Biology subjects

Reid, J.

Publications and source records attributed to Reid, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Differing components of plasticity in quantitative genetic threshold traits cause diverging eco-evolutionary responses to spatio-seasonal environmental deterioration

Eco-evolutionary responses to long-term environmental deteriorations will fundamentally depend on interactions between plasticity and evolution of life-history traits that shape population dynamics. Counter-intuitive evolutionary and (meta)population dynamics could arise when different components of individual-specific and/or shared site-specific developmental and labile plasticity affect traits with intrinsically non-linear genotype-environment-phenotype relationships, especially given density-dependent fitness outcomes. Frequency-dependent evolutionary responses could then emerge, but resulting eco-evolutionary dynamics and outcomes have rarely been considered. By modelling a partially-migratory metapopulation encompassing facultative seasonal migration versus residence formulated as a quantitative genetic threshold trait, we show how different forms of plasticity in liability to migrate interact with spatio-seasonal metapopulation dynamics to generate divergent eco-evolutionary responses to spatially restricted environmental deterioration. Temporary and permanent individual-specific environmental effects induced faster evolutionary recovery than might simply be expected, by revealing cryptic genetic variation and allowing adaptive phenotypic changes through repeated episodes of selective disappearance. Conversely, shared subpopulation-specific environmental effects caused among-year variation in phenotype frequencies, impeding evolutionary responses to the extent that migratory metapopulation connectivity was ultimately eradicated. We thereby reveal key principles of how structurally different forms of plasticity in a dichotomous quantitative genetic trait can induce complex eco-evolutionary dynamics, culminating in differing degrees of evolutionary rescue versus constraint.

evolutionary biology↗

bioRxiv2026

Epileptogenesis dynamics driven by peritumoral circuit rewiring in gangliogliomas

Gangliogliomas (GGs) are emblematic low-grade epilepsy-associated tumors, yet the developmental mechanisms underlying their epileptogenicity remain unclear. Here, we investigated how tumor-network interactions evolve across postnatal maturation using an in-utero electroporated BRAFV600E-driven mouse model combining multiscale electrophysiology with histology, single-nucleus RNA sequencing, and complementary analyses in human GG tissue. We show that GGs induce early and evolutive modification of cortical organization and glioneuronal architecture. Despite glioneuronal preservation, seizure initiation shifted from distal cortical regions at postnatal stages to tumor-adjacent areas in adult networks. In both mouse and human, GG slices exhibited seizure activity localized to the peritumoral cortex. At the cellular level, neurons exhibited a developmental arrest of intrinsic electrophysiological maturation from postnatal to adult stages. Transcriptomic profiling identified stage-specific neuronal remodeling, with early alterations in inhibitory neurons and later changes affecting excitatory populations. Such developmental spatial seizure dynamics were associated with a pharmacological shift as NKCC1 inhibition with bumetanide selectively reduced seizure-like activity in neonatal but not mature tumor networks, indicating a restricted window of chloride-dependent epileptogenesis relevant to GABAergic maturation. Together, our results demonstrate that GG-associated epileptogenesis arises from developmentally regulated tumor-network interactions, highlighting distinct cellular and molecular mechanisms across maturation and revealing potential age-specific therapeutic targets.

neuroscience↗

bioRxiv2026

nf-cavalier: A Nextflow Pipeline for Rare Disease Variant Prioritization and Reporting

nf-cavalier is a Nextflow pipeline that automates genomic variant annotation, filtering, and reporting for individuals with rare Mendelian diseases. The pipeline takes as input variant callsets for an individual, family, or rare disease cohort, together with a target gene panel or a phenotype of interest. Variants are then filtered using various customisable criteria, including predicted gene consequence, computational pathogenicity predictions, population frequency, and familial segregation. The sequencing data for candidate variants is then visualised for human review. Candidate variant results are returned in user-friendly output formats, including interactive HTML reports and PowerPoint slide decks, with embedded links to external resources that enable rapid review by clinical research teams. nf-cavalier is maintained on GitHub (bahlolab/nf-cavalier) and licensed under the permissive MIT open-source licence.

bioinformatics↗

bioRxiv2026

Gel-forming fibres differentially modulate inulin fermentation: A comparison of psyllium and methylcellulose in in vitro colonic models

