Biology subjects

Otto, S.

Publications and source records attributed to Otto, S..

17 recordsLinked to original sources

bioRxiv2026

MapMyCells: High-performance mapping of unlabeled cell-by-gene data to reference brain taxonomies

Single-cell mapping methods convert raw, heterogeneous single-cell datasets into interpretable and comparable representations of biological identity. As reference cell-type taxonomies mature, mapping new datasets to shared references has become a central strategy for enabling cross-study integration, reproducible annotation, and cumulative biological knowledge. Here we present MapMyCells, an open-source framework designed to align diverse single-cell omics datasets to hierarchical reference taxonomies with minimal preprocessing. MapMyCells provides out-of-the-box support for an expanding set of high-quality brain cell-type references generated by the Allen Institute for Brain Science, the BRAIN Initiative, and the Seattle Alzheimers Disease Brain Cell Atlas, including whole-brain mouse and human atlases, aging and Alzheimers disease cohorts, and a cross-species consensus taxonomy initially focused on the basal ganglia. MapMyCells enables efficient mapping of hundreds of thousands of cells on standard workstations without specialized hardware, providing a deterministic, scalable, and modality-agnostic approach that is robust across species and molecular assays. The framework produces interpretable confidence metrics and quantitative summaries of mapping performance, allowing users to evaluate assignment precision and accuracy. We demonstrate the mapping of unlabeled transcriptomic, epigenomic, and spatial datasets to reference taxonomies and describe a general workflow for preparing arbitrary hierarchical taxonomies for reference-based mapping. As the ecosystem of single-cell reference atlases expands, MapMyCells offers a practical and reproducible solution for community-scale cell-type annotation and cross-dataset integration, supporting the development of unified and extensible brain cell atlases.

bioinformatics↗

bioRxiv2025

Digital Spatial Pathway Mapping Reveals Prognostic Tumor States in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) is a morphologically and molecularly heterogeneous disease with limited effectiveness of genotype-informed therapies. Transcriptome-derived estimates of signaling pathway activity carry prognostic and therapeutic potential but remain inaccessible in routine diagnostics due to cost and tissue constraints. Here, we introduce Digital Spatial Pathway Mapping, an AI-based computational pathology framework that infers signaling pathway activities directly from routine hematoxylin and eosin (H&E) slides, enabling in-silico spatial molecular readouts from standard histology. Models trained on HPV-negative HNSCC from TCGA and externally validated on CPTAC robustly predicted transcriptome-derived activities in cancer-relevant signaling pathways. To achieve spatial interpretability, we applied layer-wise relevance propagation (LRP) to generate heatmaps that highlight positive versus negative evidence for pathway activation. These LRP heatmaps were technically validated by patch-flipping tests and biologically validated against pathway-relevant immunohistochemistry in an independent patient cohort. From these explanations, we derived a tumor area pathway activity score (TAPAS) quantifying the spatial fraction of activated tumor regions within a slide. Applied to a retrospective HNSCC cohort of 1,066 slides from 112 resection specimens, TAPAS captured intratumoral heterogeneity and revealed two biologically dis-tinct tumor states - an oncogenic growth phenotype with widespread pathway activation and a pathway quiescent phenotype associated with higher recurrence risk independent of clinicopathological variables. These findings establish Digital Spatial Pathway Mapping as a scalable, in-silico approach to recover systems-level molecular information from standard histopathology, enabling prognostic and mechanistically grounded patient stratification in head and neck cancer.

