Biology subjects

Ye, K.

Publications and source records attributed to Ye, K..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Quartet DNA reference materials and datasets for comprehensively evaluating germline variants calling performance

Current methods for evaluating the accuracy of germline variant calls are restricted to easy-to-detect high-confidence regions, thus ignoring a substantial portion of difficult variants beyond the benchmark regions. We established four DNA reference materials from immortalized cell lines derived from a Chinese Quartet including parents and monozygotic twins. We integrated benchmark calls of 4.2 million small variants and 15,000 structural variants from multiple platforms and bioinformatic pipelines for evaluating the reliability of germline variant calls inside the benchmark regions. The genetic built-in-truth of the Quartet family design not only improved sensitivity of benchmark calls by removing additional false positive variants with apparently high quality, but also enabled estimation of the precision of variants calls outside the benchmark regions. Batch effects of variant calling in large-scale DNA sequencing efforts can be effectively identified with the concurrent use of the Quartet DNA reference materials along with study samples, and can be alleviated by training a machine learning model with the Quartet reference datasets to remove potential artifact calls. Matched RNA and protein reference materials were also established in the Quartet project, thereby enabling benchmark calls constructed from DNA reference materials for evaluation of variants calling performance on RNA and protein data. The Quartet DNA reference materials from this study are a resource for objective and comprehensive assessment of the accuracy of germline variant calls throughout the whole-genome regions.

bioinformatics↗

bioRxiv2022

Infant antibody repertoires during the first two years of influenza vaccination

The first encounter with influenza virus biases later immune responses. This "immune imprinting", formerly from infection within a few years of birth, is in the U.S. now largely from immunization with a quadrivalent, split vaccine (IIV4). In a pilot study of IIV4 imprinting, we characterized, by single-B-cell cultures, NextGen sequencing, and plasma antibody proteomics, the primary antibody responses to influenza in two infants during their first two years of seasonal influenza vaccination. One infant, who received only a single vaccination in Year 1, contracted an influenza B (IBV) infection between the two years, allowing us to compare imprinting by infection and vaccination. That infant had a shift in hemagglutinin (HA)-reactive B-cell specificity from largely influenza A (IAV)-specific in Year 1 to IBV-specific in Year 2, both before and after vaccination. HA-reactive B cells from the other infant maintained a more evenly distributed specificity. In Year 2, class-switched HA-specific B cell IGHV somatic hypermutation (SHM) levels reached average levels seen in adults. The HA-reactive plasma antibody repertoires of both infants comprised a relatively small number of antibody clonotypes, with one or two very abundant clonotypes. Thus, after the Year 2 boost, both infants had overall B cell profiles that resembled those of adult controls. ImportanceInfluenza virus is a moving target for the immune system. Variants emerge that escape protection from antibodies elicited by a previously circulating variant ("antigenic drift"). The immune system usually responds to a drifted influenza virus by mutating existing antibodies rather than by producting entirely new ones. Thus, immune memory of the earliest influenza exposure has a major influence on later responses to infection or vaccination ("immune imprinting"). In the many studies of influenza immunity in adult subjects, imprinting has been from an early infection, since only in the past two decades have infants received influenza immunizations. The work reported in this paper is a pilot study of imprinting in two infants by the flu vaccine, which they received before experiencing an influenza infection. The results suggest that a quadrivalent (four-subtype) vaccine may provide an immune imprint less dominated by one subtype than does a monovalent infection.

immunology↗

bioRxiv2022

Haplotype-resolved assemblies and variant benchmark of a Chinese Quartet

As the state-of-the-art sequencing technologies and computational methods enable investigation of challenging regions in the human genome, an update variant benchmark is demanded. Herein, we sequenced a Chinese Quartet, consisting of two monozygotic twin daughters and their biological parents, with multiple advanced sequencing platforms, including Illumina, BGI, PacBio, and Oxford Nanopore Technology. We phased the long reads of the monozygotic twin daughters into paternal and maternal haplotypes using the parent-child genetic map. For each haplotype, we utilized advanced long reads to generate haplotype-resolved assemblies (HRAs) with high accuracy, completeness, and continuity. Based on the ingenious quartet samples, novel computational methods, high-quality sequencing reads, and HRAs, we established a comprehensive variant benchmark, including 3,883,283 SNVs, 859,256 Indels, 9,678 large deletions, 15,324 large insertions, 40 inversions, and 31 complex structural variants shared between the monozygotic twin daughters. In particular, the preciously excluded regions, such as repeat regions and the human leukocyte antigen (HLA) region, were systematically examined. Finally, we illustrated how the sequencing depth correlated with the de novo assembly and variant detection, from which we learned that 30 x HiFi is a balance between performance and cost. In summary, this study provides high-quality haplotype-resolved assemblies and a variant benchmark for two Chinese monozygotic twin samples. The benchmark expanded the regions of the previous report and adapted to the evolving sequencing technologies and computational methods.

