Biology subjects

Schweiger, S.

Publications and source records attributed to Schweiger, S..

14 recordsLinked to original sources

bioRxiv2026

16p11.2 Copy Number Variation Alters Genome Architecture and Transcriptional Regulation During Neurodevelopment

Microdeletions and microduplications in 16p11.2 are responsible for a spectrum of neurodevelopmental disorders (NDDs) with partially reciprocal and overlapping symptoms. However, the clinical variability in 16p11.2 microduplication patients is significantly greater than that in patients carrying a microdeletion. Here, we use iPSCs derived from members of a family carrying a 16p11.2 microduplication and model neurodevelopment through in vitro differentiation into neural progenitor cells (NPCs) and neurons. The analysis is complemented by reanalysis of publicly available data from 16p11.2 microdeletion patients. Transcriptome analysis revealed MAPK3-centered hubs of upregulated genes in the microduplication-carrying and downregulated in the microdeletion-carrying cells, indicating that MAPK3 is a central driver of 16p11.2 Copy Number Variation (CNV) pathology. While genes within the 16p11.2 region showed about a two-fold reduction in expression in cells carrying the microdeletion, their expression levels in microduplication-derived NPCs and neurons, but not in iPSCs, were elevated to a degree much higher than expected. This observation was accompanied by a substantial number of dysregulated genes unrelated to the genes in the critical region or their interaction networks. To further investigate whether altered chromatin organization may accompany these transcriptional changes, we generated Hi-C data from patient and control iPSCs and NPCs. This revealed increased chromatin contacts within the duplicated 16p11.2 region in patient-derived iPSCs, while genome-wide compartment analysis showed that increased compartments preferentially co-occurred with upregulated differentially expressed genes, particularly in NPCs. Together, these findings suggest that 16p11.2 microduplication may influence gene expression through both local dosage-dependent mechanisms and broader, differentiation-associated changes in chromatin organization. Our data support a model in which CNV-associated genome architecture changes may modulate transcriptional dysregulation and contribute to the variable neurodevelopmental phenotypes associated with 16p11.2 rearrangements.

pathology↗

bioRxiv2026

Correcting Preprocessing Bias in Sparse Chromatin Contact Data Enables Physically Interpretable Reconstruction of Genome Architecture

DNA is the largest biopolymer in nature, and chromatin contact maps are widely interpreted as quantitative readouts of its three-dimensional organization. However, the validity of such interpretations critically depends on how these maps are processed. Here, we identify a previously overlooked but fundamental source of bias in chromatin contact data analysis. We demonstrate that a widely adopted preprocessing convention, namely whole-matrix percentile clipping, systematically distorts sparse contact maps by collapsing their dynamic range. This effect is strongest in near-diagonal interactions, precisely the regime encoding chromatin domains and looping structures, thereby compromising quantitative interpretation while preserving superficial structural features. We show that this distortion represents a sparsity-dependent failure mode of current preprocessing standards and affects the comparability of datasets and computational methods across technologies and sequencing depths. To address this, we introduce a statistically consistent preprocessing framework based on nonzero-percentile clipping and log-space normalization, which preserves the intrinsic dynamic range of observed contacts. Building on this foundation, we present CCUT, a modular deep learning framework for chromatin contact map reconstruction. Under corrected preprocessing, reconstructed maps recover domain organization, contact decay, and scaling behavior consistent with polymer physics. Importantly, we demonstrate quantitative agreement between reconstructed maps and simulated contact patterns derived from a kinetic Monte Carlo loop extrusion model, enabling direct comparison between experimental data and physical models. Together, our results establish preprocessing as a decisive determinant of the physical interpretability of chromatin contact maps and provide a principled framework for robust and comparable analysis across chromatin conformation capture technologies.

biophysics↗

bioRxiv2025

Aberrant formation of long-range projections across different neurodevelopmental disorders converges on molecular and cellular nexuses

