Biology subjects

Wagner, J.

Publications and source records attributed to Wagner, J..

At least 19 recordsLinked to original sources

bioRxiv2026

The Genome In A Bottle HG002 assembly-based variant benchmark set enables comprehensive benchmarking of small and structural variants.

High-accuracy, high-resolution benchmark data are fundamental to improving the accuracy and generalizability of sequencing technologies and associated algorithms. Most existing benchmarks for DNA sequencing rely on mapping to a single linear reference, omitting inaccessible and highly repetitive complex genomic regions. Here, we present the Genome in a Bottle (GIAB) Consortium's HG002 v5.0q benchmark set, a more comprehensive variant benchmark derived from a fully phased, highly curated, and accurate diploid assembly of HG002. Our approach leverages recent advances in long-read sequencing and assembly to provide confident small- and structural-variant calls across previously inaccessible regions, including segmental duplications, homopolymers, tandem repeats, and complex immune loci. The v5.0 benchmark significantly expands the callable genome relative to v4.2.1, adding x200 Mbp of sequence and increasing variant detection by 18 % for small variants and 3-fold for structural variants compared to previous benchmarks. The benchmark regions include more variants in repetitive regions, including 1.2 x segmental duplications, 1.8 x tandem repeats, and 2.0 x homopolymers, compared to v4.2.1. Separate and combined small- and structural-variant benchmarks are available for three versions of the human reference genome (GRCh37, GRCh38, and CHM13). We validate the reliability of this benchmark set by comparing multiple sequencing technologies and variant calling pipelines and curating differences. The v5.0q benchmark provides a critical resource for the development and validation of next-generation sequencing technologies and analysis methods.

genomics↗

bioRxiv2026

Knockout and re-expression system for mutant analysis in primary mouse T cells

We describe here an efficient method for gene editing in mouse T cells, based on well-established, high-efficiency retroviral transduction protocols. Our platform allows analysis of mutant phenotypes in primary murine T cells in vitro and in vivo. This approach uses a single retroviral vector to simultaneously knockout an endogenous gene and ectopically express its mutant version. This knockout/re-expression vector can be used as the only plasmid to transduce Cas9-expressing T cells, or used together with a Cas9 retroviral vector to transduce T cells from any mouse strain. We validated the system for analysis of murine T cells by targeting key molecules in proximal T cell signaling, i.e. CD3{gamma} and Zap70. We obtain high knockout and re-expression efficiencies in both Cas9-expressing and non-Cas9 T cells. Knockout efficiencies can be further improved by gRNA multiplexing. Endogenous proteins compete with their ectopically expressed mutants or tagged versions for cellular location, protein interactions and cellular functions. Here, we quantified the incorporation of CD3{gamma}-GFP into surface T cell receptor (TCR) complexes. Our data shows that the knockout and re-expression platform improves integration of CD3{gamma}-GFP into the TCR. Therefore, eliminating competition between endogenous and ectopic proteins benefits analyses of protein assemblies and signaling pathways in primary T cells. Furthermore, we validated advantages of our system for mutant analysis using wild-type and mutant Zap70s. Zap70 mutants deficient in TCR binding or kinase activity show their phenotypes only in the absence of endogenous protein, further validating our knockout/re-expression approach. Most importantly, this system can be used to generate gene-edited primary T cells for in vivo studies, such as the quantification of anti-tumor responses. Our knockout and re-expression platform provides a useful gene editing tool for primary T cells in fundamental research and immunotherapy development.

immunology↗

bioRxiv2026

A complete human pancreatic cancer genome

Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine.1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions.1-3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres.4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

genomics↗

bioRxiv2025

Systematic morphological profiling of human and mouse miRNAs in 24M single cells

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression whose contributions to cell biology remain underexplored. Here, we used Cell Painting to quantify the morphological effect of 2,565 human and 1,900 mouse miRNA mimics on 24 million cells across five cell lines. To do so, we developed a novel single-cell morphological profiling analysis framework, involving stringent batch correction, feature selection, and hit calling. With this, we discovered that 9% of human and 15% of mouse miRNA mimics significantly alter cell morphology in at least one cell line. Eighteen miRNAs caused significant changes in multiple cell lines, including eight orthologous miRNAs that altered morphology in both human and mouse cells. Among the replicating miRNAs were human and mouse miR-155-5p, which affected morphology in at least one replicate of four cell lines. As expected, miRNAs with identical seed sequences induced more similar morphological changes than miRNAs with different seeds. Also, morphological changes were associated with cytotoxicity and annotation confidence. This comprehensive single-cell morphological resource will help elucidate the cellular functions of human and mouse miRNAs.

