Biology subjects

Small, C. M.

Publications and source records attributed to Small, C. M..

8 recordsLinked to original sources

bioRxiv2025

Spontaneous mutant in threespine stickleback connects endosome trafficking disorders and inflammatory bowel diseases via changes in the gut microbiome

Endosomes are organelles that sort and traffic materials to different cellular compartments to enable performance of other organelles. One group of organelles supported by endosomes are lysosome related organelles (LROs) - which perform specialized functions using endocytosed or recycled materials from endosomes. LROs include melanosomes, lytic granules, platelet dense granules, lamellar bodies, and more. Individuals with endosome trafficking disorders commonly present with oculocutaneous albinism due to insufficient trafficking to - and maturation of - melanosomes. While the loss of pigment is an easily identifiable phenotype, mutations in endosome trafficking can also cause multi-organ system symptoms due to more broad disruption of LROs. Different endosome trafficking mutations impact LRO maturation at different degrees of severity and can impact a subset or all LROs leading to a wide range of symptomologies. Endosome trafficking disorders can present with oculocutaneous albinism (caused by mutated melanosomes), blood diathesis (caused by mutated platelet dense granules), pulmonary fibrosis (caused by mutated lamellar bodies), or chronic inflammation and inflammatory bowel disease (IBD) (caused by mutated lytic granules), as well as other symptoms. The shared inflammatory patterns of Hermansky-Pudlak Syndrome (HPS) and Inflammatory Bowel Disease (IBD) are well studied. However, impacts of this shared gastrointestinal inflammation on the gut microbiome remain unexplored. Using a spontaneously identified mutant family of threespine stickleback fish, we characterize changes in LROs and symptoms of oculocutaneous albinism. We further demonstrate that the shared gastrointestinal phenotypes of HPS and IBD extend to the gut microbiome showing similar shifts in microbial communities consistent with IBD. We argue endosome trafficking models should be explored as models to study the gut microbiome in addition to inflammatory phenotypes in IBD, and importantly, be used to test microbial/dietary interventions for both IBD and endosome trafficking disorders.

genetics↗

bioRxiv2024

Single Cell RNA Sequencing Provides Clues for the Developmental Genetic Basis of Syngnathidae's Evolutionary Adaptations

Seahorses, pipefishes, and seadragons are fishes from the family Syngnathidae that have evolved extraordinary traits including male pregnancy, elongated snouts, loss of teeth, and dermal bony armor. The developmental genetic and cellular changes that led to the evolution of these traits are largely unknown. Recent syngnathid genome assemblies revealed suggestive gene content differences and provide the opportunity for detailed genetic analyses. We created a single cell RNA sequencing atlas of Gulf pipefish embryos to understand the developmental basis of four traits: derived head shape, toothlessness, dermal armor, and male pregnancy. We completed marker gene analyses, built genetic networks, and examined spatial expression of select genes. We identified osteochondrogenic mesenchymal cells in the elongating face that express regulatory genes bmp4, sfrp1a, and prdm16. We found no evidence for tooth primordia cells, and we observed re-deployment of osteoblast genetic networks in developing dermal armor. Finally, we found that epidermal cells expressed nutrient processing and environmental sensing genes, potentially relevant for the brooding environment. The examined pipefish evolutionary innovations are composed of recognizable cell types, suggesting derived features originate from changes within existing gene networks. Future work addressing syngnathid gene networks across multiple stages and species is essential for understanding how their novelties evolved.

evolutionary biology↗

bioRxiv2022

Host genomic variation shapes gut microbiome diversity in threespine stickleback fish

