Biology subjects

Zhang, D.

Publications and source records attributed to Zhang, D..

At least 469 records · Page 26Linked to original sources

bioRxiv2019

A high-precision hybrid algorithm for predicting eukaryotic protein subcellular localization

MotivationSubcellular location plays an essential role in protein synthesis, transport, and secretion, thus it is an important step in understanding the mechanisms of trait-related proteins. Generally, homology methods provide reliable homology-based results with small E-values. We must resort to pattern recognition algorithms (SVM, Fisher discriminant, KNN, random forest, etc.) for proteins that do not share significant homologous domains with known proteins. However, satisfying results are seldom obtained.\n\nResultsHere, a novel hybrid method \"Basic Local Alignment Search Tool+Smith-Waterman+Needleman-Wunsch\" or BLAST+SWNW, has been obtained by integrating a loosened E-value Basic Local Alignment Search Tool (BLAST) with the Smith-Waterman (SW) and Needleman-Wunsch (NW) algorithms, and this method has been introduced to predict protein subcellular localization in eukaryotes. When tested on Dataset I and Dataset II, BLAST+SWNW showed an average accuracy of 97.18% and 99.60%, respectively, surpassing the performance of other algorithms in predicting eukaryotic protein subcellular localization.\n\nAvailability and ImplementationBLAST+SWNW is an open source collaborative initiative available in the GitHub repository (https://github.com/ZHANGDAHAN/BLAST-SWNW-for-SLP or http://202.206.64.158:80/link/72016CAC26E4298B3B7E0EAF42288935)\n\nContactzhaqi1972@163.com; zhangdahan@genetics.ac.cn\n\nSupplementary InformationSupplementary data are available at PLOS Computational Biology online.

bioinformatics↗

bioRxiv2019

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC=\"FIGDIR/small/614024v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (14K):\norg.highwire.dtl.DTLVardef@310f7org.highwire.dtl.DTLVardef@14ed578org.highwire.dtl.DTLVardef@a0d9c0org.highwire.dtl.DTLVardef@37f59a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Sing cell RNA-seq reveals cellular diversity and developmental characteristics of human infant retina

Retina, located in the innermost layer of the eye of human, holds the decisive role in visual perception. Dissecting the heterogeneity of retina is essential for understanding the mechanism of vision formation and even the development of central nervous system (CNS). Here, we performed single cell RNA-seq, analyzed 57,832 cells from human infant donors, resulting in 20 distinct clusters representing major cell types in retina: rod photoreceptors, cone photoreceptors, bipolar cells, horizontal cells, amacrine cells, Muller glia cells and microglia. We next constructed extensive networks of intercellular communication and identified ligand-receptor interactions playing crucial roles in regulating neural cell development and immune homeostasis in retina. Though re-clustering, we identified known subtypes in cone PRs and additional unreported subpopulations and corresponding markers in rod PRs as well as bipolar cells. Additionally, we linked inherited retinal disease to certain cell subtypes or subpopulations through enrichment analysis. Intriguingly, we found that status and functions of photoreceptors changed drastically between early and late retina. Overall, our study offers the first retinal cell atlas in human infants, dissecting the heterogeneity of retina and identifying the key molecules in the developmental process, which provides an important resource that will pave the way for retina development mechanism research and regenerative medicine concerning retinal biology.

cell biology↗

bioRxiv2019

Characterization of Rhodopseudomonas palustris population dynamics on tobacco phyllosphere and induction of plant resistance to Tobacco mosaic virus i

Although many biocontrol bacteria can be used to improve plant tolerance to stresses and to promote plant growth, the hostile environmental conditions on plant phyllosphere and the limited knowledge on bacterial colonization on plant phyllosphere minimized the beneficial effects produced by the biocontrol bacteria. Rhodopseudomonas palustris strain GJ-22 is known as a phyllosphere biocontrol agent. In this paper we described detailed processes of strain GJ-22 colony establishment at various colonization stages. We have shown that the preferable location sites of bacterial aggregates on leaf phyllosphere are grooves between plant epidermal cells. In this study, we categorized bacterial colonies into four phases. Analyses of expressions of plant defense-related genes showed that, starting from Phase III, bacterial cells in the Type 3 and Type 4 colonies started produce unidentified signals to induce host defense again Tobacco mosaic virus infection. To our knowledge, this is the first report focused on the colonization process of a phyllosphere biocontrol agent.