genomics↗

bioRxiv2022

Intestinal stem cell aging at single-cell resolution: functional perturbations alter cell developmental trajectory reversed by gerotherapeutics

The intestinal epithelium is consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an order fashion as the cells progress along the crypt-luminal axis. Perturbed function of Lgr5hi ISCs with aging is well documented but the consequent impact on overall mucosal homeostasis has not been defined. Using single-cell RNA sequencing, the progressive maturation of progeny was dissected in mouse intestine, which revealed that transcriptional reprogramming with aging in Lgr5hi ISCs retarded cell maturation in their progression along the crypt-luminal axis. Importantly, treatment with metformin or rapamycin at a late stage of mouse lifespan reversed the effects of aging on function of Lgr5hi ISCs and subsequent maturation of progenitors. The effects of metformin and rapamycin overlapped in reversing changes of transcriptional profiles, but were also complementary, with metformin more efficient than rapamycin in correcting the developmental trajectory. Therefore, our data identify novel effects of aging on stem cells and the maturation of their daughter cells contributing to the decline of functional Lgr5hi ISCs and the correction by geroprotectors.

cell biology↗

bioRxiv2022

Comparison and benchmark of long-read based structural variant detection strategies

BackgroundRecent advances in long-read callers and assembly methods have greatly facilitated structural variants (SV) detection via read-based and assembly-based detection strategies. However, the lack of comparison studies, especially for SVs at complex genomic regions, complicates the selection of proper detection strategy for ever-increasing demand of SV analysis. ResultsIn this study, we compared the two most widely-used strategies with six long-read datasets of HG002 genome and benchmarked them with well curated SVs at genomic regions of different complexity. First of all, our results suggest that SVs detected by assembly-based strategy are slightly affected by assemblers on HiFi datasets, especially for its breakpoint identity. Comparably, though read-based strategy is more versatile to different sequencing settings, aligners greatly affect SV breakpoints and type. Furthermore, our comparison reveals that 70% of the assembly-based calls are also detectable by read-based strategy and it even reaches 90% for SVs at high confident regions. While 60% of the assembly-based calls that are totally missed by read-based callers is largely due to the challenges of clustering ambiguous SV signature reads. Lastly, benchmarking with SVs at complex genomic regions, our results show that assembly-based approach outperforms read-based calling with at least 20X coverage, while read-based strategy could achieve 90% recall even with 5X coverage. ConclusionsTaken together, with sufficient sequencing coverage, assembly-based strategy is able to detect SVs more consistently than read-based strategy under different settings. However, read-based strategy could detect SVs at complex regions with high sensitivity and specificity but low coverage, thereby suggesting its great potential in clinical application.

bioinformatics↗

bioRxiv2022

HiCAT: A tool for automatic annotation of centromere structure

Significant improvements in long-read sequencing technologies have unlocked complex genomic areas, such as centromeres, in the genome and introduced the centromere annotation problem. Currently, centromeres are annotated in a semi-manual way. Here, we propose HiCAT, a generalizable automatic centromere annotation tool, based on hierarchical tandem repeat mining and maximization of tandem repeat coverage to facilitate decoding of centromere architecture. We applied HiCAT to human CHM13-T2T and gapless Arabidopsis thaliana genomes. Our results not only were generally consistent with previous inferences but also greatly improved annotation continuity and revealed additional fine structures, demonstrating HiCATs performance and general applicability.

bioinformatics↗

bioRxiv2022

Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHRs, LHCGRs and FSHRs. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and sub-nuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates. We also identified Lhcgr transcripts in 401 brain regions, nuclei and sub-nuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHRs in human brain samples, where transcripts were co-localized in MALAT1-positive neurons. In addition, we show high expression for all three receptors in the ventricular region--with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. TSHRs were expressed specifically in tanycytes. In contrast, Fshrs were localized to NeuN-positive neurons in the granular layer of the dentate gyrus in murine and human brain--both are Alzheimers disease vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.

