Biology subjects

Saunders, R.

Publications and source records attributed to Saunders, R..

8 recordsLinked to original sources

bioRxiv2026

Global cell-state and gene-program representations reveal conserved and context-specific perturbation responses of cells

Understanding how cell states change in response to genetic perturbations is critical for gene-function and therapeutics discovery. However, state-of-the-art deep-learning models trained on large single-cell omics datasets still struggle to accurately predict cellular responses to perturbations, highlighting the need for a better understanding of the cell-state space and how cells move through this space. Here, we present a contrastive learning model that integrates diverse scRNA-seq datasets into a global, interpretable cell-state manifold. We further develop a framework to integrate this global cell-state manifold with genome-scale perturbation data to identify gene-expression programs that define principal axes of cell-state transitions and functional embeddings of genes that define major perturbation classes. Applying this framework across Perturb-seq datasets on different cell types reveals conserved cellular responses to perturbations, as well as cell-type-specific rewiring of stress responses. Moreover, we perform a genome-scale Perturb-seq screen in human embryonic stem cells, validating and extending these findings and uncovering a class of mesenchymal transitions induced by diverse perturbations to cellular stress-response pathways.

systems biology↗

bioRxiv2023

The core microbiome of cultured Pacific oyster spat develops with age but not mortality

The Pacific oyster (Magallana gigas, also known as Crassostrea gigas) is the most widely cultured shellfish worldwide, but production has been affected by mortality events. This includes mortality events in hatcheries that can threaten the seed supply for growers. There are several pathogens that cause disease in oysters, but in many cases mortality events cannot be attributed to a single agent, and appear to be multifactorial and involve a combination of environmental variables, microbial interactions and disbiosis. In many organisms, a mature microbiome provides resilience against pathogens and environmental stressors. In this study we investigated the microbiomes of cohorts of freshly settled oyster spat, some of which experienced notable mortality. Deep sequencing of 16S rRNA gene fragments did not show a significant difference among the microbiomes of cohorts experiencing different levels of mortality, but revealed a characteristic core microbiome with 74 taxa. Irrespective of mortality, the spat core microbiomes changed significantly in the relative abundance of taxa as the spat aged; yet, remained distinct from the microbial community in the surrounding water. The core microbiome was dominated by bacteria in the families Rhodobacteraceae, Nitrosomonadaceae, Flavobacteriaceae, Pirellulaeceae and Saprospiraceae. Of these, 14 taxa were indicative for the change in the core microbiome, which we designated as the "Hard-Core Microbiome". The variability in diversity and richess of members of the core taxa decreased with oyster-spat aging, implying niche occupation. The study further accounts for the exchange of microbes with surrounding water during the core microbiome development. The observed shifts in the core microbiome with ageing oyster spat implies a crucial developmental period for the core microbiome of rearing spat. ImportanceThe Pacific oyster (Magallana gigas, also known as Crassostrea gigas) is the most widely cultivated shellfish and is important to the economy of many coastal communities. However, high mortality of spat during the first few days following metamorphosis can affect the seed supply to oyster growers. Here, we show that the microbiome composition of recently settled oyster spat experiencing low or high mortality were not significantly different. Instead, development of the core microbiome were associated with spat aging and was partially driven by dispersal through the water. These findings imply the importance of early stage rearing conditons for spat microbiome development in aquaculture facilities. Furthermore, shellfish growers could gain information about the developmental state of the oyster spat microbiome by assessing key taxa. Additionally, the study provides a baseline micriobiome for future hypothesis testing on developing spat.

microbiology↗

bioRxiv2023

The Prokaryotic and Eukaryotic Microbiome of Pacific Oyster Spat is Shaped by Ocean Warming but not Acidification

