Biology subjects

Gymrek, M.

Publications and source records attributed to Gymrek, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Haplotype-based fine-mapping of variant associations for complex traits

Genome-wide association studies (GWAS) have identified tens of thousands of associations between genomic regions and complex traits in humans, but identifying the causal variants underlying these associations is challenging. Statistical fine-mapping techniques attempt to quantify the probability of causality of individual variants while accounting for the correlation induced by linkage disequilibrium (LD) between nearby variants. Existing fine-mapping solutions are limited to considering additive and independent contributions of individual variants, and also assume the causal variant is included in the analysis. Here, we introduce a novel fine-mapping method, happler, which models the effects of variant haplotypes (sets of alleles of two or more variants in cis) in addition to individual variants. By identifying haplotype proxies for causal variants, happler can infer additional effects including those driven by combinations of variants in cis and ungenotyped causal variants, such as complex structural variants, which are in some cases better tagged by one or more haplotypes than by individual SNPs. Simulation experiments show that whereas happler can correctly identify causal haplotype effects, traditional methods based on individual variants can produce inconclusive results in such cases. We applied happler to identify 32 haplotypes associated with gene expression using 359 individuals from the Geuvadis dataset. Of these, five are confidently fine-mapped, with stronger posterior inclusion probabilities than any individual variant, in an external cohort from the Genotype Tissue Expression (GTEx) project. Finally, we used the AoU dataset to demonstrate the utility of haplotypes for tagging rare causal variants that are absent from the input dataset.

bioinformatics↗

bioRxiv2026

Point mutations and complex variants impact gene expression and addiction-related behaviors in Heterogeneous Stock rats

While various variants, including single nucleotide polymorphisms (SNPs), small insertions/deletions, short tandem repeats and structural variants, drive individual genetic differences, their influence on gene expression and complex traits remains unclear. We used short- and long-read sequencing to generate a comprehensive variant catalog in Heterogeneous Stock (HS) rats and performed joint cis-expression quantitative trait loci (cis-eQTL) mapping across five brain regions. We found that non-SNP variants accounted for over 50% of lead regulatory associations, many of which were poorly tagged by nearby SNPs using linkage disequilibrium (LD). Comparison between joint and SNP-only analyses showed that over 46% of shared eQTL genes had a non-SNP lead cis-eQTL, and fewer than half were in strong LD with the corresponding lead eSNP. Linking joint cis-eQTLs to complex trait associations identified mechanisms missed by SNP-only approaches, highlighting the importance of incorporating diverse variant types into genetic studies and providing a foundational resource for the HS rat community.

genetics↗

bioRxiv2026

Trex-QTL: A mixture-model for identification of genetic effects with global effects on molecular phenotypes

While thousands of cis expression quantitative trait loci (cis-eQTLs) have been reliably identified, detecting trans-eQTL effects has proven to be challenging due to insufficient statistical power, lack of comparable tissues and cohorts, and low reproducibility across studies. Here, we present Trex-QTL, a novel trans-eQTL detection method that models eQTL summary statistics as a mixture consisting of both target gene and null associations. Compared to other recently developed methods, Trex-QTL has improved power for trans-eQTL detection and employs a simplified framework, requiring only eQTL association summary statistics as input. We performed extensive simulations to characterize the conditions under which trans-eQTLs are detectable by Trex-QTL across a range of effect sizes and numbers of target genes. We applied Trex-QTL to the Depression Genes and Networks (DGN) dataset and replicated two well-established trans-eQTLs at ARHGEF3 and IKZF1. We then applied Trex-QTL to the deeply characterized heterogeneous stock (HS) rat cohort with matched brain transcriptomic and genomic data, identifying 7 top-scoring, linkage disequilibrium-independent trans-eQTLs. One previously unreported trans-eQTL is at the locus harboring Jag2, a critical ligand for the Notch signaling pathway, which is associated with decreased Jag2 expression and decreased expression of multiple downstream genes including known Notch targets. A second example is a strong trans-eQTL overlapping a cluster of interferon genes associated with interferon-response genes including C4a and Parp14. We show evidence that this signal is mediated by a cis-eQTL for a cluster of interferon ligand genes that operate upstream of interferon receptor signaling. Both of these signals co-localize with association signals for a range of other phenotypes measured in this cohort. Overall, we demonstrate that Trex-QTL represents a powerful method to identify trans-eQTLs with global effects on molecular phenotypes and identify novel biologically compelling examples of such loci.

