Biology subjects

Montgomery, S.

Publications and source records attributed to Montgomery, S..

13 recordsLinked to original sources

bioRxiv2025

Polygenic basis of incipient reproductive isolation in hybridizing populations is revealed by pangenomic and epigenetic divergence

Incipient reproductive isolation in the presence of gene flow has traditionally been attributed to a small number of major-effect loci under strong selection, representing only a minor fraction of the genome. Using the Heliconius erato adaptive radiation--a butterfly species with populations at varying levels of genetic differentiation--we employed a pan-genome approach to investigate genome-wide mutational divergence, epigenetic changes, and structural variation contributing to divergence. In contrast to earlier studies that identified only a few highly divergent loci, our high-resolution analysis reveals widespread divergence across the genome, suggesting polygenic barriers to gene flow. Epigenetic divergence assessed using ATAC-seq, highlights population-specific differences in chromatin accessibility, which may reflect SNPs distribution or precede genetic differentiation by reshaping regulatory landscapes. We also identified new structural variants, including polymorphic indels in open chromatin, that further associate with genomic divergence. Together, these findings show that the genomic landscape of H. erato is shaped by a dynamic interplay of mutational changes, epigenetic modifications, and structural variation. We emphasize the role of developmental, behavioral, and ecological adaptations and provide a broader perspective on the functional genetic basis of genome-wide divergence in Heliconius. This emerging polygenic framework offers a more detailed understanding of how reproductive barriers evolve under ongoing gene flow.

evolutionary biology↗

bioRxiv2023

An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism

Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.

bioinformatics↗

bioRxiv2023

Multiple axes of visual system diversity in Ithomiini, an ecologically diverse tribe of mimetic butterflies

The striking structural variation seen in arthropod visual systems can be explained by the overall quantity and spatio-temporal structure of light within habitats coupled with developmental and physiological constraints. However, little is currently known about how fine-scale variation in visual structures arise across shorter evolutionary and ecological scales. In this study, we characterise patterns of interspecific (between species), intraspecific (between sexes) and intraindividual (between eye regions) variation in the visual system of four ithomiine butterfly species. These species are part of a diverse 26-Myr-old Neotropical radiation where changes in mimetic colouration are associated with fine-scale shifts in ecology, such as microhabitat preference. By using a combination of selection analyses on visual opsin sequences, in-vivo ophthalmoscopy, micro-computed tomography (micro-CT), immunohistochemistry, confocal microscopy, and neural tracing, we quantify and describe physiological, anatomical, and molecular traits involved in visual processing. Using these data, we provide evidence of substantial variation within the visual systems of Ithomiini, including: i) relaxed selection on visual opsins, perhaps mediated by habitat preference, ii) interspecific shifts in visual system physiology and anatomy, and iii) extensive sexual dimorphism, including the complete absence of a butterfly-specific optic neuropil in the males of some species. We conclude that considerable visual system variation can exist within diverse insect radiations, hinting at the evolutionary lability of these systems to rapidly develop specialisations to distinct visual ecologies, with selection acting at both the perceptual, processing, and molecular level. Summary statementPhysiological, anatomical, and molecular evidence of extensive visual system variation within a diverse butterfly radiation, hinting at the lability of visual systems to evolve specialisations to distinct visual environments.

evolutionary biology↗

bioRxiv2023

Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

microbiology↗

bioRxiv2023

Pollen-feeding delays reproductive senescence and maintains toxicity of Heliconius butterflies