genomics↗

bioRxiv2025

Distinct Effects of Aging and Klotho Deletion on the Choroid Plexus

Klotho (Kl) is an anti-aging protein primarily produced in the kidney and the choroid plexus (CP, where it regulates cerebrospinal fluid composition and exerts neuroprotective effects. Here, we investigated the age-dependent consequences of a CP-specific Kl deletion on CP structure and function using mice lacking KL exclusively in CP epithelial cells (Kl{Delta}CP). In control mice, aging markedly disrupted CP architecture and cilia organization both in the lateral (LV-CP) and fourth ventricle (FV-CP). While CP-specific Kl deletion alone caused no major structural changes it induced region- and age-dependent calcification: FV-CP calcification increased in both aged and young Kl{Delta}CP mice, whereas LV-CP calcification emerged only in older Kl{Delta}CP mice. Proteomic analysis of the CP and hippocampus revealed mild molecular alterations, suggesting compensatory mechanisms that preserve structural and functional stability despite calcium dysregulation. Consistently, Kl{Delta}CP mice exhibited no significant behavioral or cognitive deficits. Overall, Kl deficiency sensitizes the CP to age-related calcification prior to overt structural decline, revealing a region-specific and functional link between Klotho, calcium imbalance, and brain aging.

neuroscience↗

bioRxiv2025

LuxSit Pro and sPro: Next-Generation Designed Luciferases for Bioluminescent Reporting and Complementation-Based Detection

Bioluminescent systems are widely used as molecular reporters in life sciences due to their low background, broad dynamic range, and the key advantage of not requiring external excitation. However, natural luciferases often lack the brightness, stability, and long-lasting light emission needed to support a wide range of high-sensitivity applications. Here, we describe our next-generation luciferase solution: LuxSit Pro and its substrate, Luxterazine (LTZ). LuxSit Pro is a de novo luciferase optimized for steady brightness and structural stability through an iterative combination of computational and experimental methods. Composed of only 117 amino acids, LuxSit Pro is currently the smallest highest-performing known luciferase, exhibiting exceptional brightness and biochemical stability with robust recombinant expression in both mammalian and bacterial systems. Notably, LuxSit Pro was deliberately designed devoid of lysine and cysteine residues which enormously expands its potential applications. This property renders the reporter largely resistant to post-translational modifications such as ubiquitination and also enables site-directed chemical modifications, as lysines or cysteines can be reintroduced at specific sites to serve as chemical handles for augmenting or adapting the enzymes function. The novel synthetic substrate, Luxterazine (LTZ), is a compound that enables LuxSit Pro to deliver bright, steady, blue light emission ([~]490 nm) and offers improved solubility compared to existing Coelenterazine analogs. Finally, we also developed LuxSit sPro, a highly sensitive two-component complementation system for the quantitative detection of molecular interactions. The broad potential applications of LuxSit Pro and sPro, in combination with Luxterazine, are poised to drive the development of next-generation reporters and biosensor systems for the research and in vitro diagnostics fields.