genomics↗

bioRxiv2026

The contribution of short tandem repeats to splicing variation in the human cortex

BackgroundSplicing disruption has been implicated in a range of heritable phenotypes, including numerous psychiatric and neurological disorders. Recent studies have identified thousands of common genetic variants impacting splicing in brain and other tissues, but have focused largely on single nucleotide polymorphisms or short indels. Despite growing evidence that genetic variation at short tandem repeats (STRs) influences splicing, large-scale studies of STR-mediated splicing in brain have been limited by low sample sizes of available RNA-seq data or exclusion of certain classes of STRs, such as homopolymers which account for around half of all STRs. ResultsIn this study, we leveraged deep RNA-seq and SNP array data from 336 human dorsolateral prefrontal cortex (DLPFC) samples collected by the Human Brain Collection Core (HBCC). We imputed 445,720 STRs into available genotype data and identified 51,343 unique STRs for which copy number is significantly associated with one or multiple alternative splicing events of nearby genes (spliceSTRs). We prioritized and characterized candidate causal spliceSTRs using three orthogonal fine-mapping strategies which identified 1,313 high-confidence fine-mapped spliceSTRs. Our analyses revealed strong associations between copy number of certain repeat units and binding of specific RNA-binding proteins (RBPs), including a previously known relationship between HNRNPL and AC repeat length, suggesting that the functional impact of some spliceSTRs may be mediated through their binding affinity for RBPs. Finally, co-localization analyses using summary statistics from genome-wide association studies (GWAS) for 6 brain-related disorders identified multiple signals that may be driven by spliceSTRs, including a previously identified GTn repeat that is a spliceSTR for PLEKHA1 associated with Alzheimers disease as well as a newly identified AGGn spliceSTR in SEPTIN3 co-localized with schizophrenia. ConclusionsTogether, our findings highlight the role of STRs in regulating alternative splicing in the human brain, suggest a general relationship between STR polymorphism and RBP-mediated splicing events, and identify specific spliceSTRs detected by co-localization analysis as candidate causal variants for brain-related disorders.

genomics↗

bioRxiv2026

Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation

Mouse meander tail (mea) mutations produce kinked tails and selective malformation of the cerebellum anterior compartment. The anterior cerebellum defects are cell autonomous with respect to granule cell precursors, but the molecular basis has not been known. Myb-like, SWIRM, and MPN domain containing protein 1 (MYSM1) is a chromatin-associated deubiquitinase that promotes gene expression by removing monoubiquitin from histone H2A, among other targets. Loss of MYSM1 function in mice or humans results in bone marrow failure with defective maturation of B cell lineages. Here we show that extant mea alleles have mutations in Mysm1 and cause both neurological and hematological phenotypes, as do new non-complementing endonuclease-mediated mutations. Multimodal single-nucleus assays show Mysm1 effects on gene expression in several lineages and on the proportion of granule cell precursors by E14.5. Intriguingly, Mysm1 orthologs have been independently lost in several animal and fungal lineages, including yeast, flies, and nematodes. These results unite previously disconnected literature and demonstrate a requirement for MYSM1 activity in compartment-specific development of the cerebellum and suggest potential for compensatory pathways. Significance StatementPerturbations to core regulatory machinery often produce pleiotropic effects and even intensively studied systems can have significant phenotypic effects that were not assessed in models developed for a different purpose. Here we show that classical meander tail mice, characterized by ankylosing spondylitis in tail vertebrae and a cerebellum malformation that defined the anterior-posterior compartment boundary, have mutations in Mysm1, encoding a histone 2A deubiquitinase. We show pigmentation defects and hematopoietic abnormalities that model human disease. While Mysm1 mutations change gene expression patterns in many cerebellar cell types, they selectively decrease the proportion of granule cell lineages. Recurrent loss of Mysm1 orthologs across fungal and animal phylogenies suggests the potential for bypass mechanisms.