1.Fermentable fibres such as inulin can support metabolic health but may exacerbate gastrointestinal symptoms in individuals with irritable bowel syndrome (IBS) due to rapid fermentation and gas production. The gel-forming fibre psyllium improves IBS symptoms, although the underlying mechanisms remain unclear. We hypothesised that fibre gelation alters fermentation by modulating microbial access to substrates. To test this, we compared psyllium with methylcellulose, a chemically modified, gel-forming fibre, to determine the effects of gelation on inulin fermentation. Inulin alone or combined with psyllium or methylcellulose was fermented for 48 hrs in a colonic fermentation model inoculated with healthy human faeces. Gas production, metabolite profiles, microbial community composition and microbial localisation within fibre gels were assessed. Bioactivity of fermentation products was evaluated in STC-1 cells. Psyllium co-fermentation significantly accelerated fermentation and enhanced production of metabolites, while methylcellulose had minimal effects. Psyllium maintained higher diversity and enriched polysaccharide-degrading taxa including Bacteroides and Phoecaeicola species, which were strongly associated with metabolic activity. Bacterial penetration into the psyllium matrix was observed but not into methylcellulose. Fermentation products from psyllium but not methylcellulose stimulated GLP-1 and 5-HT secretion in STC-1 cells. These findings demonstrate that delayed-onset fermentable gel-forming fibres enhance microbial access to entrapped substrates, driving metabolic and hormonal responses.

microbiology↗

bioRxiv2026

Protocol-dependent cardiomyocyte states determine disease modelling capacity of human iPSCs

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are widely used to model cardiovascular disease, yet numerous differentiation protocols generate cardiomyocytes with heterogeneous molecular and functional properties, complicating experimental design. Here we systematically compare sixteen commonly used cardiomyocyte differentiation protocols and characterize their resulting cell states using single-nucleus RNA sequencing, functional phenotyping and computational integration with human genetic data. Despite similar cardiomyocyte yields, protocols produced distinct transcriptional programs, subtype compositions and physiological properties. By integrating protocol-specific gene expression signatures with genome-wide association studies of cardiovascular traits, we identify cardiomyocyte states enriched for genetic architectures underlying specific diseases. These analyses accurately predict protocols most suitable for modelling particular disease contexts, including electrophysiological defects associated with Brugada syndrome and metabolic vulnerability relevant to myocardial infarction. Our results demonstrate that differentiation protocols encode biologically distinct cardiomyocyte states with differential disease relevance and establish a framework for aligning stem-cell differentiation strategies with human complex trait genetics to guide model selection. This approach enables rational design of iPSC-based disease models and highlights how population-scale genetic data can inform experimental systems in stem cell biology.

systems biology↗

bioRxiv2025

Enduring Autism-like Phenotypes and Deregulated Hypothalamic Prosocial Peptides After Early-Life Exposure to Indoor Flame Retardants in Male C57BL/6 Mice

BackgroundPolybrominated diphenyl ethers (PBDEs) are neuroendocrine disrupting chemicals that produce adverse neurodevelopmental effects. PBDEs have been implicated as risk factors for autism spectrum disorder (ASD), which is characterized by abnormal psychosocial functioning and is commonly accompanied by co-morbidities such as cognitive and attentional deficits. Here, we used a mouse model with translationally relevant exposure to establish direct causal evidence that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in male offspring. MethodsC57Bl6/N mouse dams were exposed to a commercial PBDE mixture, DE-71, via oral administration of 0 (vehicle control, VEH/CON), 0.1 (L-DE-71), or 0.4 (H-DE-71) mg/kg bw/d for 10 weeks, spanning three weeks prior to gestation through the end of lactation at postnatal day (PND) 21. ResultsMass spectrometric analysis indicated dose-dependent transfer of PBDEs (in ppb) to brains of F1 male offspring at PND 30, with reduction in levels by PND 110. Adult F1 male offspring displayed ASD-relevant neurobehavioral phenotypes, including impaired short- and long-term social recognition memory (SRM), despite intact general sociability, and exaggerated repetitive behavior. Exposed mice also displayed altered olfactory discrimination of social odors, impaired novel object recognition memory, and reduced open field habituation. However, no changes were observed in anxiety-like, sensorimotor, or depressive-like behaviors relative to VEH/CON. At the molecular level, DE-71 exposed males displayed deregulated gene markers of prosocial neuropeptides. Oxt was upregulated in the paraventricular nucleus (PVN); Avp was upregulated in the PVN and bed nucleus of the stria terminalis (BNST) but downregulated in the lateral septum (LS); Avp1ar and Adcyap1 were upregulated in the BNST; and Adcyap1r1 was upregulated in the PVN, supraoptic nucleus (SON), and BNST. ConclusionsThese findings demonstrate that developmental PBDE exposure produces enduring behavioral and neurochemical phenotypes that resemble core domains of ASD, which may result from early neurodevelopmental reprogramming within central social and memory networks.

neuroscience↗

bioRxiv2025

Machine Learning Guided Structure Activity Discovery of Polymer Configurations in Lipid Nanoparticles for Kiss-and-Run Endosomal Escape

Endosomal escape remains a major barrier to effective nucleic acid delivery via lipid nanoparticles (LNPs). Here, we address this challenge by incorporating a pH-sensitive polymer, polyhistidine, into LNPs (pLNPs) to facilitate endosomal escape, with a focus on optimizing the polymers molecular weight (MW) and configuration--parameters that remain largely unexplored. Through systematic engineering, we designed linear and branched polyhistidine architectures with varied MWs and configurations. In vivo screening identified an optimized pLNP formulation incorporating a symmetrical bis-lysine histidine dendron with a MW of [~]1800 g/mol, which achieved a 266-fold increase in liver bioluminescence following intravenous delivery of luciferase mRNA compared to standard LNPs at an equivalent RNA dose. Mechanistic studies revealed that polymer configuration within pLNPs is critical for eliciting the proton sponge effect, leading to osmotic swelling and endosomal rupture. This configuration also promoted rapid endosomal membrane destabilization via a kiss-and-run mechanism, enabling efficient cytosolic release. When delivering base editor mRNA and single-guide RNA, the optimized pLNPs achieved 8% gene editing efficiency in the mouse liver at a low dose of 0.1 mg/kg, compared to 1% with standard LNPs. To accelerate discovery and address macromolecular design challenges, we developed a machine learning (ML) framework based on amino acid-level graph neural networks (GNNs). This approach identified branched, dendritic configurations with densely arranged histidine residues on a multivalent core as key determinants of delivery performance. The top ML-predicted candidate, NS535, achieved a 705-fold increase in liver bioluminescence over standard LNPs, validating our data-driven design strategy. Together, these findings establish a closed-loop platform integrating rational design, mechanistic validation, and ML-guided optimization to advance RNA delivery. By elucidating structure-activity relationships for polyhistidine carriers and demonstrating efficient, low-dose genome editing, this work provides a blueprint for next-generation nucleic acid therapeutics.

bioengineering↗

bioRxiv2025

High-resolution cryo-EM analysis of the therapeutic Pseudomonas phage Pa223

Cryogenic electron microscopy (cryo-EM) analysis of bacteriophages is a valuable method for deciphering virus composition and conformational plasticity. In this study, we present a high-resolution structural atlas of the Pseudomonas virus Pa223, a phage from the Bruynoghevirus genus that has recently been used in clinical cocktails for treating cystic fibrosis and non-cystic fibrosis bronchiectasis, as well as for compassionate care. By combining bioinformatics, proteomics, cryo-EM single particle analysis, and localized reconstruction, we annotated and built atomic models for eight structural polypeptide chains that form the icosahedral capsid and noncontractile tail. We discovered that the Pa223 capsid is decorated by a spike protein that features a unique triple-{beta} helix fold with no structural homologs in the database. The Pa223 tail features six trimeric tail fibers extending upwards, similar to, but shorter than, those found in phage T7. Unlike T7, the Pa223 tail is extended by two head-to-tail adaptors and sealed by a trimeric tail needle, similar to P22-like phages. We identified a protein bound around the outer perimeter of the portal protein, positioned similarly to the ejection protein gp72, which was identified in the Pseudomonas phage DEV, a Litunavirus phage and member of the reclassified Schitoviridae family. This structural hint led us to identify the Pa223 ejection proteins gp53, gp54, and gp56, which bioinformatically resemble those of T7-like phages more closely than Schitoviridae. Thus, phage Pa223 contains diverse structural elements found in P22-like, T7-like, and Litunavirus phages, providing a framework for understanding the diversification and evolution of ejection proteins in Bruynogheviruses. HighlightsO_LIThe high-resolution structure of Bruynoghevirus Pa223 reveals hybrid structural features that are shared among P22-like, T7-like, and Litunavirus phages. C_LIO_LIThe Pa223 capsid is decorated with a trimeric spike asymmetrically bound at the icosahedral 3-fold axes. C_LIO_LIThe Pa223 tail features two quasi-equivalent conformations of the head-to-tail adaptor protein arranged into two coaxial rings. C_LIO_LIIdentification of the ejection protein gp54 through structural similarity to gp72 from the Litunavirus DEV. C_LIO_LIBioinformatic mapping of the Pa223 ejection proteins gp53 and gp56 validated through mass spectrometry analysis of infectious virions. C_LI

biochemistry↗

bioRxiv2025

Variant Classification Using Proteomics-Informed Large Language Models Increases Power of Rare Variant Association Studies and Enhances Target Discovery

Rare variant association analysis, which assesses the aggregate effect of rare damaging variants within a gene, is a powerful strategy for advancing knowledge of human biology. Numerous models have been proposed to identify damaging coding variants, with the most recent ones employing deep learning and large language models (LLM) to predict the impact of changes in coding sequences. Here, we use newly available proteomics data on 2,898 proteins across 46, 665 individuals to evaluate and refine LLM predictors of damaging variants. Using one of these refined models, we evaluate association between rare damaging variants and human phenotypes at 241 positive control gene-trait pairs. Among these gene-trait pairs, our proteomics-guided model outperforms an ensemble of conventional approaches including PolyPhen2, Mutation Taster, SIFT, and LRT, as well as newer machine learning approaches for identifying damaging missense variants, such as CADD, ESM-1v, ESM-1b and AlphaMissense. When attempting to recover known associations by correctly separating damaging singleton missense variants from other singleton variants, our approach recapitulates 36.5% of gene-trait pairs with known associations, exceeding all the alternatives we considered. Furthermore, when we apply our model to 10 exemplary traits from the UK Biobank, we identify 177 gene-trait associations - again exceeding all other approaches. Our results demonstrate that summary statistics from large-scale human proteomics data enable evaluation and refinement of coding variant classification LLMs, improving discovery potential in human genetic studies.

bioinformatics↗

bioRxiv2025

A typology of Australian terrestrial bird communities

AimIncreasing interest in holistic measurement of the response of fauna communities to interventions requires suitable community condition metrics. However, the development of such metrics is hindered by the absence of broad-scale typologies at suitable spatial and ecological resolutions. We aimed to derive a preliminary typology of terrestrial bird communities for Australia, based on bird co-occurrence data, and describe and map the likely distribution of each community type across the continent. LocationMainland Australia, continental islands Time period1973-2022 Major taxa studiedAves MethodsWe used fine-scale co-occurrence data from standard 2-ha surveys in BirdLife Australias citizen-science database. After filtering to reduce bias, we used hierarchical clustering followed by iterative consultation with experts to identify reliably distinct and recognisable terrestrial bird communities across Australia. We used Maxent to model the likely distributions of each community, and developed community descriptions based on each communitys composition and distribution. ResultsThe resultant typology included 29 reliably distinct and recognisable bird communities with major clusters corresponding with seven broad geographical regions. The distributions of bird communities did not correspond tightly to the boundaries of major vegetation groups, with most communities occurring across multiple vegetation types. Main ConclusionsOur preliminary typology of bird communities provides a standard classification at a continental scale. It newly defines distinct bird communities as entities for which condition benchmarks can be established to allow assessment of their conservation status and monitoring of change over time. Refinement will enable cryptic communities in areas with sparse data to be identified. The method could be translated to other regions where adequate coverage of data in the form of standardised surveys of fauna are available. Vast biodiversity datasets delivered through citizen science programs provide the opportunity to develop such typologies for fauna communities, as a precursor to developing targeted and informative community condition metrics.

ecology↗

bioRxiv2024

Maturation of human cardiac organoids are required for disease modelling and drug discovery

Cardiac maturation is an important developmental phase culminating in profound biological and functional changes to adapt to the high demand environment after birth1,2. Maturation of human pluripotent stem cell-derived human cardiac organoids (hCO) to more closely resemble human heart tissue is critical for understanding disease pathology. Herein, we profile human heart maturation in vivo3 to identify key signalling pathways that drive maturation in hCOs4,5. Transient activation of both the 5 AMP-activated kinase (AMPK) and estrogen-related receptor (ERR) promoted hCO maturation by mimicking the increased functional demands of post-natal development. hCOs cultured under these directed maturation (DM) conditions (DM-hCOs) display robust transcriptional maturation including increased expression of mature sarcomeric and oxidative phosphorylation genes resulting in enhanced metabolic capacity. DM-hCOs have functionally mature properties such as sarcoplasmic reticulum-dependent calcium handling, accurate responses to drug treatments perturbing the excitation-coupling process and ability to detect ectopy CASQ2 and RYR2 mutants. Importantly, DM- hCOs permit modelling of complex human disease processes such as desmoplakin (DSP) cardiomyopathy, which is driven by multiple cell types. Subsequently, we deploy DM-hCOs to demonstrate that bromodomain extra-terminal inhibitor INCB054329 rescues the DSP phenotype. Together, this study demonstrates that recapitulating in vivo development promotes advanced maturation enabling disease modelling and the identification of a therapeutic strategy for DSP- cardiomyopathy.

bioengineering↗

bioRxiv2024

Prenylation controls proliferation in human pluripotent stem cell-derived cardiomyocytes

Induction of cardiomyocyte proliferation to replace damaged heart tissue is a promising therapeutic approach. A recent drug screen revealed that cardiomyocytes require the mevalonate pathway for proliferation, although the specific mechanisms are unknown. In this study, we use human pluripotent stem cell-derived cardiomyocytes and cardiac organoids to further interrogate the role of the mevalonate pathway in cardiomyocyte proliferation. Chemical and genetic perturbations of the mevalonate pathway indicated that the post-translational modification, prenylation, regulates cardiomyocyte proliferation. We use prenyl probes and mass spectrometry to identify a catalogue of 40 prenylated proteins in human cardiac cells, including proteins where prenylated function had not yet been investigated. We show that multiple prenylated proteins control cardiomyocyte proliferation including RRAS2 and NAP1L4. We demonstrate that prenylation has differential effects on distinct proteins, with RRAS2 prenylation controlling membrane localization and NAP1L4 prenylation regulating cardiomyocyte mitosis and centrosome homeostasis. Together, these data show that protein prenylation is required for cardiomyocyte proliferation through multiple targets and these processes may need to be re-activated for cardiac regeneration.

cell biology↗

bioRxiv2023

Use of Multiple Pharmacodynamic Measures to Deconstruct the Nix-TB Regimen in a Short-Course Murine Model of Tuberculosis

A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen (bedaquiline-pretomanid-linezolid [BPaL]) during the first three weeks of treatment at human equivalent doses. RS ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, to-gether with solid culture CFU and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.

pharmacology and toxicology↗

bioRxiv2023

Cell layer specific roles for hormones in root development: Gibberellins suppress infection thread progression, promote nodule and lateral root development in the endodermis and interact with auxin and cytokinin

O_LIGibberellins have a profound influence on the formation of lateral root organs. However, the precise role this hormone plays in the cell-specific events during lateral root formation, rhizobial infection and nodule organogenesis, including interactions with auxin and cytokinin, is not clear. C_LIO_LIWe performed epidermal- and endodermal-specific complementation of the severely gibberellin-deficient na pea (Pisum sativum) mutant with Agrobacterium rhizogenes. Gibberellin mutants were used to examine the spatial expression pattern of cytokinin (TCSn) and auxin (DR5) responsive promoters and hormone levels. C_LIO_LIWe found that gibberellins produced in the endodermis promote lateral root and nodule organogenesis and can induce a mobile signal(s) that suppresses rhizobial infection. In contrast, epidermal-derived gibberellins suppress infection but have little influence on root or nodule development. Gibberellins suppress the cytokinin-responsive TCSn promoter in the cortex and are required for normal auxin activation during nodule primordia formation. C_LIO_LIOur findings indicate that gibberellins regulate the checkpoints between infection thread penetration of the cortex and invasion of nodule primordial cells and promotes the subsequent progression of nodule development. It appears that gibberellins limit the progression and branching of infection threads in the cortex by restricting cytokinin response and activate auxin response to promote nodule primordia development. C_LI

plant biology↗

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↗

bioRxiv2021

Seasonal migration as a life history trait facilitating adaptation to climate change

Predicting the geographic range of species and their response to variation in climate are entwined goals in conservation and evolutionary ecology. Species distribution models (SDMs) are foundational in this effort and used to visualize the geographic range of species as the spatial representation of its realized niche, or when based only on climate, its climate niche. SDMs can also forecast shifts in species range given climate change, but often lack of empirical support for causal links between climate and demography, yielding uncertain predictions. We addressed such uncertainties whilst also exploring the role of migration and resident life-histories in climate adaptation in mobile animals using 48 years of detailed demographic and climate data for song sparrows (Melospiza melodia), a polytypic species that varies in migratory life history. We developed SDMs representing demographic and climate niches of migratory and resident populations in western North America from California (CA) to Alaska (AK) using data from a focal population in British Columbia (BC) and 1.2 million citizen science observations. Distributions of resident and migrant populations predicted by each model agreed strongly (72.8%) in the region of our focal population, but less well in regions with dissimilar climates. Mismatches were largest in CA, smaller in AK, but in all cases supported the hypothesis that climate influences the evolution of migration and limits year-round residency. Our results imply that migrants predominated in our focal population a century ago, but that climate change has favored range expansions by non-migratory phenotypes and facilitated an upward shift in the elevational range of residents. We suggest long-term studies are crucial to evaluating the predictions of SDMs positing causal links between climatic conditions and species demography. We found such links to be robust regionally and particularly useful to elucidating the potential for migration or residence to facilitate adaptation to climate change.

ecology↗

bioRxiv2019

Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

Epigenetic regulation of gene expression occurs in a cell type-specific manner. Current cell-type specific neuroepigenetic studies rely on cell sorting methods that can alter cell phenotype and introduce potential confounds. Here we demonstrate and validate a Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) approach for temporally controlled labeling and isolation of ribosomes and nuclei, and thus RNA and DNA, from specific CNS cell types. Paired analysis of the transcriptome and DNA modifications in astrocytes and microglia demonstrates differential usage of DNA methylation and hydroxymethylation in CG and non-CG contexts that corresponds to cell type-specific gene expression. Application of this approach in LPS treated mice uncovers microglia-specific transcriptome and epigenome changes in inflammatory pathways that cannot be detected with tissue-level analysis. The NuTRAP model and the validation approaches presented can be applied to any CNS cell type for which a cell type-specific cre is available.

neuroscience↗

bioRxiv2019

Individuals' expected genetic contributions to future generations, reproductive value, and short-term metrics of fitness in free-living song sparrows (Melospiza melodia)

Appropriately defining and enumerating fitness is fundamental to explaining and predicting evolutionary dynamics. Yet theoretical concepts of fitness are often hard to translate into quantities that can be quantified in wild populations experiencing complex environmental, demographic, genetic and selective variation. While the fittest entities might be widely understood to be those that ultimately leave most descendants at some future time, such long-term legacies are hard to measure, impeding evaluation of how well more tractable short-term metrics of individual fitness directly predict longer-term outcomes. One opportunity for conceptual and empirical convergence stems from the principle of individual reproductive value (Vi), defined as the number of copies of each of an individuals alleles that is expected to be present in future generations given the individuals realised pedigree of descendants. Since Vi tightly predicts an individuals longer-term genetic contribution, quantifying Vi provides a tractable route to quantifying what, to date, has been an abstract fitness concept. We used complete pedigree data from free-living song sparrows (Melospiza melodia) to demonstrate that individuals expected genetic contributions stabilise within an observed 20-year time period, allowing individual Vi to be evaluated. Considerable among-individual variation in Vi was evident in both sexes. However, standard short-term metrics of individual fitness, comprising lifespan, lifetime reproductive success and projected growth rate, typically explained less than half the variation. Given these results, we discuss what evolutionary inferences can and cannot be directly drawn from short-term versus longer-term fitness metrics observed on individuals, and highlight that analyses of pedigree structure may provide useful complementary insights into evolutionary processes and outcomes.

evolutionary biology↗