Biology subjects

Day, T.

Publications and source records attributed to Day, T..

16 recordsLinked to original sources

bioRxiv2026

Analysis of persistence thresholds for a nonlocal PDE--ODE model of bacterial persister cells

Within many bacterial colonies, persister cells exist as a subpopulation that is tolerant to antibiotics and other stressors, yet not genetically distinct from the rest of the colony. A recent study has proposed epigenetic inheritance as a mechanism that leads to the presence of persister cells. We analyze a nonlocal PDE-ODE model introduced in that study to describe the epigenetic inheritance process and establish its mathematical well-posedness, including existence, uniqueness, and nonnegativity of solutions. We identify a sharp parameter threshold delineating extinction from persistence of the colony: below this threshold the washout equilibrium is globally asymptotically stable, while above it a unique positive equilibrium exists and the population is weakly persistent. Notably, this threshold is independent of the internal community structure.

microbiology↗

bioRxiv2026

Evolutionary invasion analysis for structured populations: a synthesis

Natural populations exhibit complex class structures that fundamentally shape evolutionary dynamics. Yet predicting adaptation in such systems remains a central challenge in ecology because ecological realism inherently generates high-dimensional models that obscure biological interpretation and hinder general evolutionary prediction. Here, we overcome this long-standing obstacle by developing structural evolutionary invasion analysis, a unifying theoretical framework integrating invasion determinants with the Projected Next-Generation Matrix (PNGM). The invasion determinant provides a general, closed-form algebraic condition for invasion, while the PNGM structurally compresses life-cycle graphs by eliminating non-focal classes. Crucially, this compression formally derives timescale separation, rigorously preserves Fishers reproductive values, and guarantees that the location, convergence, and evolutionary stability of equilibria remain identical to those of the full ecological system. By applying the framework to examples spanning evolutionary epidemiology, stage structure, and inclusive fitness, we show how to capture the direct impact of ecological complexity on evolutionary outcomes while retaining analytical tractability. Our results establish a general principle linking ecological structure to evolutionary prediction, enabling ecologists to analyze adaptation and eco-evolutionary dynamics in heterogeneous populations.

evolutionary biology↗

bioRxiv2026

Male-benefit adaptation under sex-limited selection shaped by compensatory evolution in Drosophila melanogaster.

Intralocus sexual conflict (IaSC) results from opposing selection acting on traits with correlated expression between the sexes. We recently reported on a male-limited (ML) selection experiment in Drosophila melanogaster designed to investigate IaSC through a sex-limited evolution regime that theoretically resolves conflict in favour of males. However, this experiment did not universally or unambiguously improve male fitness, although female fitness declined as predicted. Here we examine sources of unintended selection: unusual genetic features of the breeding design and the special females used to enforce male-limited inheritance that may have complicated evolutionary outcomes. Specifically, we evaluate the effects of a foreign cytoplasm, genetically marked translocated autosomes, and a female-exposed Y chromosome derived from the clone-generator (CG) system, and the unique environment of sexual selection introduced by foreign CG females. We found that selected male fitness increased by 66% when expressed within the full ML genetic context, rising to over 100% when interacting with CG females. While there is no consistent fitness advantage in the "wild type" genetic background, there is a nearly significant trend of improved fitness with CG females (26% improvement). Further, outside this context, these males do not experience a fitness loss relative to controls, even showing a marginal gain of 6%. Uniformly, these gains were mediated by precopulatory traits: ML selection produced more attractive males with greater mating success and shorter mating latencies, while sperm competition remained unchanged. Intriguingly, ML-evolved males also exhibited reduced mate harm to females, contrary to the established narrative of escalating intersexual antagonism in this system. Dissecting individual components revealed significant fitness improvements associated with adaptation to the foreign cytotype (18%) and the female-exposed Y chromosome (33%), although responses varied across replicate populations. Moreover, when selected haplotypes were expressed together with the foreign cytotype in females, we observe a recovery in fitness. Together, these findings demonstrate extensive compensatory evolution to the ML selection environment, indicating that responses to the release of IaSC were shaped not only by sexually antagonistic selection but also by adaptation to the genetic manipulations and mating context inherent to the experimental design.