Variation among host-associated microbiomes is well documented across species, populations, and individuals. However, the relative importance of host genetic differences for microbiome variation has been difficult to study. While research in humans has shown that genetic variation influences microbiome differences, confounding environmental effects have been very difficult to control. Isogenic laboratory models help isolate host genetic variants to test for influences of the environment or large-effect mutations on the microbiome, but such studies seldom incorporate natural genetic variation. Thus, although many important factors potentially impacting the microbiome have been identified, most studies have failed to test for the direct influence of natural host-genetic variation on microbiome differences within a controlled environment. Understanding the relationship between host-genetic and microbial variation also has biomedical implications, such as understanding why some humans are more susceptible to chronic inflammatory disorders like Crohns Disease and Ulcerative Colitis. To directly assess the relationship between host-genetic variation and microbiome variation, we performed a common garden experiment using laboratory lines of genetically divergent populations of threespine stickleback fish - a species that is an outbred model organism commonly used for determining the genetic basis of complex traits in the context of natural genetic variation. Using germ-free derivation and the powerful common garden design with these divergent lines, as well as hybrids between them, we detected clear associations between stickleback genetic dissimilarity and microbiome dissimilarity. Using genome-wide RAD-seq data we also identified regions of the genome underlying differences in microbiome composition. Importantly, we highlight that heritable morphological traits such as body size that are correlated with microbiome dissimilarity also need consideration in future microbiome studies.

evolutionary biology↗

bioRxiv2022

Candidate Genes Underlying Wolbachia-Associated Plastic Recombination Revealed by Ovarian Transcriptomics of D. melanogaster

Phenotypic plasticity is prevalent in nature and can facilitate the acclimation of organisms to changing environments. Recombination rate is plastic in a diversity of organisms and under a variety of stressful conditions. However, the recent finding that Wolbachia pipientis induces plastic recombination in Drosophila melanogaster was surprising because Wolbachia is not strictly considered a stressor to this host. We investigate the molecular mechanisms of Wolbachia-associated plastic recombination by comparing the ovarian transcriptomes of D. melanogaster infected and uninfected with Wolbachia. Our data suggest that infection explains a small amount of transcriptional variation but specifically affects genes related to cell cycle, translation, and metabolism. We also find enrichment of cell division and recombination processes among genes with infection-associated differential expression. Broadly, the transcriptomic changes identified in this study provide insight for the mechanisms of microbe-mediated plastic recombination, an important but poorly understood facet of host-microbe dynamics. Significance StatementThough it is documented that Wolbachia is associated with increased recombination in D. melanogaster, the underlying mechanisms remain unknown. Here we use ovarian transcriptomics in Wolbachia-infected and uninfected flies to identify candidate genes underlying Wolbachia-associated plastic recombination. We find that infection alters ovarian gene expression in subtle ways, and also identify exciting candidate genes for functional analysis in subsequent work. These candidate genes may be the first step in determining the molecular mechanisms underlying Wolbachia-associated plastic recombination. Moreover, our data contribute to the growing body of knowledge surrounding how Wolbachia affects host gene expression, and highlights how context-dependent these effects are.

evolutionary biology↗

bioRxiv2021

Leafy and Weedy Seadragon Genomes Connect Genic and Repetitive DNA Features to the Extravagant Biology of Syngnathid Fishes

Seadragons are a remarkable lineage of teleost fishes, and they are members of the family Syngnathidae renowned for having evolved male pregnancy. Comprising three known species, seadragons are widely recognized and admired for their fantastical body forms and coloration, and their specific habitat requirements have made them flagship representatives for marine conservation and natural history interests. Until recently, a gap has been the lack of significant genomic resources for seadragons. We have produced gene-annotated, chromosome-scale genome models for the leafy and weedy seadragon to advance investigations into evolutionary innovation and elaboration of morphological traits in seadragons as well as their pipefish and seahorse relatives. We identified several interesting features specific to seadragon genomes, including divergent non-coding regions near a developmental gene important for integumentary outgrowth, a high genome-wide density of repetitive DNA, and recent expansions of transposable elements and a vesicular trafficking gene family. Surprisingly, comparative analyses leveraging the seadragon genomes and additional syngnathid and outgroup genomes revealed striking, syngnathid-specific losses in the family of fibroblast growth factors (FGFs), which likely involve re-organization of highly conserved gene regulatory networks in ways that have not previously been documented in natural populations. The resources presented here serve as important tools for future evolutionary studies of developmental processes in syngnathids and will be a key resource for conservation studies of the extravagant seadragons and their relatives.

genomics↗

bioRxiv2019

QTL mapping of intestinal neutrophil variation and inflammation between threespine stickleback populations reveals links to neurodegenerative disease