Dietary shifts may act to ease energetic constraints and allow organisms to optimise life-history traits. Heliconius butterflies differ from other nectar-feeders due to their unique ability to digest pollen, which provides a reliable source of amino acids to adults. Pollen-feeding has been associated with prolonged adult lifespan and increased fertility, yet there is a lack of empirical data demonstrating how pollen consumption influences key fitness traits, including chemical defences and adult body weight, as well as fertility over their elongated lifespan. Here, we investigated the effect of pollen-feeding on fertility, weight and chemical defences, as well as offspring defences, controlling for butterfly age and sex. Recently emerged Heliconius erato butterflies of similar size were fed for 14 or 45 days on one of three diets: sugar solution only, or sugar solution replenished with either amino acid supplement or pollen. At the end of the experiment, oviposition assays were performed to evaluate fertility, and afterwards all butterflies and eggs were weighed and used for quantification of cyanogenic glucosides (CG). We found that there is an age-specific and sex-specific effect of pollen-feeding on butterfly weight, with both the sugar-only and amino-acid supplement diets reducing the weight of old females (45d), but not young females (14d) or males of any age. Females fed only sugar significantly reduced their egg-laying through adulthood, whereas females that had access to pollen maintained their fertility. Diet had a significant effect on the maintenance of the chemical defence of females, but not males. Curiously, even though females that have access to pollen were heavier, more toxic and laid more eggs, this did not translate into improvements in offspring defences, as eggs from butterflies of all ages and diet treatments had similar CG content. Our results emphasise the importance of controlling for age-specific and sex-specific effects in studies of life-history evolution and demonstrate that dietary novelty can relax energetic constraints.

evolutionary biology↗

bioRxiv2022

Fc mediated pan-sarbecovirus protection after alphavirus vector vaccination

Two group 2B {beta}-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. The mechanisms of cross protection driven by the sarbecovirus spike, a dominant immunogen, are less clear yet critically important for pan-sarbecovirus vaccine development. We evaluated the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination did not prevent virus replication, it protected against lethal heterologous disease outcomes in both SARS-CoV-2 and clade 2 bat sarbecovirus HKU3-SRBD challenge models. The spike vaccines tested primarily elicited a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. We found non-neutralizing antibody functions that mediated cross protection in wild-type mice were mechanistically linked to FcgR4 and spike S2-binding antibodies. Protection was lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.

microbiology↗

bioRxiv2021

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in PSC.

ObjectiveConflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: Define complex interactions between resident microbes and their association in PSC patients by studying antibiotic-treated specific pathogen-free (SPF) and germ-free (GF) multi-drug-resistant 2 deficient (mdr2-/-) mice. DesignWe measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, fecal 16s rRNA gene profiling, and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients. ResultsGF mdr2-/- mice had exaggerated hepatic inflammation and fibrosis with 100% mortality by 8 weeks; early SPF autologous stool transplantation rescued liver-related mortality. Broad-spectrum antibiotics and vancomycin alone accelerated disease in weanling SPF mdr2-/- mice, indicating that vancomycin-sensitive resident microbiota protect against hepatobiliary disease. Vancomycin treatment selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased cytolysin-expressing E. faecalis and E. coli liver translocation; colonization of gnotobiotic mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated liver inflammation and mortality. Lachnospiraceae colonization of antibiotic pre-treated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, while Lachnospiraceae-produced SCFA decreased fibrosis. Fecal E. faecalis/ Enterobacteriaceae was positively and Lachnospiraceae was negatively associated with PSC patients clinical severity Mayo risk scores. ConclusionsWe identified specific functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical outcomes. These insights may guide personalized targeted therapeutic interventions in PSC patients.

microbiology↗

bioRxiv2021

A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice

SARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.

microbiology↗

bioRxiv2021

Identification of putative causal loci in whole-genome sequencing data via knockoff statistics

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimers Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

genetics↗

bioRxiv2021

Early therapy with remdesivir and antibody combinations improves COVID-19 disease in mice