Pacific oysters (Magallana gigas, also known as Crassostrea gigas), the most widely farmed oysters, are under threat from climate change and emerging pathogens. In part, their resilience may be affected by their microbiome, which, in turn, may be influenced by ocean warming and acidification. Consequently, for three weeks, we exposed early-development Pacific oyster spat to different temperatures (18 and 24 {degrees}C) and pCO2 levels (800, 1600 and 2800 {micro}atm) in a fully crossed design. Under all conditions, the microbiome developed over time, with potentially pathogenic ciliates (Uronema marinum) greatly reduced in all treatments, suggesting that the spats microbiome undergoes adaptive shifts as the oysters age. The microbiome composition also differed significantly with temperature, but not acidification, indicating that M. gigas spat microbiomes can be altered by ocean warming but resilient to ocean acidification in our experiments. These findings highlight the spat microbiomes flexibility to environmental changes as well as its "protective" capability against potentially pathogenic microbes.

microbiology↗

bioRxiv2022

Metatranscriptomics reveals a shift in microbial community composition and function during summer months in a coastal marine environment

Temperate coastal marine waters are often thermally stratified from spring through fall but can be dynamic and disrupted by tidal currents and wind-driven upwelling. These mixing events introduce deeper, cooler water with a higher partial pressure of CO2 (pCO2), and its associated microbial communities to the surface. Anecdotally, these events impact shellfish hatcheries and farms, warranting improved understanding of changes in composition and activity of marine microbial communities in relation to environmental processes. To characterize both compositional and functional changes associated with abiotic factors, here we generate a reference metatranscriptome from the Strait of Georgia over representative seasons and analyze metatranscriptomic profiles of the microorganisms present within intake water containing different pCO2 levels at a shellfish hatchery in British Columbia from June through October. Abiotic factors studied include pH, temperature, alkalinity, aragonite, calcite and pCO2. Community composition changes were observed to occur at broad taxonomic levels, and most notably to vary with temperature and pCO2. Functional gene expression profiles indicated a strong difference between early (June-July) and late summer (August-October) associated with viral activity. The taxonomic data suggests this could be due to the termination of cyanobacteria and phytoplankton blooms by viral lysis in the late season. Functional analysis indicated fewer differentially expressed transcripts associated with abiotic variables (e.g., pCO2) than with the temporal effect. Microbial composition and activity in these waters varies with both short-term effects observed alongside abiotic variation as well as long-term effects observed across seasons. The analysis of both taxonomy and functional gene expression simultaneously in the same samples by environmental RNA (eRNA metatranscriptomics) provided a more comprehensive view for monitoring water bodies than either would in isolation.

genetics↗

bioRxiv2021

Flanking sequences regulate the toxicity, non-ATG translation, and aggregation of RNA with tandem CAG Repeats

Nucleotide repeat-expansions cause several neurodegenerative disorders, including Huntingtons disease and spinocerebellar ataxia. The expanded repeat-containing RNA transcribed from the affected loci agglomerate in the nucleus as pathogenic foci. Here we demonstrate that depending on their surrounding sequence context, RNAs with expanded CAG repeats can also undergo nuclear export and aggregate in the cytoplasm. Cytoplasmic aggregation of repeat-containing RNA coincides with several disease hallmarks, including repeat-associated non-AUG (RAN) translation, mislocalization of RNA binding proteins, and cell toxicity. Interestingly, the repeat-containing RNA co-aggregate with RAN translation products. Inhibition of RAN translation prevents cytoplasmic RNA aggregation and also alleviates cell toxicity. Our findings provide a cogent explanation for aberrant cytoplasmic localization of RNA binding proteins and implicate cis-acting flanking sequences in mediating RAN translation and disease.

molecular biology↗

bioRxiv2019

Relative genomic impacts of translocation history, hatchery practices, and farm selection in Pacific oyster Crassostrea gigas throughout the Northern Hemisphere

