Biology subjects

Mundlos, S.

Publications and source records attributed to Mundlos, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Evolution and mechanism of MEIS2-mediated forelimb specialization in bats

The genomic basis of limb adaptations in tetrapods is thought to be largely driven by changes in gene regulation. However, the mechanisms by which regulatory programs evolve are not well understood. In bats, wing membrane development has been shown to be associated with expression of the transcription factor MEIS2 in the interdigital tissue of the forelimb. However, MEIS2 alone is insufficient to recapitulate wing morphology, suggesting that its regulatory context has also undergone divergence. Here, we integrate functional genomics with sequence-to-function deep learning to dissect both the mechanistic and evolutionary roles of MEIS2 in bat forelimb development. Using models trained on embryonic limb data from bat and mouse, we identify a strong association between MEIS2 binding and the transcription factor TWIST1, a finding which is supported by single-cell transcriptomic analyses. To investigate the evolutionary dimension, we applied these models across more than 100 genomes, including extant bats, closely related species, and reconstructed ancestors. This analysis identified divergences in regulatory regions, which likely contribute to bat-specific forelimb expression of genes that lead to wing morphogenesis. Notably, these changes are prominent in the regulatory domains of the MEIS dimerization partner PBX1, indicating coordinated regulatory evolution. Together, our results demonstrate that the evolution of a complex morphological trait involves coordinated changes in both trans-regulatory environments and cis-regulatory landscapes. More broadly, this study provides a framework for integrating deep learning with comparative and functional genomics to investigate regulatory evolution.

evolutionary biology↗

bioRxiv2025

Enhancer-promoter compatibility is mediated by the promoter-proximal region

Gene promoters induce transcription in response to distal enhancers. How enhancers specifically activate their target promoter while bypassing other promoters remains unclear. Here, we find that the promoter-proximal region is critical for cell-type specific enhancer-promoter compatibility. Using high-throughput genome-engineering in mouse embryonic stem cells (mESC), we systematically replace the endogenous Sox9 promoter with different libraries of core and extended (i.e. full) promoters and assess their response to long-range regulatory elements in mESCs and neural progenitor cells. We find that only a subset of full promoters is activated by distal neuronal enhancers and that the promoter-proximal region is necessary for this enhancer-promoter compatibility. Core promoters alone are insufficient to respond to distal enhancers but modulate the transcriptional output of responsive promoters. Our results suggest that within multipartite regulatory domains, the promoter-proximal region fulfills a facilitator-like function that filters and transmits signal from distal enhancers, ultimaltely conferring enhancer-promoter compatibility.

genetics↗

bioRxiv2025

Accurate detection of pathogenic structural variants guided by multi-platform comparison

Structural variants (SVs) are a common cause of human diseases and greatly contribute to inter-individual variability. Their detection represents a significant challenge due to their diversity, size, and enrichment in repetitive regions. With the use of high quality long-read technologies, the majority of these challenges can now be mitigated. However, many downstream applications ranging from clinical diagnostics and genome-wide association studies to large-scale aggregation of population variants continue to rely on short-read-sequencing data due to its high through-put and cost-effectiveness. Thus, the challenges of short-read sequencing SV detection remain a constant and relevant obstacle. We created dicast, a machine-learning method to improve the identification of true-positive SVs from short-read sequencing using genomic context and alignment features. Dicast is driven by a novel and comprehensive benchmark call-set created through the combination of several sequencing technologies and rigorous manual curation. This benchmark set served as the basis for a systematic evaluation of five sequencing platforms and fifteen SV detection methods across different SV classes, sizes, and genomic contexts, enabling us to quantify the strengths and weaknesses of each and inform the training of our model. Leveraging these insights, dicast outperforms state-of-the-art short-read-based callers and consensus approaches, identifying considerably more true-positive variants while maintaining a high precision. We also demonstrate the methods applicability in diagnostic scenarios using putative pathogenic candidates in a limb malformation cohort, as well as known pathogenic variants in atrial fibrillation and neuromuscular disease cohorts. Dicast identifies all known pathogenic variants and 20% more manually confirmed candidate deletions than a consensus approach, and therefore can be used to reliably reduce time-consuming manual inspection in diagnostics. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/655285v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1c1702aorg.highwire.dtl.DTLVardef@aaecddorg.highwire.dtl.DTLVardef@1a4de08org.highwire.dtl.DTLVardef@ed0811_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Reconfiguration of genome-lamina interactions marks the commissioning of limb cell-fates