molecular biology↗

bioRxiv2025

Medin drives Aβ40 to adopt Aβ42-like fibril polymorphs in vitro

Medin, a vascular amyloid derived from MFG-E8, is the most prevalent form of localized human amyloid and co-localizes with A{beta} in Alzheimers disease and, in particular, cerebral amyloid angiopathy (CAA). While it was shown that medin can promote A{beta} aggregation, it remains unclear whether this amyloid-amyloid interaction affects the structure of the resulting fibrils. Here, we investigate how medin modulates A{beta}40 fibril assembly in vitro using cryo-electron microscopy, aggregation kinetics, and immunogold electron microscopy. We show that medin accelerates A{beta}40 aggregation, co-assembles into hybrid fibrils, and modulates fibril morphology. Cryo-EM analysis reveals two fibril populations: one corresponding to a previously described in vitro A{beta}40 morphology, and a second, previously unobserved polymorph with A{beta}42-like features, including a structured N-terminus and a compact hydrophobic C-terminal core. The presence of a peripheral, unresolved cryo-EM density near the fibril surface suggests that the new polymorph is stabilised through heterotypic interactions, yet the atomic details remain unresolved, likely due to substantial structural heterogeneity. Rather than representing a limitation, this highlights how not all determinants critical for fibril assembly are necessarily ordered or resolvable in the final fibril structure, reflecting the inherent dynamic and heterogeneous nature of amyloid interactions. Our findings provide structural evidence that heterotypic co-aggregation can redirect A{beta}40 into distinct conformational states and suggest that dynamic or transient interactions contribute to fibril polymorphism beyond what can be fully captured in static structural models.

biochemistry↗

bioRxiv2025

The targeting of non-fibrillar polyQ via distinct VCP-proteasome coupling

The aggregation of proteins containing expanded poly-glutamine (polyQ) repeat sequences is a cytopathological hallmark of several dominantly inherited neurodegenerative diseases (ND), including Huntingtons disease (HD). Previously, we observed that long polyQ repeats form a fibrillar core, surrounded by amorphous and soluble intermediates, which compared to the fibrils, are more readily taken up by autophagosomes 1. In this study, we investigated how the alternative major degradation pathway in cultured cells, ubiquitin proteasome system (UPS), interacts with the different pools of polyQ. We observed that the AAA+ ATPase, valosin-containing protein VCP/p97, in collaboration with proteasomes, plays a crucial role in degrading non-fibrillar polyQ. As both VCP and proteasomes were recruited to the polyQ intermediates peripheral to the fibrils, we imaged these regions by in situ cryo-ET for subtomogram averaging. VCP predominantly adopts an ATP-bound state, often in an active processing conformation with resolved NPLOC4-like cofactor density. The region was also enriched with the 26S proteasome (26S), 20S proteasome core (20S), and 19S regulatory particles (19S). Distance analysis of the macromolecules revealed a striking proximity between VCP and the 20S in situ. This is likely mediated by VCPs C-terminal hydrophobic-tyrosine-X (HbYX) motif, which binds the 20S via hydrophobic interactions, as confirmed by cryo-EM single-particle analysis (SPA) and in vitro assays. Our study highlights a distinct VCP-20S coupling mechanism, where VCP functionally overlaps with the 19S complex in substrate unfolding, facilitating the degradation of polyQ intermediates by the 20S catalytic core.

biochemistry↗

bioRxiv2025

Optogenetic stimulation of Lbc GEF-mediated Rho activity dynamics promotes cell invasion

Cancer cell invasion relies on dynamic cell shape changes, which originate from protrusive and contractile intracellular forces. Previous studies revealed that contractile forces are controlled by positive-feedback amplification of the contraction regulator Rho by Lbc GEFs. These GEFs were previously linked to tumor progression, however, the underlying mechanisms are poorly understood. Here, we generated a mouse melanoma model, in which cytosolic levels of the Lbc GEF GEF-H1 are controlled by light. Using this model, we found that increased GEF-H1 levels strongly stimulate cell contraction dynamics. Interestingly, increased contraction dynamics rapidly induced expansion of tumor spheroids via a focal adhesion kinase-dependent mechanism. Furthermore, long-term stimulation led to the escape of individual cells from spheroids. These findings reveal new insights into the oncogenic roles of Lbc GEFs, and how they might promote tumor cell invasion. We propose a mechanism, in which increased cell contraction dynamics results in asymmetric pulling forces at the tumor border, promoting the detachment and escape of individual cells.

