Biology subjects

Randall, J.

Publications and source records attributed to Randall, J..

7 recordsLinked to original sources

bioRxiv2026

ATG-9-Induced Lysosomal Membrane Permeabilization and Cell Death in a Caenorhabditis elegans model of Mucolipidosis type IV

Mucolipidosis type IV is a lysosomal storage disease that is characterized by delayed psychomotor development and retinal degeneration due to cell death, in addition to other symptoms that are due to aberrant functions of live tissues. Caenorhabditis elegans CUP-5 is the orthologue of human TRPML1, the protein that is dysfunctional in Mucolipidosis type IV patients. Mirroring Mucolipidosis type IV pathology, loss of C. elegans CUP-5 results in developing intestinal cell death in embryos leading to embryonic lethality, while other tissues in adults lacking CUP-5 are alive but dysfunctional. We had previously shown that ESCRT-Associated proteins and the ATP-Binding Cassette Transporter MRP-4 are necessary for acquiring aberrant and poorly functional lysosomes in the absence of CUP-5. In this study, we show that the aberrant lysosomes permeabilize or rupture, thus releasing lysosomal degradative enzymes that kill cells in the absence of CUP-5. We also show that the autophagy-related protein ATG-9 mediates, in an autophagy-independent manner, this lysosomal permeabilization. We finally propose phenotypic and biochemical models linking CUP-5 to lysosomal defects and cell death.

cell biology↗

bioRxiv2026

Sea-level and climate changes drive lineage diversification in the imperiled Venus flytrap (Dionaea muscipula J. Ellis, Droseraceae)

Venus flytrap (Dionaea muscipula) is an insectivorous plant in the monotypic genus Dionaea, endemic to the Southeastern United States, and found in a small geographic range in North and South Carolina. Its unique morphology and natural history have intrigued biologists for centuries, yet the evolution of populations has not been adequately characterized. Population decline, driven primarily by disruptive land conversion, fire suppression, and illegal harvesting/poaching underscores the urgency of defining the genetic diversity in the present population to guide species conservation. We applied a genome-wide SNP dataset to analyze admixture and population structure and used coalescent modeling to trace the ancestry and migration of geographically distinct population clusters. Our population dynamics model supports four lineages, with the North Cape Fear Arch lineage as the ancestor of all lineages and two genetically distinct Sandhills lineages derived from the South Cape Fear Arch lineage independently at [~]13 Ma and [~]3 Ma, respectively, during peak climate optima periods and maximal sea level rise. Severe population decline events occurred among all lineages, with two ancient instant bottleneck population decline events in Sandhills lineages and two recent ones in the two Cape Fear Arch lineages, which contributed to the current genetic structure. Shorter peduncle lengths in Sandhills populations correspond with suspected local adaptation to Sandhills habitats.

evolutionary biology↗

bioRxiv2026

Dissecting the regulatory and genomic drivers of the dichogamy determining G-locus in pecan

Many hermaphroditic species increase outcrossing rates by partitioning reproduction so that male and female organs mature at different times, a phenomenon known as dichogamy. Previous work has documented that dichogamy in pecan trees is governed by the Mendelian super-gene "G-locus"; however, its non-recombinant sex chromosome-like architecture has impeded quantitative genetic exploration and candidate gene discovery. Here, we probe the genetic drivers of the G-locus through a pangenome-integrated quantitative genomics experiment. We first provide one of the clearest examples to date of mapping bias, where a linear reference-based GWAS discovered 66 off-target peaks while mapping with a pangenome graph reference resolved the known single Mendelian locus. Across six new genome assemblies, the fully haplotype phased G-locus QTL spanned 223-491kb and included 25 candidate gene families. The strongest candidate gene encoded a MATE efflux protein and had dominant allele-specific action during male flower developmental stages. Combined, these candidates and genomic resources provide a powerful foundation for breeding and optimal dichogamy phenotype engineering for future pecan orchards.

genomics↗

bioRxiv2025

Leveraging species-wide variation and patterns of adaptation to inform pecan crop improvement efforts