microbiology↗

bioRxiv2019

Single cell RNA sequencing reveals cellular diversity of trisomy 21 retina

Retina is a crucial tissue for the capturing and processing of light stimulus. Characterization of the retina at single cell level is essential for the understanding of its biological functions. A variety of abnormalities in terms of morphology and function were reported in T21 retina. To evaluate the effects of chromosome aneuploidy on retina development, we characterized single cell transcriptional profiles of a T21 fetus and performed comprehensive bioinformatic analyses. Our data revealed the diversity and heterogeneity of cellular compositions in T21 retina. In total, we identified seven major cell types, and detected several subtypes within each cell type, followed by the detection of corresponding molecular markers including previously reported ones and a series of novel markers. Our analyses identified extensive communication networks between distinct cellular types, among which a few ligand-receptor interactions were associated with the development of retina and immunoregulatory interactions. Taken together, our data provided the first single cell transcriptome profile for human T21 retina which facilitates our understanding on the dosage effects of chromosome 21 on the development of retina.

cell biology↗

bioRxiv2019

Mitochondrial architecture rearrangements produce asymmetrical nonadaptive mutational pressures that subvert the phylogenetic reconstruction in Isopoda

The phylogeny of Isopoda, a speciose order of crustaceans, remains unresolved, with different datasets often producing starkly incongruent phylogenetic hypotheses. We hypothesised that extreme diversity in their life histories might be causing compositional heterogeneity/heterotachy in their mitochondrial genomes, and compromising the phylogenetic reconstruction. We tested the effects of different datasets (mitochondrial, nuclear, nucleotides, amino acids, concatenated genes, individual genes, gene orders), phylogenetic algorithms (assuming data homogeneity, heterogeneity, and heterotachy), and partitioning; and found that almost all of them produced unique topologies. As we also found that mitogenomes of Asellota and two Cymothoida families (Cymothoidae and Corallanidae) possess inversed base (GC) skew patterns in comparison to other isopods, we concluded that inverted skews cause long-branch attraction phylogenetic artefacts between these taxa. These asymmetrical skews are most likely driven by multiple independent inversions of origin of replication (i.e., nonadaptive mutational pressures). Although the PhyloBayes CAT-GTR algorithm managed to attenuate some of these artefacts (and outperform partitioning), mitochondrial data have limited applicability for reconstructing the phylogeny of Isopoda. Regardless of this, our analyses allowed us to propose solutions to some unresolved phylogenetic debates, and support Asellota are the most likely candidate for the basal isopod branch. As our findings show that architectural rearrangements can produce major compositional biases even on short evolutionary timescales, the implications are that proving the suitability of data via composition skew analyses should be a prerequisite for every study that aims to use mitochondrial data for phylogenetic reconstruction, even among closely related taxa.

evolutionary biology↗

bioRxiv2019

Re-configuration of Chromatin Structure During the Mitosis-G1 Phase Transition

Higher-order chromatin organization such as A/B compartments, TADs and chromatin loops are temporarily disrupted during mitosis. These structures are thought to organize aspects of gene regulation, and thus it is important to understand how they are re-established after mitosis. We examined the dynamics of chromosome reorganization by Hi-C at defined time points following exit from mitosis in highly purified, synchronous cell populations. We observed that A/B compartments are rapidly established and progressively gain in strength following mitotic exit. Contact domain formation occurs from the \"bottom-up\" with smaller sub-TADs forming initially, followed by convergence into multi-domain TAD structures. CTCF is strongly retained at a significant fraction of sites on mitotic chromosomes and immediately resumes full binding at ana/telophase, the earliest tested time point. In contrast, cohesin is completely evicted from mitotic chromosomes and resumes focal binding with delayed kinetics. The formation of CTCF/cohesin co-anchored structural loops follows the kinetics of cohesin positioning. Stripe-shaped contacts anchored by CTCF grow in length, consistent with a loop extrusion process after mitosis. Interactions between cis-regulatory elements can form rapidly, preceding CTCF/cohesin anchored structural loops. Strikingly, we identified a group of rapidly emerging transient contacts between cis-regulatory elements in ana/telophase, that are dissolved upon G1 entry, co-incident with the establishment of inner boundaries or nearby interfering loops. Our findings indicate that distinct but mutually influential forces drive post-mitotic chromatin re-configuration to shape compartments, contact domains, cis-element contacts, and CTCF/cohesin dependent loops.