Diverse forms of heterochromatin block inappropriate transcription and safeguard differentiation and cell identity. Yet, how and when heterochromatin is reconfigured to facilitate changes in cell- fate remains a key open question. Here, we address this by mapping a prevalent heterochromatic feature - genome-lamina interactions - relative to transcription in single-cells during mouse embryogenesis. We find that genome-lamina interactions remain relatively uniform between germ layers following gastrulation but are extensively reconfigured in diverse tissues during later organogenesis. Focusing on limb development, we demonstrate that genome-lamina interactions are selectively released in early multipotent progenitors at key developmental genes and their surrounding regulatory domains. This "lamina-release" often precedes gene expression at later developmental stages, suggesting it primes regulatory domains for future potential activation. Conversely, lamina-release coincides with chromatin opening at sites of crucial limb transcription factor binding, and so is closely intertwined with the regulatory machinery driving limb formation. Finally, we show that the boundaries of topologically-associated domains (TADs) constrain the spread of lamina-release at a limb gene locus. This ensures independent lamina dynamics between neighbouring domains. Together, our data suggest a previously unrecognised process where genome-lamina interactions are selectively released at regulatory domains to transition loci toward more permissive chromatin states, thereby potentiating cell type specific activation. Our work thus reveals how systematic heterochromatin reorganization links to developmental multipotency, providing mechanistic insights into cell-fate decisions in vivo.

developmental biology↗

bioRxiv2024

Atheroprone Flow Activates SMAD-FOXO1 to drive Endothelial-to-Mesenchymal Transition and Atherosclerosis

BackgroundCardiovascular diseases are the leading cause of death worldwide with atherosclerosis as the main underlying pathology. A hallmark of atherosclerotic lesion formation is endothelial-to-mesenchymal transition (EndoMT) triggered by perturbed blood flow patterns at arterial bifurcations and curvatures. SMAD transcription factors (TFs), activated by bone morphogenetic protein (BMP) 9/10 or transforming growth factor beta (TGF{beta}) signaling, are indispensable for endothelial homeostasis. Yet, they also play a significant role in stimulating EndoMT. How different interacting co-factors mediate the shift towards a pathological SMAD response remains elusive. MethodsWe generated endothelial cell (EC)-specific SMAD1/5 or SMAD2/3 knock-out mice and performed assay for transposase accessible chromatin sequencing (ATAC-Seq) of EC nuclei from regions of atheroprone (aortic arch) and atheroprotective (descending thoracic aorta) flow to identify transcriptional co-regulators of SMADs. We validated this using single-cell (sc)ATAC-Seq and immunofluorescence staining data from wild-type mice. To assess conservation of our findings for the human situation, we performed co-immunoprecipitation and proximity ligation assays in human aortic ECs (HAoECs). We exposed HAoECs to pathological or physiological (i.e. oscillatory or pulsatile) flow and performed ATAC- and RNA-Seq. Next, transcriptomic and chromatin accessibility data were integrated and motif enrichment and TF footprinting analysis were performed. Finally, we used siRNA-mediated approaches, TF inhibition, and luciferase-based reporter gene assays to analyze the transcriptional response of target TFs and explored their presence in plaques of atheroprone low-density lipoprotein receptor-deficient mice. ResultsWe observed enrichment of FOXO TF family motifs in DNA loci with increased accessibility in response to atheroprone flow in vitro and in vivo. These motifs were associated with genes displaying enhanced mRNA expression. We observed that FOXO motifs are enriched in peaks lost upon EC-specific SMAD KO in mice. We identified SMADs and FOXO1 as interacting partners that form complexes upon atheroprone flow stimulation. Inhibitor experiments revealed that FOXO1 and SMADs mediate EndoMT upon atheroprone flow exposure by upregulating SNAI2. ConclusionWe identified SMAD/FOXO1 complexes that mediate EndoMT in response to atheroprone flow. Targeting this interaction can potentially reduce atherosclerotic burden by interfering with pathological flow-induced EndoMT and thus disease progression.

genomics↗

bioRxiv2024

Comparative single-cell analyses reveal evolutionary repurposing of a conserved gene program in bat wing development