Establishing long-range connections during human brain development is an intricate multi-step process disturbed in many neurodevelopmental disorders (NDDs). The aberrant formation of these connections is caused by mutations in a plethora of different genes with distinct molecular functions, triggering the question of whether there are common key downstream mediators at which different pathologies are converging. We employed brain organoids to model early human brain developmental aspects of Coffin-Siris-like 9, Opitz BBB/G, and Pitt-Hopkins syndromes. These NDDs are caused by mutations in SOX11, MID1, and TCF4 respectively, and are characterized by a multitude of distinct symptoms yet share alterations in long-range projections as a common feature. Here, we uncover that mutations in all three genes phenotypically converge, showing impaired neurite extension with increased tortuosity and decreased growth speed resulting in shorter beelines. Moreover, the mutant neurites exhibit a decrease in growth persistence providing a conceptual framework explaining why long- but not short-range connections are affected. Correlating with the converging cellular phenotype, molecular characterization revealed a striking convergence on signaling pathways implicated in the interaction of neurites with their extracellular environment. In-silico modeling and perturbation of neurite outgrowth suggest that altered neurite-extracellular environment interactions are sufficient to recapitulate the mutant phenotypes but also facilitate the prediction of specific parameters causing disturbed neurite growth in mutant neurons.

developmental biology↗

bioRxiv2025

Skin development and metamorphic re-arrangement in Arthroleptella villiersi Hewitt, 1935 reveals distinct heterochronic patterns in anurans with different life histories

BackgroundThe evolvability of ontogenetic trajectories, driven by modular developmental processes and their evolutionary repatterning, plays a crucial role in the diversity of animal diversity. Anurans offer a model for exploring how developmental repatterning, including the loss of larval features and heterochronic shifts of metamorphic processes lead to the diversity of, often terrestrialized, life histories. Ancestrally, anurans exhibit an aquatic larva (tadpoles) that differs tremendously from their semi-terrestrial adult forms. The transition from this tadpole to the adult is a thyroid hormone-dependent metamorphosis that results in the rearrangement of almost all organ systems. One of the organ systems that experiences the most extensive rearrangements is the skin. Is the ancestral pattern of metamorphic skin rearrangement altered in anurans with a completely terrestrial tadpole phase? ResultsSkin development and metamorphic rearrangement in the terrestrial tadpole of Arthroleptella villiersi is investigated based on histological sections. It follows the major pattern observed in anurans with an aquatic tadpole phase and correlates with thyroid gland maturation. Neuromasts develop and are present during a short developmental time. Both, metamorphic skin rearrangement and neuromast degeneration correlate with histological thyroid gland maturation. A few minor heterochronic shifts are detectable compared to aquatic indirect and terrestrial direct developing anurans. ConclusionSkin development and metamorphic rearrangement in anurans with different reproductive modes is very similar and correlates with thyroid gland maturation indicating that skin development in anurans might be constrained by thyroid hormone activity. Neuromasts are the major exception being present in aquatic and terrestrial indirect developing species but not in terrestrial direct developing anurans. Heterochronic shifts detected during skin development indicate that at least the differentiation of multicellular gland complexes might represent a developmental module similar to neuromasts.

zoology↗

bioRxiv2025

Developmental stages of Arthroleptella villiersi (Pyxicephalidae)

Terrestrialization in anurans is associated with the evolution of endotrophy. It is hypothesized that heterochrony, or changes in the time or rate of developmental events, is associated with the development in endotrophic species. To analyse the developmental heterochrony, we investigated and revised the description of the development in Arthroleptella villierisi, a small frog species of the family Pyxicephalidae, found in the Cape fold mountain region of the Western Cape, South Africa. We also compared the developmental stages of A. villiersi to the heterochronic patterns of taxa with endotrophic terrestrial indirect and direct development using heterochrony plots to identify heterochronic shifts during development. As a result, we found that the terrestrial endotrophic larva of A. villiersi shares external similarities with exotrophic, aquatic larvae in having a long muscularized tail with a fin, a lateral line system and an opercular fold that completely covers the forelimbs. However, other developmental events like the reduction of larval mouthparts and the pre-displaced fore- and hindlimb development is comparatively similar to direct developing taxa. The results of our study show that the timing of early developmental events can be shifted profoundly, while the timing of later events seem to be more conserved in anuran development. We interpret that some of these heterochronic shifts might be consequences of functional and developmental constraints underlying the establishment of the adult body plan.

developmental biology↗

bioRxiv2024

Direct RNA sequencing (RNA004) allows for improved transcriptome assessment and near real-time tracking of methylation for medical applications