evolutionary biology↗

bioRxiv2025

Additivity of the genetic load is a product of both synergistic and antagonistic epistasis in Drosophila

Epistasis has been theoretically implicated in several major evolutionary processes, including the evolution of sex and speciation, but empirical evidence for its impact is still lacking. We tested for epistatic interactions using a full-sib inbreeding design in Drosophila melanogaster. We examined the effects of deleterious mutations on two sequential components of life-history: pupal productivity and pupa-to-adult viability. We observed an accelerating decline in pupal productivity with increasing inbreeding coefficient, consistent with synergistic epistasis, whereas pupa-to-adult viability exhibited a decelerating decline, consistent with antagonistic epistasis. This decoupling led to an overall linear decline in the production of adult offspring with increasing inbreeding. Our findings suggest that epistatic interactions can be highly trait-specific, underscoring the importance of analyzing individual, physiologically interconnected, fitness traits to understand the role of epistasis in evolutionary processes.

evolutionary biology↗

bioRxiv2024

Mixed evidence for intralocus sexual conflict from male-limited selection in Drosophila melanogaster.

Sexual conflict over shared traits - intralocus sexual conflict (IaSC) - may be common and consequential, but experimental tests of its relative magnitude are challenging and limited in number. We use a sex-limited selection experiment, designed to subject genomic haplotypes of Drosophila melanogaster to selection for male fitness without opposing selection acting on female fitness. Importantly, we use three novel base populations to compare results with those from the LHM population, the sole population investigated using this technique. In contrast with previous studies, we find that male fitness of haplotypes subject to male-limited selection (ML populations) are not consistently better than their matched (MC) controls when tested in the "wildtype" state. Males from ML lines did not outperform controls in competitive fitness assays, mate choice trials, fecundity induction or sperm offense tests. As predicted, genetic variation for male fitness was reduced, with low fitness haplotypes apparently removed by selection, but this was only surveyed in one replicate population pair and included a potential artefact in the protocol. Female fitness was markedly reduced by carriage of ML genomic haplotypes, as predicted by sexual antagonism. Hence, our results are only partially consistent with the IaSC hypothesis, raising questions about the relative contribution of sexual conflict to the standing genetic variation in these populations and the potential role of artefacts in the protocol that may have obscured our ability to detect IaSC.

evolutionary biology↗

bioRxiv2024

Early Life Neuroimaging: The Generalizability of Cortical Area Parcellations Across Development

The cerebral cortex consists of distinct areas that develop through intrinsic embryonic patterning and postnatal experiences. Accurate parcellation of these areas in neuroimaging studies improves statistical power and cross-study comparability. Given significant brain changes in volume, microstructure, and connectivity during early life, we hypothesized that cortical areas in 1- to 3-year-olds would differ markedly from neonates and increasingly resemble adult patterns as development progresses. Here, we parcellated the cerebral cortex into putative areas using local functional connectivity gradients in 92 toddlers at 2 years old. We demonstrate high reproducibility of these cortical regions across 1- to 3-year-olds in two independent datasets. The area boundaries in 1- to 3-year-olds were more similar to those in adults than those in neonates. While the age-specific group area parcellation better fit the underlying functional connectivity in individuals during the first 3 years, adult area parcellations might still have some utility in developmental studies, especially in children older than 6 years. Additionally, we provide connectivity-based community assignments of the parcels, showing fragmented anterior and posterior components based on the strongest connectivity, yet alignment with adult systems when weaker connectivity was included.

neuroscience↗

bioRxiv2024

Variety is the spice of life: nongenetic variation in life histories influences population growth and evolvability