genetics↗

bioRxiv2025

Systematic evaluation of the impact of promoter proximal short tandem repeats on expression

Genetic variation at thousands of short tandem repeats (STRs), which consist of consecutive repeated sequences of 1-6bp, has been statistically associated with gene expression and other molecular phenotypes in humans. However, the causality and regulatory mechanisms for most of these STRs remains unknown. Massively parallel reporter assays (MPRA) enable testing the regulatory activity of a large number of synthesized variants, but have not been applied to STRs due to experimental and computational challenges. Here, we optimized an MPRA framework based on random barcoding to study the impact of variation in repeat copy number on expression. We first performed an MPRA on sequences derived from 30,516 promoter-proximal STR loci along with up to 152bp of genomic context, testing 3-4 variants with differing repeat copy numbers for each locus in HEK293T cells. We identified 1,366 loci with significant associations between repeat copy number and expression, which were enriched for positive effect sizes (P=2.08e-110). We then designed a second MPRA in which we performed deeper perturbations, including systematic manipulation of the repeat unit sequence, orientation, and copy number, with 200-300 perturbations for each of the 300 loci with the strongest signals. Our results revealed that the repeat unit sequence is the primary driver of differences in the relationship between copy number and expression across loci, whereas orientation and flanking sequence have weaker effects, primarily for AT-rich repeat units. The high resolution of these perturbations enabled us to detect non-linear effects, most notably for AAAC/GTTT repeats, which emerge only beyond a certain copy number threshold. Finally, we observed that a subset of STRs in our library show expression levels that are tightly linked with predicted DNA secondary structure formation. We repeated our perturbation MPRA in HeLa S3 cells under wildtype and RNase H1 knockdown conditions, which, via reduction in RNase H1 activity, are expected to hinder resolution of R-loops. This demonstrated that associations between copy number and expression at G-quadruplex-forming CCCCG/CGGGG repeats are particularly sensitive to loss of RNase H1, providing support for an R-loop mediated mechanism for these repeats. Altogether, we establish STRs as a critical component of the non-coding regulatory grammar and provide a framework for understanding how this dynamic form of genetic variation shapes gene expression.

genomics↗

bioRxiv2025

Estimating the cis-heritability of gene expression using single cell expression profiles controls false positive rate of eGene detection

For gene expression traits, cis-genetic heritability can quantify the strength of genetic regulation in particular cell types, elucidating the cell-type-specificity of disease variants and genes. To estimate gene expression heritability, standard models require a single gene expression value per individual, forcing data from single cell RNA-sequencing (scRNA-seq) experiments to be "pseudobulked". Here, we show that applying standard heritability models to pseudobulk data overestimates gene expression heritability and produces inflated false positive rates for detecting cis-heritable genes. Therefore, we introduce a new method called scGeneHE (single cell Gene expression Heritability Estimation), a Poisson mixed-effects model that quantifies the cis-genetic component of gene expression using individual cellular profiles. In simulations, scGeneHE has a consistently well-calibrated false positive rate for eGene detection and unbiasedly estimates cis-heritability at many parameter settings. We applied scGeneHE to scRNA-seq data from 969 individuals, 11 immune cell types, and 822,552 cells from the OneK1K cohort to infer cell-type-specificity of genetic regulation at risk genes for immune-mediated diseases and trace the fluctuation of cis-heritability across cellular populations of varying resolution. In summary, we developed a new statistical method that resolves the analytical challenge of estimating gene expression cis-heritability from native scRNA-seq data.