neuroscience↗

bioRxiv2022

The tissue-specific chromatin accessibility landscape of Papaver somniferum

Accessible chromatin regions (ACRs) at promoters, enhancers, and other gene regulatory regions allow transcription factors (TFs) to bind, which regulate gene transcription involved in plant development and metabolism. Papaver somniferum has been widely applied in clinical medicine as one of the most important and oldest medicinal plants due to its unique and effective active ingredients. However, the transcriptional regulatory mechanism of tissue-specific distribution of active ingredients remains unknown. In this study, transcriptome and chromatin accessibility analysis by RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq) was performed to investigate these underlying molecular mechanisms. We identified tissue-specific chromatin Tn5 hypersensitive site (THS) and gene expression by examining the variation of THS and transcripts across six tissues (capsule, stem, fine root, tap root, leaf, and petal). Our results provide insight into the epigenetic mechanism of transcriptional plasticity for P. somniferum organ development. Sequence motif analysis within accessible chromatin regions for co-expressed gene modules revealed enriched binding sites of hub transcription factors that regulate tissue-specific functions. Furthermore, we identified regulatory elements for tissue-specific accumulation of morphine and noscapine in P. somniferum. This is the first tissue-specific chromatin accessibility landscape of P. somniferum providing an important resource for functional epigenetic analysis and future molecular breeding in P. somniferum for variety improvement.

plant biology↗

bioRxiv2022

Dietary Induced Dynamic Plasticity of Intestinal Stem Cells and the Mucosa in Elevating Risk for Tumor Development

NWD1, a purified rodent diet establishing mouse exposure to key nutrients recapitulating levels that increase risk for intestinal cancer, reproducibly causes sporadic intestinal and colonic tumors in the mouse, reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 reprogramming of stem cells and lineages was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly reprogrammed Lgr5hi stem cells, epigenetically down-regulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lg5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Thus, although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.

cancer biology↗

bioRxiv2021

Long read sequencing reveals sequential complex rearrangements driven by Hepatitis B virus integration

Integration of Hepatitis B virus (HBV) into human genome disrupts genetic structures and cellular functions. Here, we conducted multiplatform long read sequencing on two cell lines and five clinical samples of HBV-infected hepatocellular carcinomas (HCC). We resolved three types of viral integration-induced complex genome rearrangements (CGR) and proposed a model of multi-hits and sequential-breaks to depict their formation process by differentiating inserted HBV copies with HiFi long reads. We deduced that all three complex types were initialized from focal replacement and fragile virus-human junctions triggered subsequent rearrangements. We further revealed that such rearrangements caused a prevalent loss-of-heterozygosity at chr4q, accounting for 19.5% of HCC samples in ICGC cohort and contributing to immune and metabolic dysfunction. Overall, our long read based analysis reveals novel sequential rearrangement processes initiated by HBV integration, hinting its structural and functional impact on HCC.

genomics↗

bioRxiv2021

Transcriptional regulation of neonatal neural stem cells is a determinant of social behavior

Rare gene variants confer a high level of penetrance to neurodevelopmental disorders, but their developmental origin and cellular substrates remain poorly understood. To address this limitation, we explored the role of TBX1, a gene encoded in a rare copy number variant, in cell and mouse models. Here, we report that neonatal Tbx1 deficiency contributes to defective peripubertal social behavior and impairs the proliferation of neonatal neural stem/progenitor cells. Moreover, TBX1 transcriptionally regulates genes linked to post-embryonic neurogenesis and neurodevelopmental disorders associated with other rare gene variants. Our data indicate a precise time window and cell type through which the social dimension is altered by a gene encoded in a rare CNV and provide a potential common mechanistic basis for a group of neurodevelopmental disorders. One-Sentence SummaryTbx1, a gene affecting neonatal stem cell proliferation, influences peripubertal social behavior.

neuroscience↗

bioRxiv2021

Pan-cancer in silico analysis of somatic mutations in G-protein coupled receptors: The effect of evolutionary conservation and natural variance

