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in category genomics
4,242 results found. For more information, click each entry to expand.
6,010 downloads genomics
We assembled the sequences from 9,795 RNA sequencing experiments, collected from 31 human tissues and hundreds of subjects as part of the GTEx project, to create a new, comprehensive catalog of human genes and transcripts. The new human gene database contains 43,162 genes, of which 21,306 are protein-coding and 21,856 are noncoding, and a total of 323,824 transcripts, for an average of 7.5 transcripts per gene. Our expanded gene list includes 4,998 novel genes (1,178 coding and 3,819 noncoding) and 97,511 novel splice variants of protein-coding genes as compared to the most recent human gene catalogs. We detected over 30 million additional transcripts at more than 650,000 sites, nearly all of which are likely to be nonfunctional, revealing a heretofore unappreciated amount of transcriptional noise in human cells.
5,997 downloads genomics
While introgression from Neanderthals and Denisovans has been well-documented in modern humans outside Africa, the contribution of archaic hominins to the genetic variation of present-day Africans remains poorly understood. Using 405 whole-genome sequences from four sub-Saharan African populations, we provide complementary lines of evidence for archaic introgression into these populations. Our analyses of site frequency spectra indicate that these populations derive 2-19% of their genetic ancestry from an archaic population that diverged prior to the split of Neanderthals and modern humans. Using a method that can identify segments of archaic ancestry without the need for reference archaic genomes, we built genome-wide maps of archaic ancestry in the Yoruba and the Mende populations that recover about 482 and 502 megabases of archaic sequence, respectively. Analyses of these maps reveal segments of archaic ancestry at high frequency in these populations that represent potential targets of adaptive introgression. Our results reveal the substantial contribution of archaic ancestry in shaping the gene pool of present-day African populations.
5,756 downloads genomics
Long-read sequencing technologies are transforming our ability to assemble highly complex genomes. Realising their full potential relies crucially on extracting high quality, high molecular weight (HMW) DNA from the organisms of interest. This is especially the case for the portable MinION sequencer which potentiates all laboratories to undertake their own genome sequencing projects, due to its low entry cost and minimal spatial footprint. One challenge of the MinION is that each group has to independently establish effective protocols for using the instrument, which can be time consuming and costly. Here we present a workflow and protocols that enabled us to establish MinION sequencing in our own laboratories, based on optimising DNA extractions from a challenging plant tissue as a case study. Following the workflow illustrated we were able to reliably and repeatedly obtain > 8.5 Gb of long read sequencing data with a mean read length of 13 kb and an N50 of 26 kb. Our protocols are open-source and can be performed in any laboratory without special equipment. We also illustrate some more elaborate workflows which can increase mean and average read lengths if this is desired. We envision that our workflow for establishing MinION sequencing, including the illustration of potential pitfalls, will be useful to others who plan to establish long-read sequencing in their own laboratories.
5,754 downloads genomics
Justin M Zook, David Catoe, Jennifer McDaniel, Lindsay Vang, Noah Spies, Arend Sidow, Ziming Weng, Yuling Liu, Chris Mason, Noah Alexander, Elizabeth Henaff, Feng Chen, Erich Jaeger, Ali Moshrefi, Khoa Pham, William Stedman, Tiffany Liang, Michael Saghbini, Zeljko Dzakula, Alex Hastie, Han Cao, Gintaras Deikus, Eric Schadt, Robert Sebra, Ali Bashir, Rebecca M. Truty, Christopher C Chang, Natali Gulbahce, Keyan Zhao, Srinka Ghosh, Fiona Hyland, Yutao Fu, Mark Chaisson, Chunlin Xiao, Jonathan Trow, Stephen T Sherry, Alexander W Zaranek, Madeleine Ball, Jason Bobe, Preston Estep, George M Church, Patrick Marks, Sofia Kyriazopoulou-Panagiotopoulou, Grace X.Y. Zheng, Michael Schnall-Levin, Heather S Ordonez, Patrice A Mudivarti, Kristina Giorda, Ying Sheng, Karoline Bjarnesdatter Rypdal, Marc Salit
The Genome in a Bottle Consortium, hosted by the National Institute of Standards and Technology (NIST) is creating reference materials and data for human genome sequencing, as well as methods for genome comparison and benchmarking. Here, we describe a large, diverse set of sequencing data for seven human genomes; five are current or candidate NIST Reference Materials. The pilot genome, NA12878, has been released as NIST RM 8398. We also describe data from two Personal Genome Project trios, one of Ashkenazim Jewish ancestry and one of Chinese ancestry. The data come from 12 technologies: BioNano Genomics, Complete Genomics paired-end and LFR, Ion Proton exome, Oxford Nanopore, Pacific Biosciences, SOLiD, 10X Genomics GemCodeTM WGS, and Illumina exome and WGS paired-end, mate-pair, and synthetic long reads. Cell lines, DNA, and data from these individuals are publicly available. Therefore, we expect these data to be useful for revealing novel information about the human genome and improving sequencing technologies, SNP, indel, and structural variant calling, and de novo assembly.