Host selection is often required to foster beneficial microbial symbionts and suppress deleterious pathogens. In animals, the host immune system is at the center of this relationship. Failed host immune system-microbial interactions can result in a persistent inflammatory response in which the immune system indiscriminately attacks resident microbes, and at times the host cells themselves, leading to diseases such as Ulcerative Colitis, Crohns Disease, and Psoriasis. Host genetic variation has been linked to both microbiome diversity and to severity of such inflammatory disease states in humans. However, the microbiome and inflammatory states manifest as quantitative traits, which encompass many genes interacting with one another and the environment. The mechanistic relationships among all of these interacting components are still not clear. Developing natural genetic models of host-microbe interactions is therefore fundamental to understanding the complex genetics of these and other diseases. Threespine stickleback (Gasterosteus aculeatus) fish are a tractable model for attacking this problem because of abundant population-level genetic and phenotypic variation in the gut inflammatory response. Previous work in our laboratory identified genetically divergent stickleback populations exhibiting differences in intestinal neutrophil activity. We took advantage of this diversity to genetically map variation in an emblematic element of gut inflammation - intestinal neutrophil recruitment - using an F2-intercross mapping framework. We identified three regions of the genome associated with increased intestinal inflammation containing several promising candidate genes. Within these regions we found candidates in the Coagulation/Complement System, NFkB and MAPK pathways along with several genes associated with neurodegenerative diseases commonly accompanying intestinal inflammation as a secondary symptom. These findings highlight the utility of using naturally genetically diverse evolutionary mutant models such as threespine stickleback to better understand interactions among host genetic diversity and microbiome variation in health and disease states.

genetics↗

bioRxiv2018

Highly reproducible 16S sequencing facilitates measurement of host genetic influences on the stickleback gut microbiome

Multicellular organisms interact with resident microbes in important ways, and a better understanding of host-microbe interactions is aided by tools such as high-throughput 16S sequencing. However, rigorous evaluation of the veracity of these tools in a different context from which they were developed has often lagged behind. Our goal was to perform one such critical test by examining how variation in tissue preparation and DNA isolation could affect inferences about gut microbiome variation between two genetically divergent lines of threespine stickleback fish maintained in the same lab environment. Using careful experimental design and intensive sampling of individuals, we addressed technical and biological sources of variation in 16S-based estimates of microbial diversity. After employing a two-tiered bead beating approach consisting of tissue homogenization followed by microbial lysis in subsamples, we found an extremely minor effect of DNA isolation protocol relative to among-host microbial diversity differences. Individual abundance estimates for rare OTUs, however, showed much lower reproducibility. We found that the stickleback gut microbiome was highly variable, even among siblings housed together, but that an effect of host genotype (stickleback lineage) was detectable for some microbial taxa. Our findings demonstrate the importance of appropriately quantifying biological and technical variance components when attempting to understand major influences on high-throughput microbiome data.

microbiology↗

bioRxiv2018

Developmental tuning of mineralization drives morphological diversity of gill cover bones in sculpins and their relatives

The role of osteoblast placement in skeletal morphological variation is relatively wellunderstood, but alternative developmental mechanisms affecting bone shape remain largely unknown. Specifically, very little attention has been paid to variation in later mineralization stages of intramembranous ossification as a driver of morphological diversity. We discover the occurrence of specific, sometimes large regions of nonmineralized osteoid within bones that also contain mineralized tissue. We show through a variety of histological, molecular, and tomographic tests that this \"extended\" osteoid material is most likely nonmineralized bone matrix. This tissue type is a significant determinant of gill cover bone shape in the teleostean suborder Cottoidei. We demonstrate repeated evolution of extended osteoid in Cottoidei through ancestral state reconstruction and test for an association between its presence and habitat differences among species. Through measurement of extended osteoid at various stages of gill cover development in species across the phylogeny, we gain insight into possible evolutionary developmental origins of the trait. We conclude that this finetuned developmental regulation of bone matrix mineralization reflects heterochrony at multiple biological levels and is a novel mechanism for the evolution of diversity in skeletal morphology. This research lays the groundwork for a new model in which to study bone mineralization and evolutionary developmental processes, particularly as they may relate to adaptation during a prominent evolutionary radiation of fishes.

evolutionary biology↗