Direct RNA sequencing (DRS) is a nanopore-based technique for analyzing RNA in its native form, promising breakthroughs in diagnostics and biomarker development. Coupled to RNA002 sequencing chemistry, its clinical implementation has been challenging due to low throughput, low accuracy, and lack of large-scale RNA-modification models. In this study, we evaluate the improvements achieved by pairing the latest RNA004 chemistry with novel modified-base-calling models for pseudouridine and N6-methyladenosine using diverse RNA samples from cell lines, synthetic oligos, and human blood. Finally, we present the first clinical application of DRS by confirming the loss of RNA methylation in a patient carrying truncating mutations in the methyltransferase METTL5. Conclusively, the combined use of RNA004 chemistry with the base-calling models significantly improved the throughput, accuracy, and site-specific detection of modifications. From this perspective, we offer an outlook on the potential suitability of DRS for use in routine diagnostics, the first comprehensive benchmark of human peripheral blood and quality assessments of RNA therapeutics.

bioinformatics↗

bioRxiv2024

Direct CCUT: A Versatile and Standardized Framework to Train 3C Deep Restoration Models

Chromatin Capture Experiments such as Hi-C and Micro-C have become popular methods for genome architecture exploration. Recently, also a protocol for long read sequencing, Pore-C, was introduced, allowing the characterization of three-dimensional chromatin structures using Oxford Nanopore Sequencing Technology. Here, we present a framework that focuses on the efficient reconstruction of low-resolution Pore-C data but can also process all other 3C data, such as Hi-C and Micro-C matrices, using models that can be trained on a consumer GPU. Furthermore, we integrate building blocks of popular super-resolution methods such as SWIN-Transformer or residual-in-residual-blocks to modify or build customized networks on the fly. Pre-built models were trained and evaluated on multiple publicly available gold-standard Micro-C and Pore-C datasets, allowing for fine-scale structure prediction. Our work aims to overcome the drawback of high sequencing costs to construct high resolution contact matrices, as well as the problem of mapping low-coverage libraries to high-resolution structures in the genome. Although there have been major breakthroughs regarding NGS-based methods for the reconstruction of high-resolution chromatin interaction matrices from low-resolution data, for data obtained by long-read sequencing, there is currently no solution to reconstruct missing and sparse information and to improve the quality. AvailabilityThe tool is available at (https://github.com/stasys-hub/CCUT)

bioinformatics↗

bioRxiv2023

Dynamic X-chromosomal reactivation enhances female brain resilience

While random X-chromosome inactivation in female cells of placental mammalians silences one allele of the majority of X-chromosomal genes, a considerable fraction is only incompletely and variably inactivated resulting in a tissue-specific pattern of mono- and biallelic expression. Here we used clonal human female induced pluripotent stem cells (iPSCs) allowing to trace the (in)activation status of the two X-chromosomes individually along neural differentiation trajectories. We discovered X-chromosome-wide locus- and lineage-specific dynamic usage of the two X-chromosomal alleles in female cells induced by differentiation. Leveraging iPSCs derived from patients with an X-linked neurodevelopmental disorder, we demonstrate that activation of alleles on the inactive X-chromosome can exert protective effects on the manifestation of disease phenotypes in female neural cells and tissue. Taken together, our data demonstrate that alleles on the inactive X-chromosome can serve as a critical reservoir reactivated during differentiation, thereby enhancing resilience of female neural tissue.

neuroscience↗

bioRxiv2022

Hotspots for snake fungal disease across Europe are maintained by host and pathogen identity

1. Infectious diseases are influenced by interactions between host and pathogen, and are rarely homogenous across the landscape. Areas with elevated pathogen prevalence maintain a high force of infection, can facilitate pathogen spread to new regions, and may indicate areas with impacts on host populations. However, isolating the ecological processes that result in increases in infection prevalence and intensity remains a challenge. 2. Here we elucidate the contribution of pathogen clade and host species in disease hotspots of Ophidiomyces ophidiicola, the pathogen that causes snake fungal disease, in 21 species of snakes infected with multiple pathogen strains across 10 countries in Europe. 3. We found isolated areas of disease hotspots in a landscape where infections were otherwise low. O. ophidiicola clade had important effects on transmission, and areas with multiple pathogen clades had higher host infection prevalence. Snake species identity further influenced infection, with most positive detections coming from the Natrix genus. Most species present in the community only experienced increased levels of infection when multiple strains were present. However, one species, N. tessellata, appeared highly susceptible, having increased infection prevalence regardless of pathogen strain, indicating that this species may be important in pathogen maintenance. 4. Our results suggest that both host and pathogen identity are essential components contributing to increased pathogen prevalence. More broadly, our findings indicate that coevolutionary relationships between hosts and pathogens may be key mechanisms explaining variation in landscape patterns of disease.

