Biology subjects

Lucas, L.

Publications and source records attributed to Lucas, L..

11 recordsLinked to original sources

bioRxiv2026

The C. elegans endonuclease NUC-1 acts in engulfing cells to degrade the apoptotic cell DNA

During C. elegans embryonic development, cells undergoing programmed cell death are engulfed by neighboring cells and degraded inside phagosomes. Here we characterize a DNase responsible for the degradation of the chromatin DNA of apoptotic cells. In the past, NUC-1, a homolog of mammalian DNase II, which is only active at acidic pH, was claimed to act in apoptotic cell nuclei for chromatin DNA degradation by some researchers, yet proposed to act in engulfing cells by others. We found that NUC-1 acts exclusively in engulfing cells to degrade apoptotic cell DNA. In nuc-1 mutant embryos, apoptotic cell chromatin DNA remains undegraded. We observed that being engulfed is necessary for the apoptotic chromatin DNA to be degraded. In addition, specific expression of nuc-1 in the engulfing but not dying cells rescues the nuc-1 mutant phenotype. Furthermore, blocking the fusion between lysosomes and a phagosome in engulfing cells blocks apoptotic chromatin DNA degradation. NUC-1 was reported to be a lysosome-located enzyme. We not only confirmed this localization pattern, but also further determined that NUC-1 does not reside in the nuclei of either apoptotic or live cells. This, together with our finding that the nucleus of an apoptotic cell is not acidic, indicates that NUC-1 does not act in the apoptotic cell nucleus; rather, it acts in the engulfing cell phagosomal lumen to degrade apoptotic chromatin DNA. Our work clarified a long-standing controversy regarding the action of NUC-1 and advanced our knowledge of the mechanisms that drive the degradation of specific components of dying cells.

genetics↗

bioRxiv2026

Mechanistic and machine learning models design human gut consortia that robustly inhibit Clostridioides difficile

Identifying design principles for robust inhibition of human pathogens is a major goal of microbiome engineering. By building synthetic microbial communities from the bottom-up guided by Bayesian active learning, we investigate the Clostridioides difficile growth landscape across thousands of species-metabolite conditions. Mechanistic consumer resource and machine learning models uncover significant interactions linking metabolites and species, and exhibit concordance with microbial interactions identified in human microbiome datasets. Guided by machine learning and mechanistic models, we elucidate microbial communities capable of robustly inhibiting C. difficile across diverse nutrient environments in vitro. Metabolomic profiling identified sorbitol, mannitol, and proline as key metabolites mediating community-driven C. difficile inhibition. Model-optimized communities significantly reduced C. difficile colonization in the murine gut whereas a model-designed non-inhibitory community did not exhibit this property. Communities display consistent metabolomic patterns in vitro and in vivo, suggesting that resource competition is a design principle of robust inhibition. Together, these findings establish an integrated experimental and computational framework for the rational design of microbial communities that robustly suppress pathogens across diverse environmental contexts.

systems biology↗

bioRxiv2026

Genomic offset is not predictive of recent demographic trends in Lycaeides butterflies

Genomic offset (GO) is increasingly used to predict population maladaptation risk under climate change, with larger offsets assumed to indicate greater vulnerability. Despite rapid adoption in conservation planning, it remains unclear how sensitive GO estimates are to key methodological choices, including SNP set composition, genotype-environment association (GEA) methods, and the specific GO metric used. Empirical validation against observed population dynamics also remains limited. Here, we evaluate the methodological robustness and predictive performance of GO using multidecadal demographic monitoring data from Lycaeides butterflies, a system with short generation times and high fecundity that may facilitate rapid adaptive responses. GO estimates were broadly consistent across SNP sets, regardless of composition or size, with climate-associated and randomly selected SNPs yielding largely concordant values. Consistency across GEA methods was moderate and depended on the SNP set used. In contrast, GO metrics differed substantially in the magnitude of maladaptation estimated, suggesting they capture distinct biological signals and should not be treated as interchangeable. Crucially, GO was a poor predictor of observed population trends, regardless of SNP set composition, GO metric, or GEA method, both at sites used to fit GEA models and when extrapolated to independent demographic sites. These findings suggest that, while GO provides a valuable conceptual framework for assessing potential maladaptation, its quantitative estimates and predictive power are sensitive to methodological choices and species-specific biological context. We therefore urge careful alignment of GO metric assumptions with conservation objectives, along with rigorous empirical validation, before GO estimates are used to inform management decisions.