genomics↗

bioRxiv2019

Integrated phylogenomic analyses reveal recurrent ancestral large-scale duplication events in mosses

O_LIMosses (Bryophyta) are a key group occupying important phylogenetic position for understanding land plant (embryophyte) evolution. The class Bryopsida represents the most diversified lineage and contains more than 95% of the modern mosses, whereas the other classes are by nature species-poor. The phylogeny of mosses remains elusive at present.\nC_LIO_LIRecurrent whole genome duplications have shaped the evolution trajectory of angiosperms, but little is known about the genome evolutionary history in mosses. It remains to be answered if there existed a historical genome duplication event associated with the species radiation of class Bryopsida.\nC_LIO_LIHere, the high-confidence moss phylogeny was generated covering major moss lineages. Two episodes of ancient genomic duplication events were elucidated by phylogenomic analyses, one in the ancestry of all mosses and another before the separation of the Bryopsida, Polytrichopsida and Tetraphidopsida, with estimated ages of the gene duplications clustered around 329 and 182 million year ago, respectively.\nC_LIO_LIThe third episode of polyploidy event (termed {psi}) was tightly associated with the early diversification of Bryopsida with an estimated age of ~87 million years. By scrutinizing the phylogenetic timing of duplicated syntelogs in Physcomitrella patens, the WGD1 and WGD2 events were confidently re-recognized as the {psi} event and the Funarioideae duplication event (~65 mya), respectively. Together, our findings unveiled four episodes of polyploidy events in the evolutionary past of Physcomitrella patens.\nC_LI

evolutionary biology↗

bioRxiv2019

ERASE: Extended Randomization for assessment of annotation enrichment in ASE datasets

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with various human phenotypes and many of these loci are thought to act at a molecular level by regulating gene expression. Detection of allele specific expression (ASE), namely preferential usage of an allele at a transcribed locus, is an increasingly important means of studying the genetic regulation of gene expression. However, there are currently a paucity of tools available to link ASE sites with GWAS risk loci. Existing integration methods first use ASE sites to infer cis-acting expression quantitative trait loci (eQTL) and then apply eQTL-based approaches. ERASE is a method that assesses the enrichment of risk loci amongst ASE sites directly. Furthermore, ERASE enables additional biological insights to be made through the addition of other SNP level annotations. ERASE is based on a randomization approach and controls for read depth, a significant confounder in ASE analyses. In this paper, we demonstrate that ERASE can efficiently detect the enrichment of eQTLs and risk loci within ASE data and that it remains sensitive even when used with underpowered GWAS datasets. Finally, using ERASE in combination with GWAS data for Parkinsons disease and data on the splicing potential of individual SNPs, we provide evidence to suggest that risk loci for Parkinsons disease are enriched amongst ASEs likely to affect splicing. Thus, we show that ERASE is an important new tool for the integration of ASE and GWAS data, capable of providing novel insights into the pathophysiology of complex diseases.