ecology↗

bioRxiv2022

Land-use preferences of the European green toad (Bufotes viridis) in the city of Vienna (Austria): the importance of open land in urban environments

Urban areas are increasing worldwide, which poses treats to animal wildlife. However, in certain cases cities can provide refuges for endangered animals. The European green toad (Bufotes viridis) is one of such examples, which is known from cities throughout their distribution. In contrast, considerable areas of their former (primary) habitats have been degraded. The primary habitats of this species include steppes and wild river floodplains, both characterized by dynamic changes and the presence of open areas. We used available green toad observation data (2007-2020) to model the effects of land-use types on occurrence probability in the city of Vienna. Forest and densely populated areas were highly significantly negatively associated with green toad presence, while transformation/construction site areas showed a strong positive effect. Such occurrence pattern might be characteristic for early succession species, which depend on stochastic environmental disturbances (e.g., droughts and floods) in their primary habitats. We argue that urban landscape planning should appreciate the potential ecological value of open land in cities which is either in a transition phase or a permanent wasteland. Ecological managing of such landscape could vastly increase urban biodiversity.

ecology↗

bioRxiv2020

Parallel evolution of direct development in frogs - Skin and thyroid gland development in African Squeaker Frogs (Anura: Arthroleptidae: Arthroleptis)

Cases of parallel evolution offer the possibility to identify adaptive traits and to uncover developmental constraints on the evolutionary trajectories of these traits. The independent evolution of direct development, from the ancestral biphasic life history in frogs is such a case of parallel evolution. In frogs, aquatic larvae (tadpoles) differ profoundly from their adult forms and exhibit a stunning diversity regarding their habitats, morphology and feeding behaviors. The transition from the tadpole to the adult is a climactic, thyroid hormone (TH)-dependent process of profound and fast morphological rearrangement called metamorphosis. One of the organ systems that experiences the most comprehensive metamorphic rearrangements is the skin. Direct-developing frogs lack a free-swimming tadpole and hatch from terrestrial eggs as fully formed froglets. In the few species examined, development is characterized by the condensed and transient formation of some tadpole-specific features and the early formation of adult-specific features during a "cryptic" metamorphosis. In this study we show that skin in direct-developing African squeaker frogs (Arthroleptis) is also repatterned from a tadpole-like to an adult-like histology during a cryptic metamorphosis. This repatterning correlates with an increase of thyroid gland activity. A comparison with data from the Puerto Rican coqui (Eleutherodactylus coqui) reveals that direct development might have evolved in parallel in these frogs by a comparable heterochronic shift of thyroid gland activity. This suggests that the development of many adult-features is still constrained by the ancestral dependency on thyroid hormone signaling.

developmental biology↗

bioRxiv2020

mTOR inhibition in primary neurons and the developing brain represses transcription of cholesterol biosynthesis genes and alters cholesterol levels

Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1 and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.

neuroscience↗

bioRxiv2020

Dynamic longitudinal behavior in animals exposed to chronic social defeat stress

Chronic social defeat (CSD) can lead to impairments in social interaction and other behaviors that are supposed to model features of major depressive disorder (MDD). Not all animals subjected to CSD, however, develop these impairments, and maintained social interaction in some animals is widely used as a model for resilience to stress-induced mental dysfunctions. So far, animals have mainly been studied shortly (24 hours and 7 days) after CSD exposure and longitudinal development of behavioral phenotypes in individual animals has been mostly neglected. We have analyzed social interaction and novel object recognition behavior of stressed mice at different time points after CSD and have found very dynamic courses of behavior of individual animals. Instead of the two groups, resilient or susceptible, that are found at early time points our data suggest four groups with (i, ii) animals behaving resilient or susceptible at early and late time points, respectively (iii) animals that start susceptible and recover with time or (iv) animals that are resilient at early time points but develop vulnerability later on.

animal behavior and cognition↗

bioRxiv2017

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of the DNA methylation dynamics in matched primary and recurring glioblastoma tumors, based on a national population registry and a comprehensively annotated clinical cohort. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected formalin-fixed paraffin-embedded (FFPE) samples, and we validate bisulfite sequencing as a multi-purpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional tumor characteristics. Based on these data, we identified characteristic differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study provides a resource for dissecting DNA methylation heterogeneity in genetically diverse and heterogeneous tumors, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology in a representative national cohort, leveraging samples and data collected as part of routine clinical practice.

cancer biology↗