evolutionary biology↗

bioRxiv2025

Gut microbes mediate the synergistic effects of dietary cholesterol and saturated fat in driving fibrosing MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population and can progress to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis, increasing risk of cirrhosis, hepatocellular carcinoma, and mortality. Gut microbes driven by diets high in saturated fat, simple sugar, and cholesterol contribute to disease progression, yet underlying mechanisms remain undefined. We explored the independent and synergistic effects of dietary saturated fat and cholesterol on MASH development using specific pathogen-free (SPF) and germ-free (GF) mice. We demonstrate that 1) both dietary cholesterol and saturated fat are required to induce fibrosing MASH in SPF mice, whereas GF mice are protected, 2) saturated fat and cholesterol individually alter gut microbial membership, potentially via altered bile acid metabolism, while their combination promotes a distinct composition, including an increase in Parasutterella spp. which correlates with hepatic fibrosis, and 3) diluted cecal contents from SPF, but not GF, mice fed high-fat, high-cholesterol diets are enriched in deoxycholic acid and activate human hepatic stellate cells in vitro, suggesting a mechanistic link between dietary lipid-induced microbiota and liver fibrogenesis. These findings reveal how specific Western dietary components shape the gut microbiota and contribute to hepatic liver fibrosis via stellate activation, offering potential targets for therapeutic intervention in MASLD/MASH.

physiology↗

bioRxiv2025

Tubulin transforms Tau and -synuclein condensates from pathological to physiological

Proteins phase-separate to form condensates that partition and concentrate biomolecules into membraneless compartments. These condensates can exhibit dichotomous behaviors in biology by supporting cellular physiology or instigating pathological protein aggregation1-3. Tau and - synuclein (Syn) are neuronal proteins that form heterotypic (Tau:Syn) condensates associated with both physiological and pathological processes. Tau and Syn functionally regulate microtubules8-12, but are also known to misfold and co-deposit in aggregates linked to various neurodegenerative diseases4,5,6,7, which highlights the paradoxically ambivalent effect of Tau:Syn condensation in health and disease. Here, we show that tubulin modulates Tau:Syn condensates by promoting microtubule interactions, competitively inhibiting the formation of homotypic and heterotypic pathological oligomers. In the absence of tubulin, Tau-driven protein condensation accelerates the formation of toxic Tau:Syn heterodimers and amyloid fibrils. However, tubulin partitioning into Tau:Syn condensates modulates protein interactions, promotes microtubule polymerization, and prevents Tau and Syn oligomerization and aggregation. We distinguished distinct Tau and Syn structural states adopted in tubulin-absent (pathological) and tubulin-rich (physiological) condensates, correlating compact conformations with aggregation and extended conformations with function. Furthermore, using various neuronal cell models, we showed that loss of stable microtubules, which occurs in Alzheimers disease and Parkinsons disease patients13,14, results in pathological oligomer formation and loss of neurites, and that functional condensation using an inducible optogenetic Tau construct resulted in microtubule stablization. Our results identify that tubulin is a critical modulator in switching Tau:Syn pathological condensates to physiological, mechanistically relating the loss of stable microtubules with disease progression. Tubulin restoration strategies and Tau-mediated microtubule stabilization can be potential therapies targeting both Tau-specific and Tau/Syn mixed pathologies.

biophysics↗

bioRxiv2024

Portal bile acids and microbiota along the murine intestinal tract exhibit sex differences in physiology