bioinformatics↗

bioRxiv2019

Regulatory sites for known and novel splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants that affect neurological and psychiatric disease risk. Given that many causal variants are likely to operate by regulating gene expression, an improved understanding of the genetic control of gene expression in human brain is vital. However, the difficulties of sampling human brain, and its complexity, has meant that brain-related expression quantitative trait loci (eQTL) and allele specific expression (ASE) signals have been more limited in their explanatory power than might otherwise be expected. To address this, we use paired genomic and transcriptomic data from putamen and substantia nigra dissected from 117 brains, combined with a comprehensive set of analyses, to interrogate regulation at different stages of RNA processing and uncover novel transcripts. We identify disease-relevant regulatory loci and reveal the types of analyses and regulatory positions yielding the most disease-specific information. We find that splicing eQTLs are enriched for neuron-specific regulatory information; that ASE analyses provide highly cell-specific regulatory information; and that incomplete annotation of the brain transcriptome limits the interpretation of risk loci for neuropsychiatric disease. We release this rich resource of regulatory data through a searchable webserver, http://braineacv2.inf.um.es/.

bioinformatics↗

bioRxiv2019

Circular RNA profiling in the oocyte and cumulus cells reveals that circARMC4 is essential for porcine oocyte maturation

Thousands of circular RNAs (circRNAs) have been recently discovered in cumulus cells and oocytes from several species. However, the expression and function of circRNA during porcine oocyte meiotic maturation have been never examined. Here, we separately identified 7,067 and 637 circRNAs in both the cumulus cell and the oocyte via deep sequencing and bioinformatic analysis. Further analysis revealed that a faction of circRNAs is differentially expressed (DE) in a developmental stage-specific manner. The host genes of DE circRNAs are markedly enriched to multiple signaling pathways associated with cumulus cell function and oocyte maturation. Additionally, most DE circRNAs harbor several miRNA targets, suggesting that these DE circRNAs potentially act as miRNA sponge. Importantly, we found that maternal circARMC4 knockdown by siRNA microinjection caused a severely impaired chromosome alignment, and significantly inhibited first polar body extrusion and early embryo development. Taken together, these results demonstrate for the first time that circRNAs are abundantly and dynamically expressed in a developmental stage-specific manner in cumulus cells and oocytes, and maternally expressed circARMC4 is essential for porcine oocyte meiotic maturation and early embryo development.

developmental biology↗

bioRxiv2019

Dietary intake regulates the circulating inflammatory monocyte pool

Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPAR) reduced monocyte mobilization from the bone marrow. Importantly, while caloric restriction improves chronic inflammatory diseases, fasting did not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.\n\nHighlightsO_LIFasting reduces the numbers of peripheral pro-inflammatory monocytes in healthy humans and mice.\nC_LIO_LIA hepatic AMPK-PPAR energy-sensing axis controls homeostatic monocyte numbers via regulation of steady-state CCL2 production.\nC_LIO_LIFasting reduces monocyte metabolic and inflammatory activity.\nC_LIO_LIFasting improves chronic inflammatory diseases but does not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair.\nC_LI

immunology↗

bioRxiv2019

Biologically inspired model of associative memory storage with noisy neurons and synapses

Neural networks in the brain can function reliably despite various sources of errors and noise present at every step of signal transmission. These sources include errors in the presynaptic inputs to the neurons, noise in synaptic transmission, and fluctuations in the neurons postsynaptic potentials. Collectively they lead to errors in the neurons outputs which are, in turn, injected into the network. Does unreliable network activity hinder fundamental functions of the brain, such as learning and memory retrieval? To explore this question, this article examines the effects of errors and noise on properties of biologically constrained networks of inhibitory and excitatory neurons involved in associative sequence learning. The associative learning problem is solved analytically and numerically, and it is also shown how memory sequences can be loaded into the network with a more biologically plausible perceptron-type learning rule. Interestingly, the results reveal that errors and noise during learning increase the probability of memory recall. There is a tradeoff between the capacity and reliability of stored memories, and, noise during learning is required for optimal retrieval of stored information. What is more, networks loaded with associative memories to capacity display many structural and dynamical features observed in local cortical circuits. Due to the similarities between the associative and brain networks, this article predicts that the connections originating from unreliable inhibitory and excitatory neurons or neuron classes in the cortex must be depressed or eliminated during learning, while the connections onto noisy neurons or neuron classes must have lower probabilities and higher weights.