5,618 downloads genomics
The development of single cell RNA sequencing technologies has emerged as a powerful means of profiling the transcriptional behavior of single cells, leveraging the breadth of sequencing measurements to make inferences about cell type. However, there is still little understanding of how well these methods perform at measuring single cell variability for small sets of genes and what “complexity threshold” (e.g. genes detected per cell) is needed for accurate measurements. Here, we use single molecule RNA FISH measurements of 26 genes in thousands of melanoma cells to provide an independent reference dataset to assess the performance of the DropSeq and Fluidigm single cell RNA sequencing platforms. We quantified the Gini coefficient, a measure of rare-cell expression variability, and find that the correspondence between RNA FISH and single cell RNA sequencing for Gini, unlike for mean, increases markedly with per-cell library complexity up to a threshold of ~2000 genes detected. A similar complexity threshold also allows for robust assignment of multi-genic cell states such as cell cycle phase. Our results provide guidelines for selecting sequencing depth and complexity thresholds for single cell RNA sequencing. More generally, our results suggest that if the number of genes whose expression levels are required to answer any given biological question is small, then greater transcriptome complexity per cell is likely more important than obtaining very large numbers of cells.
5,615 downloads genomics
Timothy R Fallon, Sarah E Lower, Ching-Ho Chang, Manabu Bessho-Uehara, Gavin J Martin, Adam J Bewick, Megan Behringer, Humberto J Debat, Isaac Wong, John C Day, Anton Suvorov, Christian J Silva, Kathrin F Stanger-Hall, David W Hall, Robert J Schmitz, David R. Nelson, Sara M. Lewis, Shuji Shigenobu, Seth M Bybee, Amanda M Larracuente, Yuichi Oba, Jing-Ke Weng
Fireflies and their fascinating luminous courtships have inspired centuries of scientific study. Today firefly luciferase is widely used in biotechnology, but the evolutionary origin of their bioluminescence remains unclear. To shed light on this long-standing question, we sequenced the genomes of two firefly species that diverged over 100 million-years-ago: the North American Photinus pyralis and Japanese Aquatica lateralis. We also sequenced the genome of a related click-beetle, the Caribbean Ignelater luminosus, with bioluminescent biochemistry near-identical to fireflies, but anatomically unique light organs, suggesting the intriguing but contentious hypothesis of parallel gains of bioluminescence. Our analyses support two independent gains of bioluminescence between fireflies and click-beetles, and provide new insights into the genes, chemical defenses, and symbionts that evolved alongside their luminous lifestyle.
5,603 downloads genomics
Urmo Võsa, Annique Claringbould, Harm-Jan Westra, Marc Jan Bonder, Patrick Deelen, Biao Zeng, Holger Kirsten, Ashis Saha, Roman Kreuzhuber, Silva Kasela, Natalia Pervjakova, Isabel Alvaes, Marie-Julie Fave, Mawusse Agbessi, Mark Christiansen, Rick Jansen, Ilkka Seppälä, Lin Tong, Alexander Teumer, Katharina Schramm, Gibran Hemani, Joost Verlouw, Hanieh Yaghootkar, Reyhan Sönmez, Andrew Brown, Viktorija Kukushkina, Anette Kalnapenkis, Sina Rüeger, Eleonora Porcu, Jaanika Kronberg-Guzman, Johannes Kettunen, Joseph Powell, Bernett Lee, Futao Zhang, Wibowo Arindrarto, Frank Beutner, BIOS Consortium, Harm Brugge, i2QTL Consortium, Julia Dmitreva, Mahmoud Elansary, Benjamin P. Fairfax, Michel Georges, Bastiaan T. Heijmans, Mika Kähönen, Yungil Kim, Julian C Knight, Peter Kovacs, Knut Krohn, Shuang Li, Markus Loeffler, Urko M Marigorta, Hailang Mei, Yukihide Momozawa, Martina Müller-Nurasyid, Matthias Nauck, Michel Nivard, Brenda Penninx, Jonathan Pritchard, Olli Raitakari, Olaf Rotzchke, Eline P Slagboom, Coen D.A. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A.C. ‘t Hoen, Joachim Thiery, Anke Tönjes, Jenny van Dongen, Maarten van Iterson, Jan Veldink, Uwe Völker, Cisca Wijmenga, Morris Swertz, Anand Andiappan, Grant W. Montgomery, Samuli Ripatti, Markus Perola, Zoltan Kutalik, Emmanouil Dermitzakis, Sven Bergmann, Timothy Frayling, Joyce van Meurs, Holger Prokisch, Habibul Ahsan, Brandon Pierce, Terho Lehtimäki, Dorret Boomsma, Bruce M Psaty, Sina A. Gharib, Philip Awadalla, Lili Milani, Willem Ouwehand, Kate Downes, Oliver Stegle, Alexis Battle, Jian Yang, Peter M. Visscher, Markus Scholz, Gregory Gibson, Tõnu Esko, Lude Franke
While many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear. To identify these effects, we performed cis- and trans-expression quantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium. We observed that cis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to use cis-eQTLs to pinpoint causal genes within susceptibility loci. In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology. We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.