Bats are the only mammals capable of self-powered flight, an evolutionary innovation based on the transformation of forelimbs into wings. The bat wing is characterized by an extreme elongation of the second to fifth digits and a wing membrane called chiropatagium connecting them. Here we investigated the developmental and cellular origin of this structure by comparing bat and mouse limbs using omics tools and single-cell analyses. Despite the substantial morphological differences between the species, we observed an overall conservation of cell populations and gene expression patterns including interdigital apoptosis. Single-cell analyses of micro-dissected embryonic chiropatagium identified a specific fibroblast population, independent of apoptosis-associated interdigital cells, as the origin of this tissue. These distal cells express a conserved gene program including the transcription factors MEIS2 and TBX3, which are commonly known to specify and pattern the early proximal limb. Transgenic ectopic expression of MEIS2 and TBX3 in mouse distal limb cells resulted in the activation of genes expressed during wing development and phenotypic changes related to wing morphology, such as the fusion of digits. Our results elucidate fundamental molecular mechanisms of bat wing development and illustrate how drastic morphological changes can be achieved through repurposing of existing developmental programs during evolution.

evolutionary biology↗

bioRxiv2024

Enhancer adoption by an LTR retrotransposongenerates viral-like particles causingdevelopmental limb phenotypes

Mammalian genomes are scattered with transposable elements (TEs). TEs are epigenetically silenced to prevent harmful effects caused by either global activation leading to genome instability or insertional mutation disturbing gene transcription. However, whether the activation of a single element can contribute to pathological phenotypes without directly affecting gene expression is largely unknown. Here, we show that tissue-specific expression of a TE in the embryo leads to the production of viral-like particles (VLPs) which can affect organ formation. Failure to silence an LTR retrotransposon inserted upstream of the Fgf8 gene results in its co-expression with Fgf8 in the developing embryo. While local gene regulation is unaffected, the LTR retrotransposon participates in chromatin folding at the locus and adopts the expression of the regulatory domain it is located in. This drives the production of VLPs in the Fgf8-expressing cells of the developing limb, triggering apoptotic cell death at the time of digit outgrowth and resulting in a limb malformation resembling human ectrodactyly. This phenotype can be rescued by knock-out or knock-in of the retrotransposon causing mutations preventing its full retroviral cycle. Insertion of the same element at other developmental loci faithfully recapitulates expression according to the neighboring regulatory activity. Our findings provide a mechanism by which TE insertion is incorporated into the local genomic regulatory landscape and show how VLP production in post-implantation embryos can interfere with organ formation.

developmental biology↗

bioRxiv2024

Temporally restricted activities of En1 regulatory elements underlie distinct limb malformations

The precise spatiotemporal regulation of developmental genes is required for proper organogenesis. Engrailed-1 (En1) is essential for dorsal-ventral patterning during mouse limb development from embryonic day E9.5 to E11.5. Previously, we identified the long non-coding RNA locus Maenli, which drives limb-specific En1 expression at E9.5. In this study, we investigated the regulatory mechanisms sustaining En1 expression at later developmental stages when Maenli transcriptional activity is drastically reduced. Using in vivo CRISPR editing, we identified two intergenic enhancer elements, LSEE1 and LSEE2, that maintain En1 expression at E10.5 and E11.5. Mice lacking these enhancers exhibit only a subset of the limb malformations observed in En1 and Maenli mutants, indicating that the timing of En1 misexpression causes distinct phenotypes. These findings underscore the role of temporally restricted activities of cis-regulatory elements, including lncRNA loci and enhancers, in modulating gene expression and explaining subtle differences in complex disease phenotypes.

developmental biology↗

bioRxiv2023

Incomplete transcriptional dosage compensation of vertebrate sex chromosomes is balanced by post-transcriptional compensation.

Heteromorphic sex chromosomes (XY or ZW) present problems of gene dosage imbalance between the sexes, and with the autosomes. Mammalian X chromosome inactivation was long thought to imply a critical need for dosage compensation in vertebrates. However, the universal importance of sex chromosome dosage compensation was questioned by mRNA abundance measurements that demonstrated sex chromosome transcripts are neither balanced between the sexes or with autosomes in monotreme mammals or birds. Here, we demonstrate unbalanced mRNA levels of X genes in platypus males and females that correlate with differential loading of histone modifications, and confirm that transcripts of Z genes are unbalanced between males and females also in chicken. However, we found that in both species, median male to female protein abundance ratios were 1:1, implying an additional level of post-transcriptional control. We conclude that parity of sex chromosome output is achieved in birds, as well as all mammal groups, by a combination of transcriptional and post-transcriptional control, consistent with an essential role for sex chromosome dosage compensation in vertebrates.

evolutionary biology↗

bioRxiv2022

Failure of digit tip regeneration in the absence of suggests Lmx1b functions disparate from dorsoventral polarity

