Biology subjects

Allen, B. M.

Publications and source records attributed to Allen, B. M..

7 recordsLinked to original sources

bioRxiv2026

Context-dependent ATP7 Interactions with Parkinson's Disease-associated Genes Modulate Copper Homeostasis Phenotypes

Copper is an essential micronutrient required by enzymes that catalyze oxygen-dependent reactions, but toxic in excess. Mutations in the ATP7A and ATP7B copper transporters cause neuropsychiatric symptoms and neurodegeneration by mechanisms that remain to be elucidated. We previously reported that the ATP7A biochemical interactome is enriched in Parkinsons disease (PD) and neurodegeneration associated proteins, yet the functional outcomes of these interactions are unknown. Using Drosophila, we tested genetic interactions between ATP7 mutants that alter copper levels and a subset of these PD and neurodegeneration causative genes and found sex differences with some candidate genes enhancing ATP7 deleterious phenotypes in both sexes, while others were sex specific. Most notably, we found that Lrrk2 (Lrrk), the most commonly mutated gene in familial forms of PD, protects against ATP7 dysfunction in epidermal epithelial cells with a stronger effect in males than females. However, in dopaminergic neurons Lrrk plays a role in intracellular copper induced toxicity in females but not males, supporting context dependent interactions between ATP7A and PD-associated genes to protect against disruptions in copper homeostasis. Summary StatementWe performed a genetic interaction screen to explore the relationship between copper homeostasis and Parkinsons disease and other neurodegeneration associated genes.

genetics↗

bioRxiv2026

Distinct signaling mechanisms and proteome phenotypes are elicited by compartment-specific genetic defects of copper homeostasis

Impairments to the complex machinery regulating copper homeostasis lead to neurodevelopmental diseases, demonstrating the importance of copper for neuronal health and maintenance. The exact mechanisms by which the brain responds to copper deficiency following disruptions to the copper transporters ATP7A and CTR1 in conditions such as Menkes disease remain unclear, though failure to supply complex IV of the respiratory chain with copper is suspected to account for substantial pathology. Here, we studied mechanisms of copper deficiency using systems biology approaches to contrast isogenic CTR1- and COX17-deficient cells, which model copper deficiency at the level of the whole cell or complex IV, respectively. Multiomics approaches revealed distinct signaling mechanisms elicited by compartment-specific genetic defects of copper homeostasis, spanning multiple organelles and biological functions. Specifically, COX17 KO cells exhibited elevated AMPK activity and blunted mTOR activity relative to CTR1-null cells. Manipulating mTOR activity elicited inverse effects on survival in CTR1-deficient cells and flies as compared to their COX17-deficient counterparts. Increased mTOR activity and downstream protein synthesis is adaptive in models of copper deficiency but deleterious in COX17-deficient cells and flies. We propose that mTOR activation represents a resilience mechanism that fails following sustained copper deficiency and impairments to mitochondrial respiration. SignificanceO_LIComparative proteomics reveals distinct molecular mechanisms downstream of compartmentalized copper deficiency C_LIO_LICOX17- and CTR1-deficient cells exhibit distinct patterns of AMPK/mTOR pathway activity C_LIO_LImTOR and downstream S6K activity is protective in cellular copper deficiency but not in compartmentalized mitochondrial copper deficiency C_LI

cell biology↗

bioRxiv2024

Biosynthetic Gene Cluster Diversity Across Native and Introduced Populations of an Ectomycorrhizal Fungus, Suillus luteus

Non-pathogenic fungi are being increasingly recognized for their involvement in biological invasions, where they have the potential to cause ecological and economical harm. One notable example is the ectomycorrhizal (EcM) fungus, Suillus luteus, which is commonly found co-invading with non-native pines that have escaped from commercial pine plantations across the Southern Hemisphere. In such invasions, selection pressures imposed by novel plants, soil microbes, and environmental conditions, as well as impoverished assemblages of co-invading EcM fungi, may exert particularly strong selective effects and contribute to driving evolutionary divergence in traits. We investigated the potential impact of this global co-introduction on biosynthetic gene cluster (BGC) diversity in native and introduced populations of S. luteus. We found that native populations demonstrated higher BGC diversity at both the gene and clan levels compared to introduced populations. Additionally, we identified a collection of unique BGCs as well as 24 highly conserved clans, including two featuring known pathways, within both native and introduced populations. Furthermore, our study confirmed the presence of three previously identified clades of S. luteus with distinct gene cluster family (GCF) diversity. Thus, our study concludes that the introduction of S. luteus has driven evolutionary changes in its BGCs, underscoring the broader implications of global co-introductions on fungal adaptation in new environments.