G protein-coupled receptors (GPCRs) form the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used an aggregated dataset of mutations found in cancer patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 Genomes project. While the location of these mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment was observed in cancer patients among conserved residues in GPCRs such as the "DRY" motif. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). The validity of our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, and we identified novel GPCRs that had not been directly linked to cancer before such as the P2Y Receptor 10 (P2RY10). As a proof of concept, we projected the structurally investigated mutations in the crystal structure of the C-C Chemokine (CCR) 5 receptor, one of the high-ranking GPCRs previously linked to cancer. Several positions were pinpointed that relate to either structural integrity or endogenous and synthetic ligand binding, providing a rationale to their mechanism of influence in cancer. In conclusion, this study identifies a list of GPCRs that are prioritized for experimental follow up characterization to elucidate their role in cancer. The computational approach here described can be adapted to investigate the roles in cancer of any protein family. Author summaryDespite cancer being one of the most studied diseases due to its high mortality rate, one underexplored aspect is the association of certain protein families with tumor pathogenicity. We focused hereon the G protein-coupled receptorsfamily for three reasons. Firstly, it has been shown that this is the second most mutated class of proteins in cancer following kinases. Secondly, this family has been extensively studied resulting in a wide availability of experimental data for these proteins. Finally, more than 30 % of the drugs currently in the market targetitsmembers.For these receptors, weexplored the mutational landscape across cancer patients compared to healthy individuals. Our findings show the existence of cancer-related alteration patterns thatoccuratconserved positions. Additionally, we computationally ranked these G protein-coupled receptors on their importance in the pathogenesis of cancer based on multiple objectives. The result is a list of recommendations on where to focus next. These results suggest that there is room for repurposing existing therapies for cancer treatment while also highlighting the risk of potential interactions between cancer treatmentsand common drugs. All in all, we present a window of opportunity for new targeting strategies in oncology for G protein-coupled receptors.

bioinformatics↗

bioRxiv2021

Evolution of a chordate-specific mechanism for myoblast fusion

The size of an animal is determined by the size of its musculoskeletal system. Myoblast fusion is an innovative mechanism that allows for multinucleated muscle fibers to compound the size and strength of individual mononucleated cells. However, the evolutionary history of the control mechanism underlying this important process is currently unknown. The phylum Chordata hosts closely related groups that span distinct myoblast fusion states: no fusion in cephalochordates, restricted fusion and multinucleation in tunicates, and extensive, obligatory fusion in vertebrates. To elucidate how these differences may have evolved, we studied the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here we report that Myomaker likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while Myomixer appears to have evolved de novo in early vertebrates. Functional tests revealed an unexpectedly complex evolutionary history of myoblast fusion in chordates. A pre-vertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Thus, our findings reveal the evolutionary origins of chordate-specific fusogens and illustrate how new genes can shape the emergence of novel morphogenetic traits and mechanisms.

developmental biology↗

bioRxiv2021

High-quality Arabidopsis thaliana genome assembly with Nanopore and HiFi long reads

Arabidopsis thaliana is an important and long-established model species for plant molecular biology, genetics, epigenetics, and genomics. However, the latest version of reference genome still contains significant number of missing segments. Here, we report a high-quality and almost complete Col-0 genome assembly with two gaps (Col-XJTU) using combination of Oxford Nanopore Technology ultra-long reads, PacBio high-fidelity long reads, and Hi-C data. The total genome assembly size is 133,725,193 bp, introducing 14.6 Mb of novel sequences compared to the TAIR10.1 reference genome. All five chromosomes of Col-XJTU assembly are highly accurate with consensus quality (QV) scores > 60 (ranging from 62 to 68), which are higher than those of TAIR10.1 reference (QV scores ranging from 45 to 52). We have completely resolved chromosome (Chr) 3 and Chr5 in a telomere-to-telomere manner. Chr4 has been completely resolved except the nucleolar organizing regions, which comprise long repetitive DNA fragments. The Chr1 centromere (CEN1), reportedly around 9 Mb in length, is particularly challenging to assemble due to the presence of tens of thousands of CEN180 satellite repeats. Using the cutting-edge sequencing data and novel computational approaches, we assembled about 4 Mb of sequence for CEN1 and a 3.5-Mb-long CEN2. We investigated the structure and epigenetics of centromeres. We detected four clusters of CEN180 monomers, and found that the centromere-specific histone H3-like protein (CENH3) exhibits a strong preference for CEN180 cluster 3. Moreover, we observed hypomethylation patterns in CENH3-enriched regions. We believe that this high-quality genome assembly, Col-XJTU, would serve as a valuable reference to better understand the global pattern of centromeric polymorphisms, as well as genetic and epigenetic features in plants.

genomics↗

bioRxiv2021

Structural variants contribute to pangenome evolution of a plant pathogenic fungus