Pacific oyster Crassostrea gigas, endemic to coastal Asia, has been translocated globally throughout the past century, resulting in self-sustaining introduced populations (naturalized). Oyster aquaculture industries in many parts of the world depend on commercially available seed (hatchery-farmed) or naturalized/wild oysters to move onto a farm (naturalized-farmed). It is therefore important to understand genetic variation among populations and farm types. Here we genotype naturalized/wild populations from France, Japan, China, and most extensively in coastal British Columbia, Canada. We also genotype cultured populations from throughout the Northern Hemisphere to compare with naturalized populations. In total, 16,942 markers were identified using double-digest RAD-sequencing in 182 naturalized, 112 hatchery-farmed, and 72 naturalized-farmed oysters (n = 366). Consistent with previous studies, very low genetic differentiation was observed around Vancouver Island (mean FST = 0.0019), and low differentiation between countries in the Japan-Canada-France historical translocation lineage (France-Canada FST = 0.0024; Japan-Canada FST = 0.0060). Chinese populations were more differentiated (China-Japan FST = 0.0241). Hatchery-propagated populations had higher inter-individual relatedness suggesting family structure. Within-population inbreeding was not detected on farms, but nucleotide diversity and polymorphism rate was lower in one farm population. Moving oysters from nature onto farms did not result in strong within-generation selection. Private alleles at substantial frequency were identified in several hatchery populations grown in BC, suggesting non-local origins. Tests of selection identified outlier loci consistent with selective differences associated with domestication, in some cases consistently identified in multiple farms. Top outlier candidates were nearby genes involved in calcium signaling and calmodulin activity. Implications of potential introgression from hatchery-farmed oysters depends on whether naturalized populations are valued as a locally-adapted resource or as an introduced, invasive species. Given the value of the industry in BC and the challenges the industry faces (e.g., climate change, crop losses, biotic stressors), this remains an important question.

genetics↗

bioRxiv2019

Dimensionality, information and learning in prefrontal cortex

Learning leads to changes in population patterns of neural activity. In this study we wanted to examine how these changes in patterns of activity affect the dimensionality of neural responses and information about choices. We addressed these questions by carrying out high channel count recordings in dorsal-lateral prefrontal cortex (dlPFC; 768 electrodes) while monkeys performed a two-armed bandit reinforcement learning task. The high channel count recordings allowed us to study population coding while monkeys learned choices between actions or objects. We found that the dimensionality of neural population activity was higher across blocks in which animals learned the values of novel pairs of objects, than across blocks in which they learned the values of actions. The increase in dimensionality with learning in object blocks was related to less shared information across blocks, and therefore patterns of neural activity that were less similar, when compared to learning in action blocks. Furthermore, these differences emerged with learning, and were not a simple function of the choice of a visual image or action. Therefore, learning the values of novel objects increases the dimensionality of neural representations in dlPFC.

neuroscience↗

bioRxiv2018

Rhythmic neural spiking and attentional samplingarising from cortical receptive field interactions

Growing evidence suggests that distributed spatial attention may invoke theta (3-9 Hz) rhythmic sampling processes. The neuronal basis of such attentional sampling is however not fully understood. Here we show using array recordings in visual cortical area V4 of two awake macaques that presenting separate visual stimuli to the excitatory center and suppressive surround of neuronal receptive fields elicits rhythmic multi-unit activity (MUA) at 3-6 Hz. This neuronal rhythm did not depend on small fixational eye movements. In the context of a distributed spatial attention task, during which the monkeys detected a spatially and temporally uncertain target, reaction times (RT) exhibited similar rhythmic fluctuations. RTs were fast or slow depending on the target occurrence during high or low MUA, resulting in rhythmic MUA-RT cross-correlations at at theta frequencies. These findings suggest that theta-rhythmic neuronal activity arises from competitive receptive field interactions and that this rhythm may subserve attentional sampling.\n\nHighlightsO_LICenter-surround interactions induce theta-rhythmic MUA of visual cortex neurons\nC_LIO_LIThe MUA rhythm does not depend on small fixational eye movements\nC_LIO_LIReaction time fluctuations lock to the neuronal rhythm under distributed attention\nC_LI

neuroscience↗