cell biology↗

bioRxiv2025

Benchmarking of Human ReadRemoval Strategies for Viral andMicrobial Metagenomics

Human reads are a key contaminant in microbial metagenomics and enrichment-based studies, requiring removal for computational efficiency, biological analysis, and privacy protection. Various in silico methods exist, but their effectiveness depends on the parameters and reference genomes used. Here, we assess different methods, including the impact of the updated T2T-CHM13 human genome versus GRCh38. Using a synthetic dataset of viral and human reads, we evaluated performance metrics for multiple approaches. We found that the usage of high-sensitivity configuration of Bowtie2 with the T2T-CHM13 reference assembly significantly improves human read removal with minimal loss of specificity, albeit at higher computational cost compared to other methods investigated. Applying this approach to a publicly available microbiome dataset, we effectively removed sex-determining SNPs with little impact on microbial assembly. Our results suggest that our high-sensitivity Bowtie2 approach with the T2T-CHM13 is the best method tested to minimise identifiability risks from residual human reads.

genomics↗

bioRxiv2025

A novel CAR T cell blend targeting PDPN and GD2 to overcome glioblastoma heterogeneity

BackgroundWhile chimeric antigen receptor (CAR) T cells have achieved encouraging remission rates in hematological malignancies, they demonstrated limited success in treating Glioblastoma (GBM), particularly due to high intra- and intertumoral heterogeneity. In this study, we identified a relevant and preserved target antigen, Podoplanin (PDPN), and evaluated the potential of a PDPN- and GD2-CAR T cell blend to overcome GBM heterogeneity. MethodsTarget antigen screening included clinical samples, healthy tissues and cell lines, as well as publicly available RNA sequencing datasets. The anti-tumor function of CAR T cells were examined in co-culture experiments with GBM cell lines and patient-derived organoids (PDOs), and in vivo after locoregional delivery in orthotopic xenograft models. ResultsThe generated CAR T cells demonstrated strong anti-tumor activity against several cell lines and PDOs from multiple patients. PDPN and GD2 expression was detectable in all PDOs at varying densities and regardless of the antigenic profile, the CAR T cell blend induced significantly higher levels of apoptosis in organoids than single antigen targeting counterparts. In vivo, we observed efficient tumor regression after locoregional administration of monospecific CAR T cells. While heterogeneous orthotopic tumors eventually relapsed in these groups, blended therapy resulted in a significantly increased overall survival and even achieved cure in the majority of mice. ConclusionThis novel PDPN-/GD2-CAR T cell blend demonstrated strong efficacy in advanced preclinical models of glioblastoma. The results suggest that this approach can overcome GBM heterogeneity in clinical application and address previous limitations of single antigen CAR T cell therapies. KEYPOINTSO_LIPDPN is a relevant and consistent CAR T cell target antigen in primary and recurrent GBM C_LIO_LIPDPN- and GD2-CAR T cells display synergistic anti-tumor activity in patient-derived organoids C_LIO_LILocal delivery of our CAR T cell blend confers long-term survival and cure in GBM-bearing mice C_LI IMPORTANCE OF THE STUDYThe highly variable landscape of tumor antigens in GBM represents a serious obstacle to single antigen CAR T cell therapies. In this study, we identified Podoplanin (PDPN) and GD2 as the most preserved target antigens in a screening campaign, with an even increased density in recurrent GBM compared to primary GBM. We combined PDPN- and GD2-CAR T cells in a blended treatment approach to counter antigen heterogeneity, and achieved a substantial gain in efficacy against patient-derived organoids (PDOs). In an orthotopic xenograft model, locoregional administration of the PDPN- and GD2-CAR T cell blend conferred long-term complete remission and increased survival compared to single antigen targeting. This study provides a hierarchy of CAR target antigens for treating GBM and illustrates the therapeutic potential of combinatorial antigen targeting using a PDPN/GD2-CAR T cell blend. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/636223v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@109a9aaorg.highwire.dtl.DTLVardef@16215faorg.highwire.dtl.DTLVardef@910623org.highwire.dtl.DTLVardef@129f79c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACT:C_FLOATNO C_FIG

immunology↗

bioRxiv2024

Evolution of ivermectin resistance in the nematode model Caenorhabditis elegans: critical influence of population size and unexpected cross-resistance to emodepside