evolutionary biology↗

bioRxiv2024

Variation in Biosynthetic Gene Clusters Among Lifestyles Across Kingdom Fungi

Biosynthetic gene clusters (BGCs) produce secondary metabolites, many of which are involved in trophic interactions and carbon acquisition lifestyles of fungi. As such, BGCs are hypothesized to exhibit evolutionary diversification across those lifestyles. We tested this hypothesis by analyzing predicted BGCs in more than 1000 fungal genomes, and their variation among fungal lineages and across putative fungal lifestyles (trophic modes). Analyses revealed that specific BGC classes, such as PKSI, RiPPs, and terpenes, exhibit significant phylogenetic signals, whereas others, like NRPS and PKS-NRPS Hybrids, do not. BGC abundance was associated with fungal lifestyles: pathotrophs generally had lower BGC abundance, while combined lifestyles such as saprotroph-symbiotrophs had higher BGC abundances. These findings suggest that both phylogenetic history and ecological strategies drive BGC distribution, highlighting their roles in fungal biochemical diversification. Understanding these patterns provides insights into fungal community ecology and the evolutionary processes shaping their biosynthetic potential.

genomics↗

bioRxiv2024

An Experimental Test of Local Adaptation in Native and Introduced Populations of an Ectomycorrhizal Fungus, Suillus luteus

After species introductions and subsequent invasions, organisms often encounter intense selection pressures from biotic and abiotic aspects of novel environments, driving rapid evolutionary changes that potentially lead to local adaptation. This study aimed to investigate how invasion has influenced symbiotic interactions through rapid evolution in exotic isolates of the ectomycorrhizal (EcM) fungus Suillus luteus, which was co-introduced with obligately symbiotic pine trees into the Southern Hemisphere. We conducted a cross-inoculation experiment testing the compatibility of sympatric and allopatric pairings between pines and isolates of S. luteus from native and introduced populations. Our results showed that plant and fungal performance were substantially affected by these pairings, largely supporting a hypothesis of local maladaptation. Several performance metrics indicated stronger outcomes in allopatric pairings compared to sympatric ones. This suggests that fungal isolates may have evolved traits that are less beneficial or even somewhat harmful to their local host plants. These findings highlight the complex dynamics of coevolution and emphasize the necessity of considering both local adaptation and maladaptation in understanding species interactions.

evolutionary biology↗

bioRxiv2021

Meta-analysis of immune induced gene expression changes in diverse Drosophila melanogaster innate immune responses

BackgroundOrganisms are commonly infected by a diverse array of pathogen types including bacteria, fungi, viruses, and parasites, and mount functionally distinct responses to each of these varied immune challenges. Host immune responses are characterized by the induction of gene expression in response to infection. However, the extent to which expression changes are shared among responses to distinct pathogens is largely unknown. ResultsWe performed meta-analysis of gene expression data collected from Drosophila melanogaster following infection with a wide array of pathogens. We identified 62 genes that are significantly induced by infection. While many of these infection-induced genes encode known immune response factors, we also identified 21 genes that have not been previously associated with host immunity. Examination of the upstream flanking sequences of the infection-induced genes lead to the identification of two conserved enhancer sites. These sites correspond to conserved binding sites for GATA and nuclear factor {kappa}B (NF{kappa}B) family transcription factors and are associated with higher levels of transcript induction. We further identified 31 genes with predicted functions in metabolism and organismal development that are significantly downregulated following infection by diverse pathogens. ConclusionsOur study identifies conserved gene expression changes in Drosophila melanogaster following infection with varied pathogens, and transcription factor families that may regulate this immune induction. These findings provide new insight into transcriptional changes that accompany Drosophila immunity. They may suggest possible roles for the differentially regulated genes in innate immune responses to diverse classes of pathogens, and serve to identify candidate genes for further empirical study of these processes.

genetics↗

bioRxiv2019

The Development, Function, and Plasticity of the Immune Macroenvironment in Cancer

Harnessing immune defense mechanisms has revolutionized cancer therapy, but our understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. Here, we use mass cytometry to define the organism-wide immune landscape in response to tumor development across five tissues in eight tumor models. Systemic immunity was dramatically altered across mouse models and cancer patients, with changes in peripheral tissues differing from those in the tumor microenvironment and taking place in phases during tumor growth. This tumor-experienced immune system mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Disruptions in T cell responses were not cell-intrinsic but rather due to reduced responses in antigen-presenting cells (APCs). Promoting APC activation was sufficient to restore T cell responses to orthogonal infection. All systemic immune changes were reversed with surgical tumor resection, revealing remarkable plasticity in the systemic immune state, which contrasts with terminal immune dysfunction in the tumor microenvironment. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.

immunology↗