Individual vital rates are key determinants of lifetime reproductive success, and variability in these rates shapes population dynamics. Previous studies have found that this vital rate hetero-geneity can influence demographic properties including population growth rates, however, the explicit effects of the amount of variation within and the covariance between vital rates that can also vary throughout the lifespan on population growth remains unknown. Here, we explore the analytical consequences of nongenetic heterogeneity on long-term population growth rates and rates of evolution by modifying traditional age-structured population projection matrices to incorporate variation among individual vital rates. The model allows vital rates to be permanent throughout life ("fixed condition") or to change over the lifespan ("dynamic condition"). We reduce the complexity associated with adding individual heterogeneity to age-structured models through a novel application of matrix collapsing ("phenotypic collapsing"), showing how to collapse in a manner that preserves the asymptotic and transient dynamics of the original matrix. The main conclusion is that nongenetic individual heterogeneity can strongly impact the longterm growth rate and rates of evolution. The magnitude and sign of this impact depends heavily on how the heterogeneity covaries across the lifespan of an organism. Our results emphasize that nongenetic variation cannot simply be viewed as random noise, but rather that it has consistent, predictable effects on fitness and evolvability.

evolutionary biology↗

bioRxiv2024

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

Single-stranded DNA gaps are postulated to be fundamental to the mechanism of anti-cancer drugs. Gaining insights into their induction could therefore be pivotal for advancing therapeutic strategies. For poly (ADP-ribose) polymerase inhibitors (PARPi) to be effective, the presence of FANCJ helicase is required. However, the relationship between FANCJ dependent gaps and PARP1 catalytic inhibition or trapping--both linked to PARPi toxicity in BRCA deficient cells--is yet to be elucidated. Here, we find that the efficacy of PARPi is contingent on S-phase PARP1 activity, which is compromised in FANCJ deficient cells because PARP1, along with MSH2, is "sequestered" by G-quadruplexes. PARP1s replication activity is also diminished in cells missing a FANCJ-MLH1 interaction, but in such cells, depleting MSH2 can release sequestered PARP1, restoring PARPi-induced gaps and sensitivity. Our observations indicate that sequestered and trapped PARP1 are different chromatin-bound forms, with FANCJ loss increasing PARPi resistance in cells susceptible to canonical PARP1 trapping. However, in BRCA1 null cells, the loss of FANCJ mirrors the effects of PARP1 loss or inhibition, with the common detrimental factor being the loss of PARP1 activity during DNA replication, not trapping. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA deficient cells and emphasize the importance of understanding drug mechanisms for enhancing precision medicine.

molecular biology↗

bioRxiv2023

Stochastic within-host dynamics of antibiotic resistance: Resistant survival probability, size at the end of treatment and carriage time after treatment

The use of an antibiotic may lead to the emergence and spread of bacterial strains resistant to this antibiotic. Experimental and theoretical studies have investigated the drug dose that minimizes the risk of resistance evolution over the course of treatment of an individual, showing that the optimal dose will either be the highest or the lowest drug concentration possible to administer; however, no analytical results exist that help decide between these two extremes. To address this gap, we develop a stochastic mathematical model of bacterial dynamics under antibiotic treatment. We explore various scenarios of density regulation (bacterial density affects cell birth or death rates), and antibiotic modes of action (biostatic or biocidal). We derive analytical results for the survival probability of the resistant subpopulation until the end of treatment, the size of the resistant subpopulation at the end of treatment, the carriage time of the resistant subpopulation until it is replaced by a sensitive one after treatment, and we verify these results with stochastic simulations. We find that the scenario of density regulation and the drug mode of action are important determinants of the survival of a resistant subpopulation. Resistant cells survive best when bacterial competition reduces cell birth and under biocidal antibiotics. Compared to an analogous deterministic model, the population size reached by the resistant type is larger and carriage time is slightly reduced by stochastic loss of resistant cells. Moreover, we obtain an analytical prediction of the antibiotic concentration that maximizes the survival of resistant cells, which may help to decide which drug dosage (not) to administer. Our results are amenable to experimental tests and help link the within and between host scales in epidemiological models.

evolutionary biology↗

bioRxiv2023

Emergence and maintenance of stable coexistence during a long-term multicellular evolution experiment