genetics↗

bioRxiv2024

Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

Tandem repeats (TRs) - highly polymorphic, repetitive sequences across the human genome - are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis1. Here, we generate new whole genome and single-cell RNA sequencing from >5.4 million blood-derived cells across 1,925 individuals in two cohorts [Cuomo et al., accompanying manuscript], and perform meta-analysis to characterize the impact of variation in >1.7 million TR loci on immune cell type-specific gene expression. We identify >69,000 single-cell expression TR loci (sc-eTRs), 30.7% of which are specific to one of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell ATAC sequencing profiles from >3.4 million nuclei in 922 individuals [Xue et al., accompanying manuscript]. uncover chromatin accessibility QTLs for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight >200 genes in which TRs likely mediate genetic associations with immune and hematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.

genomics↗

bioRxiv2024

Defining a tandem repeat catalog and variation clusters for genome-wide analyses and population databases

Tandem repeat (TR) catalogs are important components of repeat genotyping studies as they define the genomic coordinates and expected motifs of all TR loci being analyzed. In recent years, genome-wide studies have used catalogs ranging in size from fewer than 200,000 to over 7 million loci. Where these catalogs overlapped, they often disagreed on locus boundaries, hindering the comparison and reuse of results across studies. Now, with multiple groups developing public databases of TR variation in large population cohorts, there is a risk that, without sufficient consensus in the choice of locus definitions, the use of divergent repeat catalogs will lead to confusion, fragmentation, and incompatibility across resources. In this paper, we compare existing TR catalogs and discuss desirable features of a comprehensive genome-wide catalog. We then present a new, richly annotated catalog designed for large-scale analyses and population databases. This new catalog, which we call the TRExplorer catalog v1.0, contains 4.86 million TR loci and, unlike most catalogs, is designed to be useful for both short-read and long-read analyses. It consists of 4,803,366 STRs and 59,675 VNTRs, of which 780,607 STRs and 21,888 VNTRs are both polymorphic and entirely absent from widely-used catalogs previously developed for short-read analyses. Additionally, our catalog stratifies TRs into two groups: 1) isolated TRs suitable for repeat copy number analysis using short-read or long-read data and 2) so-called variation clusters that contain TRs within wider polymorphic regions that are best studied through sequence-level analysis. To define variation clusters, we present a novel algorithm that leverages long-read HiFi sequencing data to group repeats with surrounding polymorphisms. We show that the human genome contains at least 25,000 complex variation clusters, most of which span over 120 bp and contain five or more TRs. Resolving the sequence of entire variation clusters instead of individually genotyping constituent TRs leads to a more accurate analysis of these regions and enables us to profile variation that would have been missed otherwise. We also share the trexplorer.broadinstitute.org portal which allows anyone to search, visualize, and download the catalog along with variation clusters and annotations.

genomics↗

bioRxiv2024

Genome-wide profiling of genetic variation at tandem repeat from long reads

Tandem repeats are frequent across the human genome, and variation in repeat length has been linked to a variety of traits. Recent improvements in long read sequencing technologies have the potential to greatly improve TR analysis, especially for long or complex repeats. Here we introduce LongTR, which accurately genotypes tandem repeats from high fidelity long reads available from both PacBio and Oxford Nanopore Technologies. LongTR is freely available at https://github.com/gymrek-lab/longtr.