Genetic variation is the driving force of plant-pathogen co-evolution. Large-scale genetic variations such as structural variations (SVs) often alter genome stability and organismal fitness. However, the pangenomic landscape and functional implications of SVs remain largely unexplored in plant pathogens. Here, we characterized the pangenomic and SV landscape in wheat head blight fungus Fusarium graminearum by producing and comparing chromosome-level (average contig N50 of 8.9 Mb) genome assemblies of 98 accessions using a reference-guided approach. Accounting for 29.05% and 19.01% of F. graminearum pangenome, respectively, accessory and private genomes are enriched with functions related to membrane trafficking, metabolism of fatty acids and tryptophans, with the private also enriched with putative effectors. Furthermore, using chromosome-level assemblies, we detected 52,420 SVs, 69.51% of which are inaccessible using read-mapping based approach. Over a half (55.65%) of 52,645 merged SVs affected 1,660 protein-coding genes, the most variable of which are involved in fungal virulence, cellular contact and communications. Interestingly, highly variable effectors and secondary metabolic enzymes are co-localized with SVs at subtelomeric and centromeric regions. Collectively, this landmark study shows the prevalence and functional relevance of SVs in F. graminearum, providing a valuable resource for future pangenomic studies in this cosmopolitan pathogen of cereal crops.

genomics↗

bioRxiv2021

Mako: a graph-based pattern growth approach to detect complex structural variants

Complex structural variants (CSVs) are genomic alterations that have more than two breakpoints and are considered as simultaneous occurrence of simple structural variants. However, detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy. As a result, there has been limited progress for CSV discovery compared with simple structural variants. We systematically analyzed the multi-breakpoint connection feature of CSVs, and proposed Mako, utilizing a bottom-up guided model-free strategy, to detect CSVs from paired-end short-read sequencing. Specifically, we implemented a graph-based pattern growth approach, where the graph depicts potential breakpoint connections and pattern growth enables CSV detection without predefined models. Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms. Notably, validation rates of CSV on real data based on experimental and computational validations as well as manual inspections are around 70%, where the medians of experimental and computational breakpoint shift are 13bp and 26bp, respectively. Moreover, Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types, including two novel types of adjacent segments swap and tandem dispersed duplication. Further analysis of these CSVs also revealed impact of sequence homology in the formation of CSVs. Mako is publicly available at https://github.com/jiadong324/Mako.

bioinformatics↗

bioRxiv2021

Molecular and structural mechanisms of ZZ domain-mediated cargo recognition by autophagy receptor Nbr1

In selective autophagy, cargo selectivity is determined by autophagy receptors. However, it remains scarcely understood how autophagy receptors recognize specific protein cargos. In the fission yeast Schizosaccharomyces pombe, a selective autophagy pathway termed Nbr1-mediated vacuolar targeting (NVT) employs Nbr1, an autophagy receptor conserved across eukaryotes including humans, to target cytosolic hydrolases into the vacuole. Here, we identify two new NVT cargos, the mannosidase Ams1 and the aminopeptidase Ape4, that bind competitively to the first ZZ domain of Nbr1 (Nbr1-ZZ1). High-resolution cryo-EM analyses reveal how a single ZZ domain recognizes two distinct protein cargos. Nbr1-ZZ1 not only recognizes the N-termini of cargos via a conserved acidic pocket, similar to other characterized ZZ domains, but also engages additional parts of cargos in a cargo-specific manner. Our findings unveil a single-domain bispecific mechanism of autophagy cargo recognition, elucidate its underlying structural basis, and expand the understanding of ZZ domain-mediated protein-protein interactions.

cell biology↗

bioRxiv2021

Spatial organization of transcript elongation and splicing kinetics

The organization of the genome in three-dimensional space has been shown to play an important role in gene expression. Specifically, facets of genomic interaction such as topologically associated domains (TADs) have been shown to regulate transcription by bringing regulatory elements into close proximity1. mRNA production is an intricate process with multiple control points including regulation of Pol II elongation and the removal of non-coding sequences via pre-mRNA splicing2. The connection between genomic compartments and the kinetics of RNA biogenesis and processing has been largely unexplored. Here, we measure Pol II elongation and splicing kinetics genome-wide using a novel technique that couples nascent RNA-seq with a mathematical model of transcription and co-transcriptional RNA processing. We uncovered multiple layers of spatial organization of these rates: the rate of splicing is coordinated across introns within individual genes, and both elongation and splicing rates are coordinated within TADs, as are alternative splicing outcomes. Overall, our work establishes that the kinetics of transcription and splicing are coordinated by the spatial organization of the genome and suggests that TADs are a major platform for coordination of alternative splicing.

molecular biology↗