspase activation, suppresses both the cytosolic mitochondrial DNA (mtDNA) accumulation and IFN-{beta} secretion. Besides, the deletion of mtDNA severely decreases the radiation-induced cGAS-STING activation. Conversely, the cytochrome c leakage in carcinoma cells MDA-MB-231 post electron irradiation is limited, especially for the case of FLASH irradiation, resulting in less cytosolic cytochrome c but stronger cGAS-STING activation than those in MCF-10A cells. The enhanced difference of cytochrome c leakage between cancer cells and normal cells post FLASH irradiation indicates a potential mechanism of FLASH effect by regulating the apoptotic and inflammatory pathway.

biophysics↗

bioRxiv2024

Leukemia aggressiveness is driven by chromatin remodeling and expression changes of core regulators

Mechanisms driving the increase of cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed towards increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in leukemic cells. Public patient data confirmed expression levels of IRX5 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.

molecular biology↗

bioRxiv2023

The incidence of movement disorders increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.

Argininosuccinate lyase is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide biosynthesis cycle. Inherited argininosuccinate lyase deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonaemia and nitric oxide deficiency. Patients present with developmental delay, epilepsy and movement disorders, associated with nitric oxide-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for movement disorders-related symptoms: movement disorders such as ataxia, tremor and dystonia, hypotonia and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an ASA patient with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appears in the 2nd and 3rd decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonaemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorders with functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy. SynopsisMovement disorders-related symptoms in ASA appear in the 2nd and 3rd decades of life, becoming more prevalent with age and shows abnormal neuroimaging features of basal ganglia in ASA patients, not recapitulated in ASA mice.

genetics↗

bioRxiv2023

The Lion's Share: Implications of carnivore diet on endangered herbivores in Tsavo

Predation by mammalian carnivores can have cascading, regulatory effects across ecological communities. An understanding of predator diet can therefore provide crucial information regarding their ecology and conservation, as well as their impacts on prey populations. Using scats collected between 2019 and 2023, coupled with estimates of prey abundance from aerial surveys, we characterized lion prey-consumption and preference in Tsavo, Kenya. A lion-specific biomass model applied to prey frequencies in scats revealed that more than 85% of lion diet consisted of large ungulates weighing over 150 kg. While large ungulates were also preferred prey items in terms of their availability, we found a disproportionately high consumption and preference of lions for the endangered hirola and Grevys zebra-- species that were introduced in Tsavo as part of ex-situ conservation programs. Hirola and Grevys zebra populations have historically remained small in Tsavo despite strong recovery efforts, and our results likely indicate a disproportionate impact of lion predation on these small but crucial populations. Preferential predation, coupled with high availability of alternative prey, may trap hirola and Grevys zebra within a predator-pit. Our findings have strong implications for understanding lion diet, optimal foraging, and the potential effects predators have on endangered prey species in a landscape of critical conservation importance.

ecology↗

bioRxiv2023

Leveraging information between multiple population groups and traits improves fine-mapping resolution

Statistical fine-mapping helps to pinpoint likely causal variants underlying genetic association signals. Its resolution can be improved by (i) leveraging information between traits; and (ii) exploiting differences in linkage disequilibrium structure between diverse population groups. Using association summary statistics, MGflashfm jointly fine-maps signals from multiple traits and population groups; MGfm uses an analogous framework to analyse each trait separately. We also provide a practical approach to fine-mapping with out-of-sample reference panels. In simulation studies we show that MGflashfm and MGfm are well-calibrated and that the mean proportion of causal variants with PP>0.80 is above 0.75 (MGflashfm) and 0.70 (MGfm). In our analysis of four lipids traits across five population groups, MGflashfm gives a median 99% credible set reduction of 10.5% over MGfm. MGflashfm and MGfm only require summary level data, making them very useful fine-mapping tools in consortia efforts where individual-level data cannot be shared.

genomics↗

bioRxiv2023

Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension

Genome-wide association studies of blood pressure (BP) have identified >1000 loci but the effector genes and biological pathways at these loci are mostly unknown. Using published meta-analysis summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with [≥]2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, DBH) and previously unreported BP candidate genes (NRIP1, MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs, and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, tissue expression data and literature review, we provide consolidated evidence for 394 BP candidate genes for future functional validation and identifies several new drug targets.

genetics↗