The emergence and spread of anthelmintic resistance represent a major challenge for treating parasitic nematodes, threatening mass-drug control programs in humans and zoonotic species. Currently, experimental evidence to understand the influence of management (e.g., treatment intensity and frequency) and parasite-associated factors (e.g., genetic variation, population size and mutation rates) is lacking. To rectify this knowledge gap, we performed controlled evolution experiments with the model nematode Caenorhabditis elegans and further evaluated the evolution dynamics with a computational model. Large population size was critical for rapid ivermectin resistance evolution in vitro and in silico. Male nematodes were favored during resistance evolution, indicating a selective advantage of sexual recombination under drug pressure in vitro. Ivermectin resistance evolution led to the expected emergence of cross-resistance to the structurally related anthelmintic moxidectin but unexpectedly also to the structurally unrelated anthelmintic emodepside that has an entirely different mode of action. In contrast, albendazole, levamisole, and monepantel efficacy were not influenced by the evolution of Ivermectin resistance. We conclude that combining computational modeling with in vitro evolution experiments to test specific aspects of evolution directly represents a promising approach to guide the development of novel treatment strategies to anticipate and mitigate resistance evolution in parasitic nematodes.

evolutionary biology↗

bioRxiv2024

CX3CR1 modulates migration of resident microglia towards brain injury

Microglia are innate immune cells of the central nervous system (CNS). They extend their processes towards and migrate towards injuries in vivo. However, whether the fractalkine receptor (CX3CR1) influences microglial migration remains unknown. Label-free proteomic profiling predicted changes in RHO-signaling activity that hint at dysregulated cytoskeleton signaling in Cx3cr1-deficient murine cortex tissue. To further investigate microglial migration, we carried out 4-hour interval two-photon in vivo imaging for 72 hours after a laser lesion in the cortex. Cx3cr1-deficient microglia showed enhanced migration towards the lesion. Additionally, length and velocity of microglial fine processes extending towards the lesion were increased in Cx3cr1-deficient microglia. Migration remained unchanged in Ccr2-deficient mice, indicating that monocyte-derived macrophages/microglia did not contribute to microglia accumulation around the lesion. These results demonstrate microglia migration towards CNS injury and suggest CX3CR1 as a modulator of this. Manipulating microglia migration via CX3CR1 therefore is a potential target for treatment of CNS-injury.

neuroscience↗

bioRxiv2024

Trophic adaptation of large terrestrial omnivores to global change

Large omnivores at the top of food webs play a key role in ecosystems, as their ability to feed on multiple trophic levels stabilizes food-web dynamics and impacts ecosystem functioning. However, it is largely unexplored how large omnivores adapt their trophic interactions to altered resource availability under global change, particularly in terrestrial ecosystems. Here, we combine macroecological and paleoecological approaches and reveal that extant bears, the largest terrestrial omnivores, adapt their trophic position in food webs dynamically to net primary productivity and growing season length. Throughout their geographic ranges, extant bears occupy higher trophic positions in unproductive ecosystems with short growing seasons than in productive ecosystems with long growing seasons. Consistent with this geographic pattern, the trophic position of the brown bear sharply decreased at the transition from the Late Pleistocene to the Holocene, coinciding with an increase in net primary productivity and growing season length. These findings demonstrate that trophic interactions of omnivores are not static but change dynamically in response to environmental change. Our findings suggest that global change impacts on primary production and vegetation seasonality may trigger shifts in the functional role of omnivores, with consequences for food webs and ecosystem functions. Significance statementLarge omnivores play a key role in ecosystems, as they stabilize food-web dynamics and impact ecosystem functioning. However, how omnivores adapt their trophic interactions to changes in resource availability under global change remains unexplored. Combining macroecological and paleoecological approaches, we show that extant bears, the largest terrestrial omnivores, occupy lower trophic positions in food webs as net primary productivity and growing season length increase. This trophic adaptation is evident across the geographic ranges of all extant terrestrial bear species and for brown bears at the transition from the Late Pleistocene to the Holocene. Therefore, impacts of global change on primary production and vegetation seasonality may trigger shifts in the functional role of omnivores, with consequences for food webs and ecosystems. One sentence summaryGlobal changes in primary productivity and vegetation seasonality alter the functional role of large omnivores in terrestrial ecosystems.