5,495 downloads genomics
Advances in CRISPR-Cas9 technology have enabled the flexible modulation of gene expression at large scale. In particular, the creation of genome-wide libraries for CRISPR knockout (CRISPRko), CRISPR interference (CRISPRi), and CRISPR activation (CRISPRa) has allowed gene function to be systematically interrogated. Here, we evaluate numerous CRISPRko libraries and show that our recently-described CRISPRko library (Brunello) is more effective than previously published libraries at distinguishing essential and non-essential genes, providing approximately the same perturbation-level performance improvement over GeCKO libraries as GeCKO provided over RNAi. Additionally, we developed genome-wide libraries for CRISPRi (Dolcetto) and CRISPRa (Calabrese). Negative selection screens showed that Dolcetto substantially outperforms existing CRISPRi libraries with fewer sgRNAs per gene and achieves comparable performance to CRISPRko in the detection of gold-standard essential genes. We also conducted positive selection CRISPRa screens and show that Calabrese outperforms the SAM library approach at detecting vemurafenib resistance genes. We further compare CRISPRa to genome-scale libraries of open reading frames (ORFs). Together, these libraries represent a suite of genome-wide tools to efficiently interrogate gene function with multiple modalities.
5,494 downloads genomics
Sofia A Quinodoz, Noah Ollikainen, Barbara Tabak, Ali Palla, Jan Marten Schmidt, Elizabeth Detmar, Mason Lai, Alexander Shishkin, Prashant Bhat, Vickie Trinh, Erik Aznauryan, Pamela Russell, Christine Cheng, Marko Jovanovic, Amy Chow, Patrick McDonel, Manuel Garber, Mitchell Guttman
Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus of each cell. There are currently two distinct views of genome organization that are derived from different technologies. The first view, derived from genome-wide proximity ligation methods (e.g. Hi-C), suggests that genome organization is largely organized around chromosomes. The second view, derived from in situ imaging, suggests a central role for nuclear bodies. Yet, because microscopy and proximity-ligation methods measure different aspects of genome organization, these two views remain poorly reconciled and our overall understanding of how genomic DNA is organized within the nucleus remains incomplete. Here, we develop Split-Pool Recognition of Interactions by Tag Extension (SPRITE), which moves away from proximity-ligation and enables genome-wide detection of higher-order DNA interactions within the nucleus. Using SPRITE, we recapitulate known genome structures identified by Hi-C and show that the contact frequencies measured by SPRITE strongly correlate with the 3-dimensional distances measured by microscopy. In addition to known structures, SPRITE identifies two major hubs of inter-chromosomal interactions that are spatially arranged around the nucleolus and nuclear speckles, respectively. We find that the majority of genomic regions exhibit preferential spatial association relative to one of these nuclear bodies, with regions that are highly transcribed by RNA Polymerase II organizing around nuclear speckles and transcriptionally inactive and centromere-proximal regions organizing around the nucleolus. Together, our results reconcile the two distinct pictures of nuclear structure and demonstrate that nuclear bodies act as inter-chromosomal hubs that shape the overall 3-dimensional packaging of genomic DNA in the nucleus.
5,449 downloads genomics
The sexually transmitted pathogen Neisseria gonorrhoeae is regarded as being on the way to becoming an untreatable superbug. Despite its clinical importance, little is known about its emergence and evolution, and how this corresponds with the introduction of antimicrobials. We present a genome-based phylogeographic analysis of 419 gonococcal isolates from across the globe. Results indicate that modern gonococci originated in Europe or Africa as late as the 16th century and subsequently disseminated globally. We provide evidence that the modern gonococcal population has been shaped by antimicrobial treatment of sexually transmitted and other infections, leading to the emergence of two major lineages with different evolutionary strategies. The well-described multi-resistant lineage is associated with high rates of homologous recombination and infection in high-risk sexual networks where antimicrobial treatment is frequent. A second, multi-susceptible lineage associated with heterosexual networks, where asymptomatic infection is more common, was also identified, with potential implications for infection control.
5,448 downloads genomics
Mihail Sarov, Chritiane Barz, Helena Jambor, Marco Y Hein, Christopher Schmied, Dana Suchold, