Biology subjects

Webb, A. E.

Publications and source records attributed to Webb, A. E..

15 recordsLinked to original sources

bioRxiv2026

Sexual reproduction impacts vertebrate organ aging

Sexual reproduction is a central component of life. Yet, an unanswered question remains: how does sexual reproduction shape physiology and health across an individual's lifetime? Unlike other external factors such as diet and exercise, the impact of sexual reproduction on organ health during aging is far less studied, particularly in vertebrates. Here, we develop the short-lived killifish as a vertebrate model to study how lifelong mating affects organ aging. We discover that mating regulates liver aging in a cell-type and sex-specific manner. In old female livers, mating dampened hepatocyte inflammation and reduced myeloid cell levels, and machine-learning models predicted that mating led to a 'younger' transcriptomic age in several liver cell types. Functionally, mating reduced hepatic accumulation of several lipid classes and was associated with enhanced female resilience against the liver toxin acetaminophen. More broadly, mating induced anti-inflammatory and metabolic rewiring transcriptomic signatures in the brain and gut, indicating that mating may affect vertebrate organ aging more globally. Using publicly available human datasets and plasma proteomics aging clocks, we observed an association between sexual experience and a 'younger' plasma proteomic age of several cell types, including hepatocytes. Our work provides evidence that lifelong mating reshapes the physiological context during aging in a vertebrate, highlighting an understudied connection between vertebrate sexual history, health, and aging.

genomics↗

bioRxiv2026

Single-cell transcriptomic and epigenomic analysis reveals X-linked sex differences in aging mouse hypothalamus

Sex differences contribute to brain aging, neurodegenerative diseases, and more broadly in determining rates of aging across species. The hypothalamus plays a central role in physiological homeostasis and healthy aging, yet how its cellular and molecular landscape diverges between males and females over the lifespan remains poorly understood. Here, we present a single-nucleus multi-omics analysis of the hypothalamus in young, middle aged, and aged male and female mice. We identified major hypothalamic cell types and characterized their sex- and age-dependent transcriptional and chromatin accessibility profiles. Notably, female-specific changes on the X chromosome (chrX) emerged as a prominent feature of aging, including changes to the X inactivation center and an overall increase in chrX gene expression and accessibility in immune cells and neurons. Pseudotime analysis of immune cells revealed an aging trajectory with sex-specific multi-omic programs, featuring increased inflammation in females compared to males. Delving deeper into the epigenetic signatures associated with these sex differences, we found that H3K27me3 - the repressive histone mark enriched on the inactive X in females - increased in abundance and underwent substantial genome-wide redistribution with age in both sexes, particularly on the inactive chrX in females. Collectively, these findings highlight distinct cell-type-specific aging trajectories in the male and female hypothalamus, identify female aging signatures associated with X-linked epigenetic regulatory programs, and provide a comprehensive resource for understanding the molecular basis of sex differences in brain aging.

genomics↗

bioRxiv2025

HypoAD: volumetric and single-cell analysis reveals changes in the human hypothalamus in aging and Alzheimer's disease

Alterations in metabolism, stress response, sleep, circadian rhythms, and neuroendocrine processes are key features of aging and neurodegeneration. These fundamental processes are regulated by the hypothalamus, yet how its functionally distinct subregions and cell types change during human aging and Alzheimers Disease (AD) remains largely unexplored. Here, we present HypoAD, a comprehensive atlas of the human hypothalamus in aging and AD, integrating high-resolution MRI from 202 individuals with single-nucleus RNA-seq (snRNA-seq) of 614,403 nuclei from young, AD, and age-matched non-dementia controls. Our analysis reveals that hypothalamic subregions governing metabolism, stress, and circadian rhythms are particularly vulnerable, exhibiting significant changes in both volumes and gene expression during aging and AD. At the molecular level, machine learning models identified the inflammatory response and regulators of circadian rhythms as key cellular predictors of AD. These signatures were reflected in specific cell types: microglia transitioned to a pro-inflammatory state, while inhibitory neurons within sleep-and circadian-regulating hypothalamic subregions showed the most profound transcriptional alterations, including disruptions in ligand-receptor interactions and G-protein-coupled receptor signaling. Together, HypoAD provides a high-resolution volumetric map and a comprehensive transcriptomic atlas of the human hypothalamus in aging and AD, linking lifestyle and behavioral changes to their underlying volumetric and molecular pathways. Additionally, HypoAD provides a framework to investigate hypothalamic dysfunction and establishes a roadmap for targeted interventions aimed at mitigating physiological disruptions to potentially slow disease progression.

neuroscience↗

bioRxiv2025

The distribution of fitness effects varies phylogenetically across animals

1The distribution of fitness effects (DFE) describes the selection coefficients (s) of newly arising mutations and fundamentally influences population genetic processes. However, the extent and mechanisms of DFE variation have not been systematically investigated across species with divergent phylogenetic histories and ecological functions. Here, we inferred the DFE in natural populations of eleven animal (sub)species, including humans, mice, fin whales, vaquitas, wolves, collared flycatchers, pied flycatchers, halictid bees, Drosophila, and mosquitoes. We find that the DFE co-varies with phylogeny, where the expected mutation effects are more similar in closely related species (Pagels{lambda} = 0.84, P = 0.01). Additionally, mammals have a higher proportion of strongly deleterious mutations (22% to 47% in mammals; 0.0% to 5.4% in insects and birds) and a lower proportion of weakly deleterious mutations than insects and birds. Population size is significantly negatively correlated with the expected impact of new deleterious mutations (PGLS{lambda}, P = 0.03), and the proportion of new beneficial mutations ([Formula], P < 0.001). These findings align with Fishers Geometric Model (FGM), which defines organismal complexity as the number of phenotypes under selection. Consistent with the FGMs predictions, we observe that mutations are more deleterious in complex organisms, while beneficial mutations occur more frequently in smaller populations to compensate for the drift load. Our study demonstrates strong phylogenetic constraints in the evolution of a fundamental population genetics parameter, and proposes that, through mechanisms of global epistasis, long-term population size and organismal complexity drive variation in the DFE across animals. 2 Significance StatementUnderstanding how mutations affect fitness is fundamental in evolution, but little is known about how and why the distribution of fitness effects (DFE) varies across species. In this study, we examine the DFE in diverse animal populations and show that closely related species exhibit similar patterns of mutation effects, with new mutations being more deleterious in mammals compared with birds and insects. Our findings corroborate Fishers Geometric Model, which explains the variation in the DFE across species as a function of organismal complexity and long-term population size. By connecting organismal complexity and population size with the DFE, we offer a phylogenetic view into the selective forces shaping species adaptation and evolution.

evolutionary biology↗

bioRxiv2025

Queen loss unmasks cryptic worker influence and decentralizes the bumble bee social network

Dominant individuals often structure group organization, but less is known about how social networks reorganize in their absence and how variation among subordinates contributes to collective outcomes. Bumble bees (Bombus impatiens) provide an ideal system to study these dynamics: queens typically monopolize reproduction, but in some contexts individual workers can adopt queenlike social roles. Using multi-animal pose tracking, we compared matched queenright and queenless partitions from the same source colonies, quantifying over 80 million social interactions. Queen-less colonies exhibited increased behavioral variation and contained a subset of highly influential workers with elevated movement, spatial centrality, and reproductive activity that was absent in queen-right conditions. The emergence of these individuals coincided with a shift from centralized to decentralized, efficient network architectures. These results demonstrate that queen presence constrains latent worker variation, revealing how individual behavioral differences can scale up to reshape collective social organization in hierarchical societies.

animal behavior and cognition↗

bioRxiv2024

pipemake: A pipeline creation tool using Snakemake for reproducible analysis of biological datasets

The exponential growth in biological data generation has created an urgent need for efficient, reproducible computational analysis workflows. Here, we present pipemake, a computational platform designed to streamline the development and implementation of efficient and reproducible Snakemake workflows. pipemake creates modular pipelines that can be seamlessly integrated or removed from the platform without requiring reconfiguration of the core system, enabling flexible adaptation of workflows to different analytical needs across diverse fields. To demonstrate the platforms capabilities, we created and implemented pipelines to reanalyze two distinct biological datasets. First, we recreated a population genomics analysis of the socially flexible halictid bee, Lasioglossum albipes, using pipemake-generated workflows for de novo genome annotation, processing of variant data, dimensionality reduction, and a genome-wide association study (GWAS). We then used pipemake to analyze behavioral tracking data from the common eastern bumble bee, Bombus impatiens. In both cases, pipemake workflows produced results consistent with published findings while substantially reducing hands-on analysis time. Overall, pipemakes modular design allows researchers to easily modify existing pipelines or develop new ones without software development expertise. Beyond streamlining workflow creation, pipemake leverages the full Snakemake ecosystem to enable parallel processing, automated error recovery, and comprehensive analysis documentation. These features make pipemake an efficient and accessible solution for analyzing complex biological datasets. pipemake is freely available as a conda package or direct download at https://github.com/kocherlab/pipemake

bioinformatics↗

bioRxiv2024

Repeated shifts in sociality are associated with fine-tuning of highly conserved and lineage-specific enhancers in a socially flexible bee

Comparative genomic studies of social insects suggest that changes in gene regulation are associated with evolutionary transitions in social behavior, but the activity of predicted regulatory regions has not been tested empirically. We used STARR-seq, a high-throughput enhancer discovery tool, to identify and measure the activity of enhancers in the socially variable sweat bee, Lasioglossum albipes. We identified over 36,000 enhancers in the L. albipes genome from three social and three solitary populations. Many enhancers were identified in only a subset of L. albipes populations, revealing rapid divergence in regulatory regions within this species. Population-specific enhancers were often proximal to the same genes across populations, suggesting compensatory gains and losses of regulatory regions may preserve gene activity. We also identified 1182 enhancers with significant differences in activity between social and solitary populations, some of which are conserved regulatory regions across species of bees. These results indicate that social trait variation in L. albipes is driven both by the fine-tuning of ancient enhancers as well as lineage-specific regulatory changes. Combining enhancer activity with population genetic data revealed variants associated with differences in enhancer activity and identified a subset of differential enhancers with signatures of selection associated with social behavior. Together, these results provide the first empirical map of enhancers in a socially flexible bee and highlight links between cis-regulatory variation and the evolution of social behavior.

evolutionary biology↗

bioRxiv2023

Developmental transcriptomes predict adult social behaviors in the socially flexible sweat bee, Lasioglossum baleicum

Natural variation can provide important insights into the genetic and environmental factors that shape social behavior and its evolution. The sweat bee, Lasioglossum baleicum, is a socially flexible bee capable of producing both solitary and eusocial nests. We demonstrate that within a single nesting aggregation, soil temperatures are a strong predictor of the social structure of nests. Sites with warmer temperatures in the spring have a higher frequency of social nests than cooler sites, perhaps because warmer temperatures provide a longer reproductive window for those nests. To identify the molecular correlates of this behavioral variation, we generated a de novo genome assembly for L. baleicum, and we used transcriptomic profiling to compare adults and developing offspring from eusocial and solitary nests. We find that adult, reproductive females have similar expression profiles regardless of social structure in the nest, but that there are strong differences between reproductive females and workers from social nests. We also find substantial differences in the transcriptomic profiles of stage-matched pupae from warmer, social-biased sites compared to cooler, solitary-biased sites. These transcriptional differences are strongly predictive of adult reproductive state, suggesting that the developmental environment may set the stage for adult behaviors in L. baleicum. Together, our results help to characterize the molecular mechanisms shaping variation in social behavior and highlight a potential role of environmental tuning during development as a factor shaping adult behavior and physiology in this socially flexible bee.

genomics↗

bioRxiv2022

NAPS: Integrating pose estimation and tag-based tracking

O_LISignificant advances in computational ethology have allowed the quantification of behavior in unprecedented detail. Tracking animals in social groups, however, remains challenging as most existing methods can either capture pose or robustly retain individual identity over time but not both. C_LIO_LITo capture finely resolved behaviors while maintaining individual identity, we built NAPS (NAPS is ArUco Plus SLEAP), a hybrid tracking framework that combines state-of-the-art, deep learning-based methods for pose estimation (SLEAP) with unique markers for identity persistence (ArUco). We show that this framework allows the exploration of the social dynamics of the common eastern bumblebee (Bombus impatiens). C_LIO_LIWe provide a stand-alone Python package for implementing this framework along with detailed documentation to allow for easy utilization and expansion. We show that NAPS can scale to long timescale experiments at a high frame rate and that it enables the investigation of detailed behavioral variation within individuals in a group. C_LIO_LIExpanding the toolkit for capturing the constituent behaviors of social groups is essential for understanding the structure and dynamics of social networks. NAPS provides a key tool for capturing these behaviors and can provide critical data for understanding how individual variation influences collective dynamics. C_LI

animal behavior and cognition↗

bioRxiv2021

Convergent selection on juvenile hormone signaling is associated with the evolution of eusociality in bees

Sweat bees have repeatedly gained and lost eusociality, a transition from individual to group reproduction. Here, we generate chromosome-length genome assemblies for 17 species and identify genomic signatures of evolutionary trade-offs associated with transitions between social and solitary living. Both young genes and regulatory regions show enrichment for these molecular patterns. We also identify loci that show evidence of complementary signals of positive and relaxed selection linked specifically to the convergent gains and losses of eusociality in sweat bees. This includes two proteins that bind and transport juvenile hormone (JH) - a key regulator of insect development and reproduction. We find one of these JH binding proteins is primarily expressed in subperineurial glial cells that form the insect blood-brain barrier and that brain levels of JH vary by sociality. Our findings are consistent with a role of JH in modulating social behavior and suggest eusocial evolution was facilitated by alteration of the proteins that bind and transport JH, revealing how an ancestral, developmental hormone may have been co-opted during one of lifes major transitions. More broadly, our results highlight how trade-offs have structured the molecular basis of eusociality in these bees and demonstrate how both directional selection and release from constraint can shape trait evolution.

evolutionary biology↗

bioRxiv2021

Single-cell transcriptomics of peripheral blood in the aging mouse

Compositional and transcriptional changes in the hematopoietic system have been used as biomarkers of immunosenescence and aging. Here, we use single-cell RNA-sequencing to study the aging peripheral blood in mice, and characterize the changes in cell-type composition and transcriptional profiles associated with age. We identified 17 clusters from a total of 14,588 single cells. We detected a general upregulation of antigen processing and presentation and chemokine signaling pathways and a downregulation of genes involved in ribosome pathways with age. We also observed increased percentage of cells expressing markers of senescence, Cdkn1a and Cdkn2a, in old peripheral blood. In addition, we detected a cluster of activated T cells that are exclusively found in old blood, with lower expression of Cd28 and higher expression of Bcl2 and Cdkn2a, suggesting that the cells are senescent and resistant to apoptosis.

molecular biology↗

bioRxiv2021

Integrative multi-omics analysis reveals conserved hierarchical mechanisms of FOXO3 pioneer-factor activity

FOXO transcription factors are critical for cellular homeostasis and have been implicated in longevity in several species. Yet how these factors directly affect aging, particularly in humans, is not well understood. Here, we take an integrated multi-omics approach to identify the chromatin-level mechanisms by which FOXO3 coordinates transcriptional programs. We find that FOXO3 functions as a pioneer factor in human cells, directly altering chromatin accessibility to regulate gene expression. Unexpectedly, FOXO3s pioneer activity at many sites is achieved through a two-step process, in which chromatin accessibility is initially reduced, then transitions to an open conformation. The direct FOXO3 network comprises chromatin remodelers, including the SWI/SNF remodeling complex, which we find is functionally required for FOXO3 activity. We also identify a novel secondary network of activator protein-1 (AP-1) transcription factors deployed by FOXO3, which orchestrate a neuronal-specific subnetwork. Together, this hierarchical FOXO3 pioneer network regulates key cellular processes including metabolism, proteostasis, epigenetics and proliferation, which must be tightly controlled under changing conditions that accompany aging.

cell biology↗

bioRxiv2021

Single cell analysis of the aging hypothalamus

Alterations in metabolism, sleep patterns, body composition, and hormone status are all key features of aging. The hypothalamus is a well-conserved brain region that controls these homeostatic and survival-related behaviors. Despite the importance of this brain region in healthy aging, little is known about the intrinsic features of hypothalamic aging. Here, we utilize single nuclei RNA-sequencing to assess the transcriptomes of 40,064 hypothalamic nuclei from young and aged female mice. We identify cell type-specific signatures of aging in neurons, astrocytes, and microglia, as well as among the diverse collection of neuronal subtypes in this region. We uncover key changes in cell types critical for metabolic regulation and body composition, as well as in an area of the hypothalamus linked to cognition. In addition, our analysis reveals an unexpected female-specific feature of hypothalamic aging. Specifically, we discover that the master regulator of X-inactivation, Xist, is elevated with age, particularly in hypothalamic neurons. Moreover, using machine learning, we show that levels of X-chromosome genes, and Xist itself, are the best predictors of cellular age. Together, this study identifies critical cell-specific changes of the aging hypothalamus in mammals, and uncovers a novel marker of neuronal aging in females.

neuroscience↗

bioRxiv2020

Differentiation drives widespread rewiring of the neural stem cell chaperone network

Neural stem and progenitor cells (NSPCs) are critical for continued cellular replacement in the adult brain. Life-long maintenance of a functional NSPC pool necessitates stringent mechanisms to preserve a pristine proteome. We find that the NSPCs chaperone network robustly maintains misfolded protein solubility and stress resilience through high levels of the ATP-dependent chaperonin TRiC/CCT. Strikingly, NSPC differentiation rewires the cellular chaperone network, reducing TRiC/CCT levels and inducing those of the ATP-independent small heat shock proteins (sHSPs). This switches the proteostasis strategy in neural progeny cells to promote sequestration of misfolded proteins into protective inclusions. The chaperone network of NSPCs is more effective than that of differentiated cells, leading to improved management of proteotoxic stress and amyloidogenic proteins. However, NSPC proteostasis is impaired by brain aging. The less efficient chaperone network of differentiated neural progeny may contribute to their enhanced susceptibility to neurodegenerative diseases characterized by aberrant protein misfolding and aggregation.

molecular biology↗

bioRxiv2020

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Adult neural stem cells are largely quiescent, and require transcriptional reprogramming to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms that underlie the rapid transcriptional overhaul during NSC activation remain undefined. Here, we identify the genome-wide chromatin accessibility differences between primary neural stem and progenitor cells in quiescent and activated states. We show that these distinct cellular states exhibit both shared and unique chromatin profiles, which are both associated with gene regulation. Interestingly, we find that accessible chromatin states specific to quiescent or activated cells are active enhancers bound by pro-neurogenic and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters harboring constitutively accessible chromatin enriched for particular core promoter elements that are functionally associated with translation and metabolic functions. Together, our findings reveal how accessible chromatin states regulate a transcriptional overhaul and drive the switch between quiescence and proliferation in NSC activation.

molecular biology↗