neuroscience↗

bioRxiv2019

TmDOTP : An NMR- based Thermometer for Magic Angle Spinning NMR Experiments

Solid state NMR is a powerful tool to probe membrane protein structure and motions in native lipid structures. Sample heating, caused by magic angle spinning and radio frequency irradiation in solid state NMR, produces uncertainties in sample temperature and thermal broadening caused by temperature distributions, which can also lead to sample deterioration. To measure the sample temperature in real time, and to quantify thermal gradients and their dependence on radio frequency irradiation or spinning frequency, we use the chemical shift thermometer TmDOTP, a lanthanide complex. Compared to other NMR thermometers (e.g., the proton NMR signal of water), the proton spectrum of TmDOTP exhibits higher thermal sensitivity and resolution. In addition, the H6 proton in TmDOTP has a large chemical shift (-175 ppm at 275 K) and is well resolved from the rest of the proton spectrum. We identified two populations of TmDOTP, with differing temperatures and dependency on the radio frequency irradiation power, within proteoliposome samples. We interpret these populations as arising from the supernatant and the pellet, which is sedimented from the sample spinning. Our results indicate that TmDOTP is an excellent internal standard for monitoring temperatures of biophysically relevant samples without distorting their properties.

biophysics↗

bioRxiv2019

Allosteric studies of an open pH gate KcsA mutant in its activated and inactivated states

Transmembrane allosteric coupling is a feature of many critical biological signaling events. Here we test whether transmembrane allosteric coupling controls the mean open time of the prototypical potassium channel KcsA in the context of C-type inactivation. Activation of KcsA is initiated by proton binding to the pH gate upon an intracellular drop in pH. Numerous studies have suggested that this proton binding also prompts a conformational switch leading to a loss of affinity for potassium ions at the selectivity filter and therefore to channel inactivation. We tested this mechanism for inactivation using a KcsA mutant (H25R/E118A) that has the pH gate open across a broad range of pH values. We present solid-state NMR measurements of this open mutant at neutral pH to probe the affinity for potassium at the selectivity filter. The potassium binding affinity in the selectivity filter of this mutant, 81 mM, is about 4 orders of magnitude weaker than that of wild type KcsA at neutral pH and is comparable to the value for wild type KcsA at low pH (pH [~] 3.5). This result strongly supports our assertion that the open pH gate allosterically effects the potassium binding affinity of the selectivity filter. In this mutant the protonation state of a glutamate residue (E120) in the pH sensor is sensitive to potassium binding, suggesting that this mutant also has flexibility in the activation gate and is subject to transmembrane allostery.\n\nSignificance statementInactivation of potassium channels controls mean open times and provides exquisite control over biological processes. In the highly conserved C-type inactivation process, opening of the activation gate causes subsequent inactivation. We test whether the open state of the channel simply has a poor ability to bind the K+ ion. Previously, activated and inactivated states were stabilized using truncations or a significant pH drop. Here, we use the H25R/E118A constitutively open mutant of KcsA and also observe a large drop in potassium binding affinity. This provides strong evidence that channel opening causes an allosteric loss of ion affinity, and that the central feature of this universal channel inactivation process is loss of ion affinity at the selectivity filter.

biophysics↗

bioRxiv2019

Cryo-EM structures reveal a conformational change of SOPA1 during mitochondrial inner membrane fusion

Mammalian mitochondrial inner membrane fusion is mediated by OPA1(optic atrophy 1). Under physiological condition, OPA1 undergoes proteolytic processing to form a membrane-anchored long isoform (LOPA1) and a soluble short isoform (SOPA1). A combination of LOPA1 and SOPA1 are required for membrane fusion, however, the relevant mechanism is not well understood. In this study, we investigate the cryo-EM structures of SOPA1 coated liposome tube at nucleotide-free and GTP{gamma}S bound states. SOPA1 exhibits a general structure of dynamin family and can assemble onto membrane in a helical array with a building block of dimer and thus induce membrane tubulation. A predicted amphipathic helix is discovered to mediate the tubulation activity of SOPA1. The binding of GTP{gamma}S causes a conformational rotation between GTPase domain and stalk region, and then induces a rearrangement of the helical array and an expansion of the tube, which is opposite to the behavior of other dynamin proteins, suggesting a unique role of SOPA1 in the fusion of mitochondrial inner membrane.