The evolution of multicellular life spurred evolutionary radiations, fundamentally changing many of Earths ecosystems. Yet little is known about how early steps in the evolution of multicellularity transform eco-evolutionary dynamics, e.g., via niche expansion processes that may facilitate coexistence. Using long-term experimental evolution in the snowflake yeast model system, we show that the evolution of multicellularity drove niche partitioning and the adaptive divergence of two distinct, specialized lineages from a single multicellular ancestor. Over 715 daily transfers, snowflake yeast were subject to selection for rapid growth in rich media, followed by selection favoring larger group size. Both small and large cluster-forming lineages evolved from a monomorphic ancestor, coexisting for over ~4,300 generations. These small and large sized snowflake yeast lineages specialized on divergent aspects of a trade-off between growth rate and survival, mirroring predictions from ecological theory. Through modeling and experimentation, we demonstrate that coexistence is maintained by a trade-off between organismal size and competitiveness for dissolved oxygen. Taken together, this work shows how the evolution of a new level of biological individuality can rapidly drive adaptive diversification and the expansion of a nascent multicellular niche, one of the most historically-impactful emergent properties of this evolutionary transition.

evolutionary biology↗

bioRxiv2021

Spontaneous emergence of multicellular heritability

The Major Transitions in evolution include events and processes that result in the emergence of new levels of biological individuality. For collectives to undergo Darwinian evolution, their traits must be heritable, but the emergence of higher-level heritability is poorly understood and has long been considered a stumbling block for nascent evolutionary transitions. A change in the means by which genetic information is utilized and transmitted has been presumed necessary. Using analytical models, synthetic biology, and biologicallyinformed simulations, we explored the emergence of trait heritability during the evolution of multicellularity. Contrary to existing theory, we show that no additional layer of genetic regulation is necessary for traits of nascent multicellular organisms to become heritable; rather, heritability and the capacity to respond to natural selection on multicellular-level traits can arise "for free." In fact, we find that a key emergent multicellular trait, organism size at reproduction, is usually more heritable than the underlying cell-level trait upon which it is based, given reasonable assumptions.

evolutionary biology↗

bioRxiv2018

Managing Marek’s disease in the egg industry

The industrialization of farming has had an enormous impact. To most, this impact is viewed solely in the context of productivity, but the denser living conditions and shorter rearing periods of industrial livestock farms provide pathogens with an ideal opportunity to spread and evolve. For example, the industrialization of poultry farms drove the Mareks disease virus (MDV) to evolve from causing a mild paralytic syndrome to causing a highly contagious, globally prevalent, disease that can have up to a 100% mortality rate. Fortunately, the economic catastrophe that would occur from MDV evolution has been prevented through widespread use of live imperfect vaccines that limit disease symptoms, but fail to prevent transmission. Unfortunately, the continued rollout of such imperfect vaccines is steering the evolution of MDV towards an even greater virulence and an ability to evade vaccine protection. Thus, there is a need to investigate alternative economically viable control measures for their ability to inhibit MDV spread and evolution. In what follows we examine the economic viability of standard husbandry practices for their ability to inhibit the spread of both virulent MDV and very virulent MDV throughout an industrialized egg farm. To do this, we parameterized a dynamic MDV transmission model and calculate the loss in egg production due to disease. We find that the MDV strain as well as the cohort duration had the greatest influence on disease burden and hence egg production. Additionally, we find that the standard husbandry practice involving conventional cages, often referred to as \"battery cages\", results in the least per capita loss in egg production due to MDV infection when compared to alternative enriched or aviary (free-run) systems for virulent MDV, but not very virulent MDV, in which case the Aviary system performs the best. These results highlight an important cost that managers will face when implementing new hen husbandry practices.