pathology↗

bioRxiv2025

Evolutionary responses to increased opportunity for sexual selection in yeast

Sexual selection contributes to biodiversity and the costs and benefits of sexual reproduction. In organisms where sex is infrequent, these impacts of sexual selection are likely to be limited. An increased frequency of obligate sex would increase the opportunity for sexual selection, which could promote the evolution of sexual traits and sexual differentiation. To study these dynamics, we conducted experimental evolution in the yeast Saccharomyces cerevisiae, which is predominantly asexual, with two isogamous mating types. We used selectable markers to impose frequent obligate sex in 96 populations. We manipulated the opportunity for sexual selection by imposing skewed mating-type ratios and by altering the degree to which mating occurred by selfing versus outcrossing. After just ten sexual cycles, we observed evolution in growth, cell size, pheromone production, and mating, with the mating types responding asymmetrically, but little evolutionary change in sporulation rate. Mating type dimorphism increased, with evident trade-offs between growth, attractiveness, and cell size. Genome sequences from a subset of populations revealed many mutations affecting sex-related genes. Unexpectedly, the selfing populations evolved to become sporulation-competent haploids, unlinking meiosis from ploidy change. Our results illustrate that sexual differentiation can evolve rapidly in response to an increased opportunity for sexual selection.

evolutionary biology↗

bioRxiv2025

Bridging energy and ribosomal allocation models to predict the cost of traits in different environments

Many traits are costly because they require the diversion of resources from cell reproduction, however, the effect of environmental conditions and genetic background on the cost of traits is not well understood. Two different frameworks have been proposed to quantify the resource costs of traits, focusing on either energy allocation or ribosome allocation. These frameworks implicitly assume energy provisioning or protein production limits growth, respectively, but the connection between the two limitations has been underexplored. To better connect these frameworks, we reformulate previous models and incorporate the degradation, recycling, and energetic demands for cell maintenance to quantify the cost of traits, depending on the nature of the resources diverted, genetic background, and the environmental conditions experienced. Notably, our model predicts that increasing food quality increases the cost of traits that require the production of new structures, while decreasing the cost of traits requiring energy expenditure. Understanding how environmental change affects the cost of traits has important implications for the evolution of various traits, including antimicrobial resistance. Moreover, the model also accounts for several aspects of the observed relationship between the macromolecular composition of the cells and growth rate (also known as bacterial growth laws). Author SummaryMany traits divert resources from reproduction and are costly due to the physiological trade-offs organisms face. These traits might require energy expenditure or production of macromolecules, and it is unclear how their costs can be compared given their different units. Moreover, the effect of environmental conditions on the cost of traits is not well understood. Here, we develop a framework that considers limitations in energy provisioning and protein production simultaneously and enables us to compare the cost of traits requiring different resources. Using this model, we explore how environmental quality and genetic background affect the cost of traits.

ecology↗

bioRxiv2025

The changing status of imperiled species in British Columbia over the last 15 years in the absence of a dedicated species at risk law

Gaps in biodiversity protection occur in Canada due to limited jurisdiction of federal species-at-risk laws and the absence of dedicated legislation in many provinces, including British Columbia (B.C.). While lacking legal protection, B.C. maintains Red, Blue, and Yellow Lists of threatened, special-concern, and secure species, respectively, using a NatureServe ranking system. We compiled historical data on species status in B.C. between 2008 and 2024 from the B.C. Conservation Data Centre. B.C. is home to 5,485 Yellow, 1,116 Blue, 491 Red-listed species. Changes in status over this time period were reported for 967 animal species, with an even split in uplistings (more imperiled) and downlistings (less imperiled). More status changes were reported for plants (2,902), mainly due to updated methodology leading to a lower risk status. Analysing the accompanying explanation for each status change revealed that most changes were non-genuine (e.g., new information, taxonomy, or methodology) rather than genuine (e.g., true changes in population size, range, or threats). Genuine improvements in the status of species in B.C. have been exceedingly rare. This analysis indicates that current laws and regulations have been insufficient to recover species at risk within B.C. Plain-language summaryBritish Columbia is the most biodiverse province in Canada, yet 1,607 species are imperiled in the province. We analysed trends, finding a 16% rise in the number of species at risk since 2008. By analysing the provided explanations, we found that status improvements were mostly "non-genuine", caused by changing methodology and/or new data. Strengthening legal protections is essential to prevent biodiversity loss in the province.