biophysics↗

bioRxiv2019

Epidemic foci of hemorrhagic fever with renal syndrome in Shandong Province, China, based on patients, rodents and molecular epidemiology characteristics, 2012-2015

BackgroundHemorrhagic fever with renal syndrome (HFRS), an infectious disease caused by hantaviruses, is endemic in China and remains a serious public health problem. Historically, Shandong Province has had the largest HFRS burden in China. However, we do not have a comprehensive and clear understanding of the current epidemic foci of HFRS in Shandong Province.\n\nMethodology/Principal FindingsThe incidence and mortality rates were calculated, and a phylogenetic analysis was performed after laboratory testing of the virus in rodents. Spatial epidemiology analysis was applied to investigate the epidemic foci, including their sources. A total of 6,206 HFRS cases and 59 related deaths were reported in Shandong Province. The virus carriage rates of the rodents Rattus norvegicus, Apodemus agrarius and Mus musculus were 10.24%, 6.31% and 0.27%, respectively. The phylogenetic analysis indicated that two novel viruses isolated from R. norvegicus in Anqiu City and Qingzhou City were dissimilar to the other isolated strains, but closely related to strains previously isolated in northeastern China. Three epidemic foci were defined, two of which were derived from the Jining and Linyi epidemic foci, respectively, while the other was the residue of the Jining epidemic focus.\n\nConclusions/SignificanceThe southeastern and central Shandong Province are current key HFRS epidemic foci dominated by A. agrarius and R. norvegicus, respectively. Our study could help local departments to strengthen prevention and control measures in key areas to reduce the hazards of HFRS.\n\nAuthor summaryHemorrhagic fever with renal syndrome (HFRS) is a global infectious disease, which is still a serious public health threat in China today. The reported HFRS cases in Shandong Province accounted for approximate one third of total cases in the whole country. HFRS is a zoonosis mainly caused by Hantaan virus (HTNV) and Seoul virus (SEOV), which natural rodent hosts are A. agrarius and R. norvegicus, respectively. To explore the current HFRS epidemic foci based on patients, rodents and molecular epidemiology characteristics in Shandong Province, we collected the records of HFRS cases from whole province and the rodents captured in 14 surveillance sites. We found that the epidemic situation of HFRS is quiet different in temporal and spatial distribution. Three epidemic foci were defined based on patients, rodents and molecular epidemiology characteristics. The situation of HFRS epidemic foci in Shandong Province was clear. Our study provides a reference for relevant departments to develop key prevention strategies.

epidemiology↗

bioRxiv2018

Incomplete annotation of OMIM genes is likely to be limiting the diagnostic yield of genetic testing, particularly for neurogenetic disorders

Although the increasing use of whole-exome and whole-genome sequencing have improved the yield of genetic testing for Mendelian disorders, an estimated 50% of patients still leave the clinic without a genetic diagnosis. This can be attributed in part to our lack of ability to accurately interpret the genetic variation detected through next-generation sequencing. Variant interpretation is fundamentally reliant on accurate and complete gene annotation, however numerous reports and discrepancies between gene annotation databases reveals that the knowledge of gene annotation remains far from comprehensive. Here, we detect and validate transcription in an annotation-agnostic manner across all 41 different GTEx tissues, then connect novel transcription to known genes, ultimately improving the annotation of 63% of the known OMIM-morbid genes. We find the majority of novel transcription to be tissue-specific in origin, with brain tissues being most susceptible to misannotation. Furthermore, we find that novel transcribed regions tend to be poorly conserved, but are significantly depleted for genetic variation within humans, suggesting they are functionally significant and potentially have human-specific functions. We present our findings through an online platform vizER, which enables individual genes to be visualised and queried for evidence of misannotation. We also release all tissue-specific transcriptomes in a BED format for ease of integration with whole-genome sequencing data. We anticipate that these resources will improve the diagnostic yield for a wide range of Mendelian disorders.

bioinformatics↗