Microbes in the intestine transform bile acids during transit, altering their functional and signaling capacities before absorption into the portal vein. Sex differences in the gut microbiota have been noted, but their consequence on bile acid composition is unclear. Here, we investigated the composition and imputed functional potential of microbes in the small and large intestine together with portal and systemic bile acids. Female and male mice exhibit distinct microbial diversity throughout the length of the intestine leading to dimorphism in genes related to bile acid transformation. Subsequently, we found that the total portal bile acid concentrations were doubled in female mice compared to males. Conversely, oxo-bile acids that are rare in systemic circulation represented almost 30 percent of the portal pool in the male mice. Oxo- and deconjugated-bile acids were absent in germ-free mice consistent with microbe-mediated bile acid transformation. More importantly, gnotobiotic mice do not show sex differences in portal bile acids. Taken together, we demonstrate that sex differences in gut microbiota cause dimorphism in bile acid levels within the enterohepatic loop. HighlightsO_LIMurine microbial diversity exhibits sex-specific patterns along the small intestinal tract and colon. C_LIO_LIDistinct gut microbial profiles confer differential abundance of secondary bile acid metabolism genes in male and female mice. C_LIO_LIPortal bile acid compositions mirror sex differences in microbe-mediated bile acid processing that are lost in germ free conditions. C_LI

physiology↗

bioRxiv2022

Population genomic evidence of selection on structural variants in a natural hybrid zone

Structural variants (SVs) can promote speciation by directly causing reproductive isolation or by suppressing recombination across large genomic regions. Whereas examples of each mechanism have been documented, systematic tests of the role of SVs in speciation are lacking. Here, we take advantage of long-read (Oxford nanopore) whole-genome sequencing and a hybrid zone between two Lycaeides butterfly taxa (L. melissa and Jackson Hole Lycaeides) to comprehensively evaluate genome-wide patterns of introgression for SVs and relate these patterns to hypotheses about speciation. We found >100,000 SVs segregating within or between the two hybridizing species. SVs and SNPs exhibited similar levels of genetic differentiation between species, with the exception of inversions, which were more differentiated. We detected credible variation in patterns of introgression among SV loci in the hybrid zone, with 562 of 1419 ancestry-informative SVs exhibiting genomic clines that deviating from null expectations based on genome-average ancestry. Overall, hybrids exhibited a directional shift towards Jackson Hole Lycaeides ancestry at SV loci, consistent with the hypothesis that these loci experienced more selection on average then SNP loci. Surprisingly, we found that deletions, rather than inversions, showed the highest skew towards excess introgression from Jackson Hole Lycaeides. Excess Jackson Hole Lycaeides ancestry in hybrids was also especially pronounced for Z-linked SVs and inversions containing many genes. In conclusion, our results show that SVs are ubiquitous and suggest that SVs in general, but especially deletions, might contribute disproportionately to hybrid fitness and thus (partial) reproductive isolation.

genomics↗

bioRxiv2020

Leveraging biological complexity to predict patch occupancy in a recent host range expansion

Specialized plant-insect interactions are a defining feature of life on earth, yet we are only beginning to understand the factors that set limits on host ranges in herbivorous insects. To understand the colonization of alfalfa by the Melissa blue butterfly, we quantified arthropod assemblages and plant metabolites across a wide geographic region, while controlling for climate and dispersal inferred from population genomic variation. The presence of the butterfly is successfully predicted by direct and indirect effects of plant traits and interactions with other species. Results are consistent with the predictions of a theoretical model of parasite host range in which specialization is an epiphenomenon of the many barriers to be overcome rather than a consequence of trade-offs in developmental physiology. One sentence summaryThe formation of a novel plant-insect interaction can be predicted with a combination of biotic and abiotic factors, with comparable importance revealed for metabolomic variation in plants and interactions with mutualists, competitors and enemies.

ecology↗

bioRxiv2019

Identification of a parasitic symbiosis between respiratory metabolisms in the biogeochemical chlorine cycle