ecology↗

bioRxiv2025

Evolution of cross-tolerance to metals in yeast

Organisms often face multiple selective pressures simultaneously (e.g., mine tailings with multiple heavy metal contaminants), yet we know little about when adaptation to one stressor provides cross-tolerance or cross-intolerance to other stressors. To explore the potential for cross-tolerance, we first adapted Saccharomyces cerevisiae to high concentrations of six single metals in a short-term evolutionary rescue experiment. We then measured the cross-tolerance of each metal-adapted line in the other five metals. We generated and tested three predictors for the degree of cross-tolerance, based on the similarity between pairs of metal environments in (1) their physiochemical properties, (2) the overlap in genes known to impact tolerance to both metals, and (3) their co-occurrence in the environment. None of these predictors explained significant variation in cross-tolerance. Instead, we observed that adapted lines in one metal were frequently cross-tolerant to certain metals (manganese and nickel) and intolerant to others (cobalt and zinc). Furthermore, cross-tolerance between pairs of metals was not reciprocal, with mutations accumulating in one metal (e.g., copper) providing adaptation to another metal (e.g., manganese), but not vice versa. Evolved lines also differed in their degree of specialization, with lines evolved in manganese or copper more specialized to that metal, but lines evolved in cobalt or zinc more generally tolerant. To determine the genetic basis of these metal adaptations, we sequenced the genomes of 109 metal-adapted yeast lines. The SNP mutation spectrum was significantly different in cadmium, cobalt, and manganese than expected in a mutation accumulation experiment in S. cerevisiae. In addition, two lines were highly mutated, bearing defects in DNA repair genes (both in manganese). Thirteen genes exhibited parallel adaptation to different metals; three of these genes generated broad cross-tolerance. Several mutations were found in vacuolar transporter genes, suggesting an important role for vacuolar proteins in adapting to metal stress. Our results with these metal-adapted lines indicate that cross-tolerance is challenging to predict, depending on the combined stressors experienced and the nature of the mutations involved.

evolutionary biology↗

bioRxiv2024

Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell type specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rat and macaque. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model.

neuroscience↗

bioRxiv2023

The maintenance of genetic polymorphism in sexually antagonistic traits

AbstractSelection often favours different trait values in males and females, leading to genetic conflicts between the sexes when traits have a shared genetic basis. Such sexual antagonism has been proposed to maintain genetic polymorphism. However, this notion is based on insights from population genetic models of single loci with fixed fitness effects. It is thus unclear how readily polymorphism emerges from sex-specific selection acting on continuous traits, where fitness effects arise from the genotype-phenotype map and the fitness landscape. Here we model the evolution of a continuous trait that has a shared genetic basis but different optima in males and females, considering a wide variety of genetic architectures and fitness landscapes. For autosomal loci, the long-term maintenance of polymorphism requires strong conflict between males and females that generates uncharacteristic sex-specific fitness patterns. Instead, more plausible sex-specific fitness landscapes typically generate stabilising selection leading to an evolutionarily stable state that consists of a single homozygous genotype. Except for sites tightly linked to the sex determining region, our results indicate that genetic variation due to sexual antagonism should arise only rarely and often be transient, making these signatures challenging to detect in genomic data.

evolutionary biology↗

bioRxiv2023

Towards Pandemic-Scale Ancestral Recombination Graphs of SARS-CoV-2

Millions of SARS-CoV-2 genome sequences were collected during the COVID-19 pandemic, forming a dataset of unprecedented richness. Estimated genealogies are fundamental to understanding this ocean of data and form the primary input to many downstream analyses. A basic assumption of methods to infer genealogies from viral genetic data is that recombination is negligible and the genealogy is a tree. However, recombinant lineages have risen to global prevalence, and simple tree representations are therefore incomplete and potentially misleading. We present sc2ts, a method to infer reticulate genealogies as an Ancestral Recombination Graph (ARG) in real time at pandemic scale. We infer an ARG for 2.48 million SARS-CoV-2 genomes, which leverages the widely used tskit software ecosystem to support further analyses and visualisation. This rich and validated resource clarifies the relationships among recombinant lineages, quantifies the rate of recombination over time, and provides a lower bound on detectable recombination.

evolutionary biology↗

bioRxiv2022

MRI-to-Synthetic 3D Gel Brain: Proof-of-Concept Fabrication For Intra-Parenchymal Diffusion Studies