bioinformatics↗

bioRxiv2023

Genome wide detection of somatic mosaicism at short tandem repeats

MotivationSomatic mosaicism, in which a mutation occurs post-zygotically, has been implicated in several developmental disorders, cancers, and other diseases. Short tandem repeats (STRs) consist of repeated sequences of 1-6bp and comprise more than 1 million loci in the human genome. Somatic mosaicism at STRs is known to play a key role in the pathogenicity of loci implicated in repeat expansion disorders and is highly prevalent in cancers exhibiting microsatellite instability. While a variety of tools have been developed to genotype germline variation at STRs, a method for systematically identifying mosaic STRs (mSTRs) is lacking. ResultsWe introduce prancSTR, a novel method for detecting mSTRs from individual high-throughput sequencing datasets. Unlike many existing mosaicism detection methods for other variant types, prancSTR does not require a matched control sample as input. We show that prancSTR accurately identifies mSTRs in simulated data and demonstrate its feasibility by identifying candidate mSTRs in whole genome sequencing (WGS) data derived from lymphoblastoid cell lines for individuals sequenced by the 1000 Genomes Project. Our analysis identified an average of 76 and 577 non-homopolymer and homopolymer mSTRs respectively per cell line as well as multiple cell lines with outlier mSTR counts more than 6 times the population average, suggesting a subset of cell lines have particularly high STR instability rates. AvailabilityprancSTR is freely available at https://github.com/gymrek-lab/trtools. DocumentationDetailed documentation is available at https://trtools.readthedocs.io/ Contactmgymrek@ucsd.edu

bioinformatics↗

bioRxiv2023

Benchmarking of small and large variants across tandem repeats

Tandem repeats (TRs) are highly polymorphic in the human genome, have thousands of associated molecular traits, and are linked to over 60 disease phenotypes. However, their complexity often excludes them from at-scale studies due to challenges with variant calling, representation, and lack of a genome-wide standard. To promote TR methods development, we create a comprehensive catalog of TR regions and explore its properties across 86 samples. We then curate variants from the GIAB HG002 individual to create a tandem repeat benchmark. We also present a variant comparison method that handles small and large alleles and varying allelic representation. The 8.1% of the genome covered by the TR catalog holds [~]24.9% of variants per individual, including 124,728 small and 17,988 large variants for the GIAB HG002 TR benchmark. We work with the GIAB community to demonstrate the utility of this benchmark across short and long read technologies.

bioinformatics↗

bioRxiv2023

A deep population reference panel of tandem repeat variation

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3,550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.

genomics↗

bioRxiv2022

Polymorphic short tandem repeats make widespread contributions to blood and serum traits

Short tandem repeats (STRs), genomic regions each consisting of a sequence of 1-6 base pairs repeated in succession, represent one of the largest sources of human genetic variation. However, many STR effects are not captured well by standard genome-wide association studies (GWAS) or downstream analyses that are mostly based on single nucleotide polymorphisms (SNPs). To study the involvement of STRs in complex traits, we imputed genotypes for 445,720 autosomal STRs into genotype array data from 408,153 White British UK Biobank participants and tested for association with 44 blood and serum biomarker phenotypes. We used two fine-mapping methods, SuSiE and FINEMAP, to identify 119 high-confidence STR-trait associations across 93 unique STRs predicted as causal variants under all fine-mapping settings tested. Using these results, we estimate that STRs account for 5.2-7.6% of causal variants identifiable from GWAS signals for these traits. Our high confidence STR-trait associations implicate STRs in some of the strongest hits for multiple phenotypes, including a CTG repeat in APOB associated with circulating apolipoprotein B levels, a CGG repeat in the promoter of CBL associated with multiple platelet traits and a poly-A repeat in TAOK1 associated with mean platelet volume. Replication analyses in additional population groups and orthogonal expression data further support the role of a subset of the candidate STRs we identify. Together, our study suggests that polymorphic tandem repeats make widespread contributions to complex traits, provides a set of stringently selected candidate causal STRs, and demonstrates the need to routinely consider a more complete view of human genetic variation in GWAS.

genetics↗

bioRxiv2022

Genome-wide selection inference at short tandem repeats

Short tandem repeats (STRs) comprising repeated sequences of 1-6 bp are one of the largest sources of genetic variation in humans. STRs are known to contribute to a variety of disorders, including Mendelian diseases, complex traits, and cancer. Based on their functional importance, mutations at some STRs are likely to introduce negative effects on reproductive fitness over evolutionary time. We previously developed SISTR (Selection Inference at STRs), a population genetics framework to measure negative selection against individual STR alleles. Here, we extend SISTR to enable joint estimation of the distribution of selection coefficients across a set of STRs. This method (SISTR2) allows for more accurate analysis of a broader range of STRs, including loci with low mutation rates. We apply SISTR2 to explore the range of feasible mutation parameters and demonstrate substantial variation in mutation and selection parameters across different classes of STRs. Finally, we show that de novo STR mutations tend to confer a greater selective burden compared to standing STR variation in the population and measure the relative burden of STRs vs. single nucleotide variants in a typical genome. Overall, we anticipate that the evolutionary insights gained from this study will be important for future studies of variation at STRs and their role in evolution and disease.