Mammalian digit tip regeneration is linked to the presence of nail tissue, but a nail-explicit model is missing. Here, we report that nail-less double-ventral digits of {Delta}LARM1/2 mutants that lack limb-specific Lmx1b enhancers fail to regenerate. To separate the nails effect from the lack of DV polarity, we also interrogate double-dorsal double-nail digits and show that they regenerate. Thus, DV polarity is not a prerequisite for regeneration and the nail requirement is supported. Transcriptomic comparison between wild-type and non-regenerative{Delta} LARM1/2 mutant blastemas reveals differential up-regulation of vascularization and connective tissue functional signatures in wild-type versus upregulation of inflammation in the mutant. These results, together with the finding of uniform Lmx1b expression in the wild-type blastema and in the dorsal dermis underneath the nail, indicate that, in addition of the nails effect, a direct role for Lmx1b in driving the progression of digit tip regeneration is likely.

developmental biology↗

bioRxiv2022

Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve Split-Hand/Foot Malformation type 3

Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigated the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice resulted in restructuring of the chromatin architecture. This led to an ectopic activation of the Lbx1 and Btrc genes in the apical ectodermal ridge (AER) in an Fgf8-like pattern. Artificial repositioning of the AER-specific enhancers of Fgf8 was sufficient to induce misexpression of Lbx1 and Btrc. We provide evidence that the SHFM3 phenotype is the result of a combinatorial effect on gene misexpression and dosage in the developing limb. Our results reveal new insights into the molecular mechanism underlying SHFM3 and provide novel conceptual framework for how genomic rearrangements can cause gene misexpression and disease.

genetics↗

bioRxiv2022

Cell adhesion and immune response, two main functions altered in the transcriptome of seasonally regressed testes of two mammalian species

In species with seasonal breeding, male specimens undergo substantial testicular regression during the non-breeding period of the year. However, the molecular mechanisms that control this biological process are largely unknown. Here, we report a transcriptomic analysis on the Iberian mole, Talpa occidentalis, in which the desquamation of live, non-apoptotic germ cells is the major cellular event responsible for testis regression. By comparing testes at different reproductive states (active, regressing and inactive), we demonstrate that the molecular pathways controlling the cell adhesion function in the seminiferous epithelium, such as the MAPK, ERK and TGF-{beta} signalling, are altered during the regression process. In addition, inactive testes display a global upregulation of genes associated with immune response, indicating a selective loss of the "immune privilege" that normally operates in sexually active testes. Interspecies comparative analyses using analogous data from the Mediterranean pine vole, a rodent species where testis regression is controlled by halting meiosis entry, revealed a common gene expression signature in the regressed testes of these two evolutionary distant species. Our study advances in the knowledge of the molecular mechanisms associated to gonadal seasonal breeding, highlighting the existence of a conserved transcriptional program of testis involution across mammalian clades. Research HighlightsBy comparing the trascriptomes of the testes from males of the iberian mole, Talpa occidentalis (order Eulipotyphla), captured at different stages of the seasonal breeding cycle of this species, we show that two main functions are altered during seasonal testis regression: cell adhesion and immune response. The fact that the same functions alre also altered in the Mediterranean pine vole, Microtus duodecimcostatus (order Rodentia), evidences the existence of a conserved transcriptional program of testis regression across mammalian clades.

molecular biology↗

bioRxiv2021

Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs

Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution. HIGHLIGHTSO_LINew genes can emerge in evolution without taking on the expression pattern of their surrounding pre-existing TAD. C_LIO_LICompartmentalisation can restructure seemingly evolutionarily stable TADs to control a promoters access to enhancers. C_LIO_LILamina-associated domains neither prevent transcriptional activation nor enhancer-promoter communication. C_LIO_LIRepression rather than promoter-specificity refines when genes respond to promiscuous enhancer activities in specific tissues. C_LI

genetics↗

bioRxiv2021

Distal and proximal cis-regulatory elements sense X-chromosomal dosage and developmental state at the Xist locus

Developmental genes such as Xist, the master regulator of X-chromosome inactivation (XCI), are controlled by complex cis-regulatory landscapes, which decode multiple signals to establish specific spatio-temporal expression patterns. Xist integrates information on X-chromosomal dosage and developmental stage to trigger XCI at the primed pluripotent state in females only. Through a pooled CRISPR interference screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements of Xist during the onset of random XCI. By quantifying how enhancer activity is modulated by X-dosage and differentiation, we find that X-dosage controls the promoter-proximal region in a binary switch-like manner. By contrast, differentiation cues activate a series of distal elements and bring them into closer spatial proximity of the Xist promoter. The strongest distal element is part of an enhancer cluster [~]200 kb upstream of the Xist gene which is associated with a previously unannotated Xist-enhancing regulatory transcript, we named Xert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specific Xist upregulation at the correct developmental time. Our study is the first step to disentangle how multiple, functionally distinct regulatory regions interact to generate complex expression patterns in mammals.