The genetic basis of adaptation is a fundamental question in evolutionary biology, and understanding how species will be able to adapt to changing conditions across their range has important implications for conservation and agriculture. To accurately interrogate the genetics of adaptation and assess the adaptive capacity of a species requires also characterizing the ways other mechanisms, including geographic distance and population dynamics, shape genetic variation. Pecan is an ecologically, culturally, and economically important North American tree, and a broader understanding of the genetics of environment adaptation will aid pecan conservation, breeding, and commercial management. Here, we use an expansive set of more than 700 pecan genotypes in combination with the first haplotype-resolved genome assembly for pecan to assess species-wide genetic variation and evaluate environmental adaptation across the native distribution. We identify five gene pools in pecan, with the lowest diversity in southern gene pools, and present evidence that gene pools began differentiating during multiple glacial cycles. Using complementary genotype-environment association approaches, we infer species-wide patterns of environmental adaptation. With these results, we predict mismatches in adaptation for pecan genotypes to different environments, including future environment scenarios. We see that in all locations, present-day genotypes incur some level of predicted maladaptation to simulated future environments, but current genetic diversity may provide a valuable source of resilience to future conditions through assisted migration. These results expand the understanding of environmental adaptation in pecan and provide insight into how long-lived species will be able to adapt to future conditions.

evolutionary biology↗

bioRxiv2025

Defining the importance of the arginine loop region of protegrin-1 for antimicrobial activity towards colistin-resistant Klebsiella pneumoniae.

Carbapenem resistant Klebsiella pneumoniae extreme drug resistance has warranted the use of colistin as a last-resort antibiotic but these isolates are now displaying increasing rates of colistin resistance. This is in large part due to the modifications made to the lipid A by the PhoPQ two component system. Host defense peptides (HDPs) are like colistin in that they are both positively charged and display amphipathic character, however are not impacted by lipid A modifications to the extent of colistin. To understand how HDPs can penetrate colistin resistant membranes we performed a deep mutational scanning analysis of protegrin-1 and revealed that amino acids mutations that resulted in alteration of peptide structure had more impact on antimicrobial activity than a reduction in charge. Probing single and double amino acid variants using membrane analysis and molecular modeling revealed the loss of antimicrobial activity correlated with decreased inner membrane leakage and pore modeling predicting decreased pore size,

microbiology↗

bioRxiv2022

Anatomical, ontogenetic, and genomic homologies guide reconstructions of the teeth-to-baleen transition in mysticete whales

The transition in Mysticeti (Cetacea) from capture of individual prey using teeth to bulk filtering batches of small prey using baleen ranks among the most dramatic evolutionary transformations in mammalian history. We review phylogenetic work on the homology of mysticete feeding structures from anatomical, ontogenetic, and genomic perspectives. Six characters with key functional significance for filter-feeding behavior are mapped to cladograms based on 11 morphological datasets to reconstruct evolutionary change across the teeth-to-baleen transition. This comparative summary within a common parsimony framework reveals extensive conflicts among independent systematic efforts but also broad support for the newly named clade Kinetomenta (Aetiocetidae + Chaeomysticeti). Complementary anatomical studies using CTscans and ontogenetic series hint at commonalities between the developmental programs for teeth and baleen, lending further support for a transitional chimaeric feeder scenario that best explains current knowledge on the transition to filter feeding. For some extant mysticetes, the ontogenetic sequence in fetal specimens recapitulates the inferred evolutionary transformation: from teeth, to teeth and baleen, to just baleen. Phylogenetic mapping of inactivating mutations reveals mutational decay of dental genes related to enamel formation before the emergence of crown Mysticeti, while baleen genes that were repurposed or newly derived during the evolutionary elaboration of baleen currently are poorly characterized. Review and meta-analysis of available data suggest that the teeth-to-baleen transition in Mysticeti ranks among the best characterized macroevolutionary shifts due to the diversity of data from the genome, the fossil record, comparative anatomy, and ontogeny that directly bears on this remarkable evolutionary transformation.

evolutionary biology↗

bioRxiv2020

Convergent and distributed effects of the schizophrenia-associated 3q29 deletion on the human neural transcriptome

The 3q29 deletion (3q29Del) confers >40-fold increased risk for schizophrenia. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, post-translational modifications, chromatin remodeling and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging "guilt by association", we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological post-mortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.

genetics↗