A key step in the chlorine cycle is the reduction of perchlorate (ClO4-) and chlorate (ClO3-) to chloride by microbial respiratory pathways. Perchlorate-reducing bacteria and chlorate-reducing bacteria differ in that the latter cannot use perchlorate, the most oxidized chlorine compound. However, a recent study identified a bacterium with the chlorate reduction pathway dominating a community provided only perchlorate. Here we confirm a metabolic interaction between perchlorate- and chlorate-reducing bacteria and define its mechanism. Perchlorate-reducing bacteria supported the growth of chlorate-reducing bacteria to up to 90% of total cells in communities and co-cultures. Chlorate-reducing bacteria required the gene for chlorate reductase to grow in co-culture with perchlorate-reducing bacteria, demonstrating that chlorate is responsible for the interaction, not the subsequent intermediates chlorite and oxygen. Modeling of the interaction suggested that cells specialized for chlorate reduction have a competitive advantage for consuming chlorate produced from perchlorate, especially at high concentrations of perchlorate, because perchlorate and chlorate compete for a single enzyme in perchlorate-reducing cells. We conclude that perchlorate-reducing bacteria inadvertently support large populations of chlorate-reducing bacteria in a parasitic relationship through the release of the intermediate chlorate. An implication of these findings is that undetected chlorate-reducing bacteria have likely negatively impacted efforts to bioremediate perchlorate pollution for decades.

microbiology↗

bioRxiv2019

Recent hybrids recapitulate ancient hybrid outcomes

Genomic outcomes of hybridization depend on selection and recombination in hybrids. Whether these processes have similar effects on hybrid genome composition in contemporary hybrid zones versus ancient hybrid lineages is unknown. Here we show that patterns of introgression in a contemporary hybrid zone in Lycaeides butterflies predict patterns of ancestry in geographically adjacent, older hybrid populations. We find a particularly striking lack of ancestry from one of the hybridizing taxa, Lycaeides melissa, on the Z chromosome in both the old and contemporary hybrids. The same pattern of reduced L. melissa ancestry on the Z chromosome is seen in two other ancient hybrid lineages. More generally, we find that patterns of ancestry in old or ancient hybrids are remarkably predictable from contemporary hybrids, which suggests selection and recombination affect hybrid genomes in a similar way across disparate time scales and during distinct stages of speciation and species breakdown.

evolutionary biology↗

bioRxiv2019

Genomic evidence of genetic variation with pleiotropic effects on caterpillar fitness and plant traits in a model legume

Plant-insect interactions are ubiquitous, and have been studied intensely because of their relevance to damage and pollination in agricultural plants, and to the ecology and evolution of biodiversity. Variation within species can affect the outcome of these interactions, such as whether an insect successfully develops on a plant species. Whereas specific genes and chemicals that mediate these interactions have been identified, studies of genome-or metabolome-wide intraspecific variation might be necessary to better explain patterns of host-plant use and adaptation often observed in the wild. Here, we present such a study. Specifically, we assess the consequences of genome-wide genetic variation in the model plant Medicago truncatula for Lycaeides melissa caterpillar growth and survival (i.e., larval performance). Using a rearing experiment and a whole-genome SNP data set (>5 million SNPs), we show that polygenic variation in M. truncatula explains 9-41% of the observed variation in caterpillar growth and survival. We detect genetic correlations among caterpillar performance and other plant traits, such as structural defenses and some anonymous chemical features; these genetic correlations demonstrate that multiple M. truncatula alleles have pleiotropic effects on plant traits and caterpillar growth or survival (or that there is substantial linkage disequilibrium among loci affecting these traits). We further show that a moderate proportion of the genetic effect of M. truncatula alleles on L. melissa performance can be explained by the effect of these alleles on the plant traits we measured, especially leaf toughness. Taken together, our results show that intraspecific genetic variation in M. truncatula has a substantial effect on the successful development of L. melissa caterpillars (i.e., on a plant-insect interaction), and further point toward traits mediating this genetic effect.

evolutionary biology↗