genomics↗

bioRxiv2020

Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction1-5. This process is essential for embryonic stem cell (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spread of H3K27me3 on the linear genome6. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear7-10. Here, we apply H3K27me3 HiChIP11-13, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture14 to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells7-10. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such as Hmx1, Wnt6 and Hoxa. Genetic deletion of H3K27me3 loop anchors revealed a coupling of Polycomb-associated genome architecture and H3K27me3 deposition evidenced by disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. Further, we find that global alterations in PRC2 occupancy resulting from an EZH2 mutant15 selectively deficient in RNA binding is accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 acts as a "genomic wormhole", using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Additionally, developmental gene loci have novel roles in Polycomb spreading, emerging as important architectural elements of the epigenome.

genetics↗

bioRxiv2020

TADA - a Machine Learning Tool for Functional Annotation based Prioritisation of Putative Pathogenic CNVs

The computational prediction of disease-associated genetic variation is of fundamental importance for the genomics, genetics and clinical research communities. Whereas the mechanisms and disease impact underlying coding single nucleotide polymorphisms (SNPs) and small Insertions/Deletions (InDels) have been the focus of intense study, little is known about the corresponding impact of structural variants (SVs), which are challenging to detect, phase and interpret. Few methods have been developed to prioritise larger chromosomal alterations such as Copy Number Variants (CNVs) based on their pathogenicity. We address this issue with TADA, a method to prioritise pathogenic CNVs through manual filtering and automated classification, based on an extensive catalogue of functional annotation supported by rigorous enrichment analysis. We demonstrate that our machine-learning classifiers for deletions and duplications are able to accurately predict pathogenic CNVs (AUC: 0.8042 and 0.7869, respectively) and produce a well-calibrated pathogenicity score. The combination of enrichment analysis and classifications suggests that prioritisation of pathogenic CNVs based on functional annotation is a promising approach to support clinical diagnostic and to further the understanding of mechanisms that control the disease impact of larger genomic alterations.View Full Text

genetics↗

bioRxiv2020

A CRISPR-Cas9-engineered mouse model for GPI anchor deficiency mirrors human phenotype and shows hippocampal synaptic dysfunctions.

Pathogenic germline mutations in PIGV lead to glycosylphosphatidylinositol biosynthesis deficiency (GPIBD). Individuals with pathogenic biallelic mutations in genes of the glycosylphosphatidylinositol (GPI) anchor pathway exhibit cognitive impairments, motor delay, and often epilepsy. Thus far, the pathophysiology underlying the disease remains unclear, and suitable rodent models that mirror all symptoms observed in human patients have not been available. Therefore, we used CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, Pigv:c.1022C>A (p.A341E), at a site that is conserved in mice. Mirroring the human pathology, mutant Pigv341E mice exhibited deficits in motor coordination, cognitive impairments, and alterations in sociability and sleep patterns, as well as increased seizure susceptibility. Furthermore, immunohistochemistry revealed reduced synaptophysin immunoreactivity in Pigv341E mice, and electrophysiology recordings showed decreased hippocampal synaptic transmission that could underlie impaired memory formation. In single-cell RNA sequencing, Pigv341E-hippocampal cells exhibited changes in gene expression, most prominently in a subtype of microglia and subicular neurons. A significant reduction in Abl1 transcript levels in several cell clusters suggested a link to the signaling pathway of GPI-anchored ephrins. We also observed elevated levels of Hdc transcripts, which might affect histamine metabolism with consequences for circadian rhythm. This new mouse model will not only open the doors to further investigation into the pathophysiology of GPIBD, but will also deepen our understanding of the role of GPI-anchor-related pathways in brain development. Significance statementInherited GPI-anchor biosynthesis deficiencies (IGDs) explain many cases of syndromic intellectual disability. Although diagnostic methods are improving, the pathophysiology underlying the disease remains unclear. Furthermore, we lack rodent models suitable for characterizing cognitive and social disabilities. To address this issue, we generated the first viable mouse model for an IGD that mirrors the condition in human patients with a behavioral phenotype and susceptibility to epilepsy. Using the new model, we obtained neurological insights such as deficits in synaptic transmission that will facilitate understanding of the pathophysiology of IGDs.

neuroscience↗

bioRxiv2020

VarFish - Collaborative and Comprehensive Variant Analysis for Diagnosis and Research

VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of panel and exome variant data for rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Filtered variants are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows user to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the softwares extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g., after update of genotype or phenotype databases.

bioinformatics↗