Bioprinting technologies utilize hydrogel-based biomaterials to more accurately depict in vivo physical conditions within in vitro studies, yet, manufacturing the human brain from soft, poroelastic hydrogels remains a fundamental challenge. Conventional manufacturing routes to fabricate hydrogel brain models using techniques, i.e., 3D printing, seems challenging. This study aims to demonstrate an inverse replica molding fabrication technique that can overcome these challenges while maintaining the complex shape of an individual subjects brain in a miniaturized model--allowing for a more robust hydrogel model that can capture the interactions between diffusing molecules and brain boundaries. This is done by taking a subjects magnetic resonance imaging (MRI) scan and reconstructing the outer pial surface into a mesh surface. The mesh was then converted to an STL and printed out using an extrusion printer. A silicon mold was made from this print into which agarose was gelled. Once fully gelated, the synthetic gel brain was then carefully removed. Two infusion trials were run in the gel brain, each using a different infusion site. Then a diffusion profile was established and compared to a simple gel infusion model. The result shows different diffusion profiles at each location and between the simple and complex models. This model can better represent the interference the complex shape of the brain has on particle movement compared to simple gel models.

bioengineering↗

bioRxiv2022

In Silico, Brain Mesh Platform for Computing Topographic Dependent Internal Facets

Individualized and anatomically correct computational models of the brain can be leveraged to improve knowledge of drug dispersal following simulation of drug delivery. Using a patients magnetic resonance image (MRI) scans, we were able to reconstruct the pial surface of the brain of the left hemisphere with strong anatomic accuracy. We then established the major internal features, including the lateral ventricle, a tumor, and drug delivery catheters. These were able to include relevant tissue characteristics such as porosity and permeability in the Multiphysics platform COMSOL to create a platform for brain modeling. To test the performance of this platform, we simulated direct drug infusion in both a healthy patient brain and a diseased patient model, focusing on glioblastoma (GBM). Using this platform, we simulated perturbed convection enhanced delivery of a cancer medication (similar to temozolomide (TMZ) but modeled using methylene blue) to the tumor. Consequently, with our patient derived model, we are able to simulate solute dispersal and fluid flow representative of in vivo conditions.

bioengineering↗

bioRxiv2022

The phoenix hypothesis of speciation

Genetic divergence among allopatric populations builds reproductive isolation over time and is thought to be the major mechanism underlying the formation of new species. This process is accelerated when populations face a changing environment, but abrupt change also places populations at risk of extinction. Here we use simulations of Fishers geometric model with explicit population dynamics to explore the genetic changes that occur in the face of extreme environmental changes to which populations must adapt or go extinct. We show that evolutionary rescue leads to the fixation of mutations whose effects are larger on average and that these mutations are more likely to lead to reproductive isolation, compared with populations not at risk of extinction. We refer to the formation of new species from the ashes of populations in decline as the phoenix hypothesis of speciation. The phoenix hypothesis predicts more substantial hybrid fitness breakdown among populations surviving a higher extinction risk. The hypothesis was supported when many loci underlie adaptation. When, however, there was only a small number of potential rescue mutations, we found that mutations fixed in different populations were more likely to be identical, with parallel changes reducing isolation. With a limited genomic potential for adaptation, we find support for a modified version of the phoenix hypothesis where reproductive isolation builds fastest in populations subject to an intermediate extinction risk. While processes driving extinction lead to the loss of lineages with deep evolutionary histories, they may also generate new taxa, albeit taxa with minimal genetic differences.

evolutionary biology↗

bioRxiv2021

Turnover of MCMV-expanded CD8+ T-cells is similar to that of memory phenotype T-cells and independent of the magnitude of the response