ecology↗

bioRxiv2024

Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing

Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain engaging in widespread functional communication, with acetylcholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor cell state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasivity. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.

cancer biology↗

bioRxiv2024

Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease

Anti-IgLON5 disease is an autoimmune disease, in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction and Tau pathology. How -IgLON5 AABs cause neuronal Tau protein pathology and neurodegeneration remains unclear. We find that patient-derived -IgLON5 AABs cluster IgLON5 proteins with other cell surface proteins, leading to neuronal hyperactivity that triggers pathological Tau missorting and phosphorylation, typically observed early in Tau-related neurodegenerative diseases. In wildtype mice, -IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. Our findings establish a causal link between the -IgLON5 AABs and Tau pathology in anti-IgLON5 disease patients, and highlight the role of neuronal hyperactivity as a disease-overarching driver of Tau pathology and provide a potential target for therapeutic intervention. Teaser-IgLON5 autoantibodies induce clustering of neuronal cell surface proteins, leading to acute neuronal hyperactivity and Tau missorting.

neuroscience↗

bioRxiv2024

Influence of environmental variables, small-scale fisheries and vessel traffic on the distribution and behavior of bottlenose dolphins in a tropical lagoon.

The distribution of marine predators is influenced by a variety of natural and, in some cases, anthropogenic environmental factors. In particular, the optimal foraging theory predicts that micro-habitat selection should be the result of a trade-off between prey availability, energy expenditure, and predation risk. In addition, the risk-disturbance hypothesis suggests that anthropogenic disturbance may be perceived by animals in the same way as predation risk. Habitat selection may also be locally influenced by individual behavior and physiological state (defining functional habitats): variation in their needs should affect their optimal trade-off. We tested these hypotheses in a population of bottlenose dolphins living in a tropical lagoon using a habitat modeling approach. Bottlenose dolphins were predominantly distributed within the lagoon, with a preference for the vicinity of fringing and inner reefs (with lower predation risk than the outer reef), and were located in areas of high fish productivity, consistent with optimal habitat selection. We also observed an interaction between habitat and dolphin behavior, suggesting the existence of functional habitats: foraging was more common in nearshore habitats with probable higher prey density while resting and socializing were more common further from shore. Similarly, females with calves were preferentially found in shallower waters compared to other social groups. We did not observe any effects of anthro-pogenic disturbance variables and therefore cannot conclude on the risk-disturbance hypothesis for this population.

ecology↗

bioRxiv2024

scGrapHiC: Deep learning-based graph deconvolution for Hi-C using single cell gene expression

Single-cell Hi-C (scHi-C) protocol helps identify cell-type-specific chromatin interactions and sheds light on cell differentiation and disease progression. Despite providing crucial insights, scHi-C data is often underutilized due the high cost and the complexity of the experimental protocol. We present a deep learning framework, scGrapHiC, that predicts pseudo-bulk scHi-C contact maps using pseudo-bulk scRNA-seq data. Specifically, scGrapHiC performs graph deconvolution to extract genome-wide single-cell interactions from a bulk Hi-C contact map using scRNA-seq as a guiding signal. Our evaluations show that scGrapHiC, trained on 7 cell-type co-assay datasets, outperforms typical sequence encoder approaches. For example, scGrapHiC achieves a substantial improvement of 23.2% in recovering cell-type-specific Topologically Associating Domains over the baselines. It also generalizes to unseen embryo and brain tissue samples. scGrapHiC is a novel method to generate cell-type-specific scHi-C contact maps using widely available genomic signals that enables the study of cell-type-specific chromatin interactions. Availabilityhttps://github.com/rsinghlab/scGrapHiC Contactritambhara@brown.edu

genomics↗