genomics↗

bioRxiv2022

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

The BXD family of recombinant inbred mice were developed by crossing and inbreeding progeny of C57BL/6J and DBA/2J strains. This family is the largest and most extensively phenotyped mammalian experimental genetic resource. Although used in genetics for 52 years, we do not yet have comprehensive data on DNA variants segregating in the BXDs. Using linked-read whole-genome sequencing, we sequenced 152 members of the family at about 40X coverage and quantified most variants. We identified 6.25 million polymorphism segregating at a near-optimal minor allele frequency of 0.42. We also defined two other major variants: strain-specific de novo singleton mutations and epoch-specific de novo polymorphism shared among subfamilies of BXDs. We quantified per-generation mutation rates of de novo variants and demonstrate how founder-derived, strain-specific, and epoch-specific variants can be analyzed jointly to model genome-phenome causality. This integration enables forward and reverse genetics at scale, rapid production of any of more than 10,000 diallel F1 hybrid progeny to test predictions across diverse environments or treatments. Combined with five decades of phenome data, the BXD family and F1 hybrids are a major resource for systems genetics and experimental precision medicine.

genomics↗

bioRxiv2022

A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements characterized by repeated units of 1 or more nucleotides. We leveraged whole genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family derived from C57BL/6J and DBA/2J mice to study the effects of genetic background on genome-wide patterns of new mutations at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and identified a locus on chromosome 13 associated with the propensity of STRs to expand. Several dozen genes lie in the QTL region, including Msh3, a known modifier of STR stability at pathogenic repeat expansions in mice and humans. Detailed analysis of the locus revealed a cluster of variants near the 5 end of Msh3, including multiple protein-coding variants within the DNA mismatch recognition domain of MSH3, and a retrotransposon insertion overlapping an annotated exon. Additionally, gene expression analysis demonstrates co-localization of this QTL with expression QTLs for multiple nearby genes, including Msh3. Our results suggest a novel role for Msh3 in regulating genome-wide patterns of germline STR mutations and demonstrate that inherited genetic variation can contribute to variability in accumulation of new mutations across individuals.

genomics↗

bioRxiv2021

Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation

Cell lines have been essential for major discoveries in cancer including Ewing sarcoma (EwS). EwS is a highly aggressive pediatric bone or soft-tissue cancer characterized by oncogenic EWSR1-ETS fusion transcription factors converting polymorphic GGAA-microsatellites (mSats) into neo-enhancers. However, further detailed mechanistic evaluation of gene regulation in EwS have been hindered by the limited number of well-characterized cell line models. Here, we present the Ewing Sarcoma Cell Line Atlas (ESCLA) comprising 18 EwS cell lines with inducible EWSR1-ETS knockdown that were profiled by whole-genome-sequencing, DNA methylation arrays, gene expression and splicing arrays, mass spectrometry-based proteomics, and ChIP-seq for EWSR1-ETS and histone marks. Systematic analysis of these multi-dimensional data illuminated hundreds of new potential EWSR1-ETS target genes, the nature of EWSR1-ETS-preferred GGAA-mSats, and potential indirect modes of EWSR1-ETS-mediated gene regulation. Moreover, we identified putative co-regulatory transcription factors and heterogeneously regulated EWSR1-ETS target genes that may have implications for the clinical heterogeneity of EwS. Collectively, our freely available ESCLA constitutes an extremely rich resource for EwS research and highlights the power of leveraging multidimensional and comprehensive datasets to unravel principles of heterogeneous gene regulation by dominant fusion oncogenes.

genomics↗