Improving the standard of clinical care for individuals infected with SARS-CoV-2 variants is a global health priority. Small molecule antivirals like remdesivir (RDV) and biologics such as human monoclonal antibodies (mAb) have demonstrated therapeutic efficacy against SARS-CoV-2, the causative agent of COVID-19. However, it is not known if combination RDV/mAb will improve outcomes over single agent therapies or whether antibody therapies will remain efficacious against variants. In kinetic studies in a mouse-adapted model of ancestral SARS-CoV-2 pathogenesis, we show that a combination of two mAbs in clinical trials, C144 and C135, have potent antiviral effects against even when initiated 48 hours after infection. The same antibody combination was also effective in prevention and therapy against the B.1.351 variant of concern (VOC). Combining RDV and antibodies provided a modest improvement in outcomes compared to single agents. These data support the continued use of RDV to treat SARS-CoV-2 infections and support the continued clinical development of the C144 and C135 antibody combination to treat patients infected with SARS-CoV-2 variants.

microbiology↗

bioRxiv2018

Reproductive capacity evolves in response to ecology through common developmental mechanisms in Hawaiian Drosophila

Lifetime reproductive capacity, or the total number of offspring that an individual can give rise to in its lifetime, is a fitness component critical to the evolutionary process. In insects, female reproductive capacity is largely determined by the number of ovarioles, the egg-producing subunits of the ovary. Recent work has provided insights into the genetic and environmental control of ovariole number in Drosophila melanogaster. However, whether regulatory mechanisms discovered under laboratory conditions also explain evolutionary variation in natural populations is an outstanding question. Here we report, for the first time, insights into the mechanisms regulating ovariole number and its evolution among Hawaiian Drosophila, a large adaptive radiation of fruit flies in which the highest and lowest ovariole numbers of the genus have evolved within 25 million years. Using phylogenetic comparative methods, we show that ovariole number variation among Hawaiian Drosophila is best explained by adaptation to specific oviposition substrates. Further, we show that evolution of oviposition on ephemeral egg-laying substrates is linked to changes the allometric relationship between body size and ovariole number. Finally, we provide evidence that the developmental mechanism principally responsible for controlling ovariole number in D. melanogaster also regulates ovariole number in natural populations of Hawaiian drosophilids. By integrating ecology, organismal growth, and cell behavior during development to understand the evolution of ovariole number, this work connects the ultimate and proximate mechanisms of evolutionary change in reproductive capacity.

evolutionary biology↗

bioRxiv2018

Zfp189 Mediates Stress Resilience Through a CREB-Regulated Transcriptional Network in Prefrontal Cortex

Stress resilience involves numerous brain-wide transcriptional changes. Determining the organization and orchestration of these transcriptional events may reveal novel antidepressant targets, but this remains unexplored. Here, we characterize the resilient transcriptome with co-expression analysis and identify a single transcriptionally-active uniquely-resilient gene network. Zfp189, a previously unstudied zinc finger protein, is the top network key driver and its overexpression in prefrontal cortical (PFC) neurons preferentially activates this network, alters neuronal activity and promotes behavioral resilience. CREB, which binds Zfp189, is the top upstream regulator of this network. To probe CREB-Zfp189 interactions as a network regulatory mechanism, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB selectively to the Zfp189 promoter. This single molecular interaction in PFC neurons recapitulates the pro-resilient Zfp189-dependent downstream effects on gene network activity, electrophysiology and behavior. These findings reveal an essential role for Zfp189 and a CREB-Zfp189 regulatory axis in mediating a central transcriptional network of resilience.

neuroscience↗

bioRxiv2017

Population-specific imputation of gene expression improves prediction of pharmacogenomic traits for African Americans

Genome-wide association studies (GWAS) are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power, and allows the effects of both protein coding variation as well as variation in expression to be combined into \"gene level\" effects.\n\nPrevious work has shown that warfarin dose can be predicted using information from genetic variation that affects protein coding regions. Here, we introduce a method that improves the predicted dose by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression--on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic (PK) and pharmacodynamic (PD) pathways of warfarin within training and validation sets comprising both European and African-descent individuals. We build gene-tissue signatures associated with warfarin dose, and identify a signature of eleven gene-tissue pairs that significantly augment the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Our results demonstrate that imputed expression can improve dose prediction, in a population-specific manner.

genomics↗