The potential of memory T-cells to provide protection against re-infection is beyond question. Yet, it remains debated whether long-term T-cell memory is due to long-lived memory cells. There is ample evidence that blood-derived memory phenotype CD8+ T-cells maintain themselves through cell division, rather than through longevity of individual cells. It has recently been proposed, however, that there may be heterogeneity in the lifespans of memory T-cells, depending on factors such as exposure to cognate antigen. Cytomegalovirus (CMV) infection induces not only conventional, contracting T-cell responses, but also inflationary CD8+ T-cell responses, which are maintained at unusually high numbers, and are even thought to continue to expand over time. It has been proposed that such inflating T-cell responses result from the accumulation of relatively long-lived CMV-specific memory CD8+ T-cells. Using in vivo deuterium labelling and mathematical modelling, we found that the average production rates and expected lifespans of mouse CMV-specific CD8+ T-cells are very similar to those of bulk memory-phenotype CD8+ T-cells. Even CMV-specific inflationary CD8+ T-cell responses that differ three-fold in size, were found to turn over at similar rates.

immunology↗

bioRxiv2020

GENE DRIVES ACROSS ENGINEERED FITNESS VALLEYS: MODELING A DESIGN TO PREVENT DRIVE SPILLOVER

1Engineered gene drive techniques for population replacement and/or suppression have potential for tackling complex challenges, including reducing the spread of diseases and invasive species. Unfortunately, the self-propelled behavior of drives can lead to the spread of transgenic elements beyond the target population, which is concerning. Gene drive systems with a low threshold frequency for invasion, such as homing-based gene drive systems, require initially few transgenic individuals to spread and are therefore easy to implement. However their ease of spread presents a double-edged sword; their low threshold makes these drives much more susceptible to spread outside of the target population (spillover). We model a proposed drive system that transitions in time from a low threshold drive system (homing-based gene drive) to a high threshold drive system (underdominance) using daisy chain technology. This combination leads to a spatially restricted drive strategy, while maintaining an attainable release threshold. We develop and analyze a discrete-time model as proof of concept and find that this technique effectively generates stable local population suppression, while preventing the spread of transgenic elements beyond the target population under biologically realistic parameters.

bioengineering↗

bioRxiv2020

Parental population range expansion before secondary contact promotes heterosis

Population genomic analysis of hybrid zones is instrumental to our understanding of the evolution of reproductive isolation. Many temperate hybrid zones are formed by the secondary contact between two parental populations that have undergone post-glacial range expansion. Here we show that explicitly accounting for historical parental isolation followed by range expansion prior to secondary contact is fundamental for explaining genetic and fitness patterns in these hybrid zones. Specifically, ancestral population expansion can result in allele surfing where neutral or slightly deleterious mutations drift to high frequency at the expansion front. If these surfed deleterious alleles are recessive, they can contribute to substantial heterosis in hybrids produced at secondary contact, counteracting negative effects of Bateson-Dobzhansky-Muller incompatibilities (BDMIs) hence weakening reproductive isolation. When BDMIs are linked to such recessive deleterious alleles the fitness benefit of introgression at these loci can facilitate introgression at the BDMIs. The extent to which this occurs depends on the strength of selection against the linked deleterious alleles and the distribution of recombination across the chromosome. Finally, surfing of neutral loci can alter the expected pattern of population ancestry, thus accounting for historical population expansion is necessary to develop accurate null genomic models of secondary-contact hybrid zones.

evolutionary biology↗

bioRxiv2020

Loss of α7 nicotinic acetylcholine receptors in GABAergic interneurons causes sex-dependent impairments in postnatal neurogenesis and cognitive and social behavior

Neural stem cells within the subgranular zone of the dentate gyrus (DG) generate new neurons that form the granule cell layer during embryonic development and continue to generate new neurons throughout life. The maturation process of newly generated granule cells is modulated by nicotinic acetylcholine receptors (nAChRs), which have been shown to play a role in cell survival, signal modulation, dendritic integration, and memory formation. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, particularly the 7 subunit, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined the effects of conditional deletion of 7 nAChRs in GABAergic interneurons on measures of postnatal neurogenesis and behavioral outcomes. Loss of 7 nAChRs resulted in a decrease of postnatal granule cells, as indicated by reduced GFAP+ cells in the DG, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition, object investigation, and spatial learning. Overall, these findings suggest 7 nAChRs expressed in GABAergic interneurons play an important role in regulating postnatal neurogenesis and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.

animal behavior and cognition↗

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↗