epidemiology↗

bioRxiv2018

Parp3 promotes long-range end-joining in murine cells

Chromosomal rearrangements, including translocations, are early and essential events in the formation of many tumors. Previous studies that defined the genetic requirements for rearrangement formation have identified differences between murine and human cells, most notably in the role of classical- and alternative-nonhomologous end joining factors (NHEJ). We reported that poly(ADP)ribose polymerase 3 (PARP3) promotes chromosomal rearrangements induced by endonucleases in multiple human cell types. In contrast to c-NHEJ factors, we show here that Parp3 also promotes rearrangements in murine cells, including translocations in murine embryonic stem cells (mESCs), class switch recombination in primary B cells and inversions in tail fibroblasts that generate Eml4-Alk fusions. In mESCs, Parp3-deficient cells had shorter deletion lengths at translocation junctions. This was corroborated using next-generation sequencing of Eml4-Alk junctions in tail fibroblasts and is consistent with a role for Parp3 in promoting the processing of DNA double-strand breaks. We confirmed a previous report that Parp1 also promotes rearrangement formation. In contrast with Parp3, rearrangement junctions in the absence of Parp1 had longer deletion lengths, suggesting Parp1 may suppress DSB processing. Together, these data indicate that Parp3 and Parp1 promote rearrangements with distinct phenotypes.

cancer biology↗

bioRxiv2018

qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps

Proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein-ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor-ligand complexes. We found that up to 29 % of a dataset of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively isoenergetic conformations in ligand-receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multi-temperature crystallography could therefore augment the structure-based drug design toolbox.

biophysics↗

bioRxiv2017

Pathogen evolution: slow and steady spreads the best

The theory of life history evolution provides a powerful framework to understand the evolutionary dynamics of pathogens in both epidemic and endemic situations. This framework, however, relies on the assumption that pathogen populations are very large and that one can neglect the effects of demographic stochasticity. Here we expand the theory of life history evolution to account for the effects of finite population size on the evolution of pathogen virulence. We show that demographic stochasticity introduces additional evolutionary forces that can qualitatively affect the dynamics and the evolutionary outcome. We discuss the importance of the shape of pathogen fitness landscape and host heterogeneity on the balance between mutation, selection and genetic drift. In particular, we discuss scenarios where finite population size can dramatically affect classical predictions of deterministic models. This analysis reconciles Adaptive Dynamics with population genetics in finite populations and thus provides a new theoretical toolbox to study life-history evolution in realistic ecological scenarios.

evolutionary biology↗

bioRxiv2017

The genetics of the human face: identification of large effect single gene variants

In order to discover specific variants with relatively large effects on the human face we have devised an approach to identifying facial features with high heritability. This is based on using twin data to estimate the additive genetic value of each point on a face, as provided by a 3D camera system. In addition, we have used the ethnic difference between East Asian and European faces as a further source of face genetic variation. We use principal components analysis to provide a fine definition of the surface features of human faces around the eyes and of the profile, and chose upper and lower 10% extremes of the most heritable PCs for looking for genetic associations. Using this strategy for the analysis of 3D images of 1832 unique volunteers from the well characterised People of the British Isles study [1, 2] and 1567 unique twin images from the TwinsUK cohort (www.twinsuk.ac.uk), together with genetic data for 500,000 SNPs, we have identified three specific genetic variants with notable effects on facial profiles and eyes.\n\nSignificance statementThe human face is extraordinarily variable and the extreme similarity of the faces of identical twins indicates that most of this variability is genetically determined. This level of genetic variability has probably arisen through natural selection, for example, for recognition of membership of a group or as a consequence of differential mate selection with respect to facial features. We have devised an approach to identifying specific genetic effects on particular facial features. This should enable the understanding, eventually at the molecular level, of the nature of this extraordinary genetic variability, which is such an important feature of our everyday human interactions.\n\nAuthor ContributionsWFB conceived the project. BW and TD organised collection of PoBI data and KH, DJMC, DM, AB and WFB assisted in data collection. TDS, PH and AN collected TwinsUK data. WPK and WJC conducted image registration analysis under supervision of JK. DJMC analysed registered image data and genetic data under supervision of WFB. WFB and DJMC wrote the manuscript, with WJC and WPK contributing additional technical material. WFB and BW supervised the project.

genetics↗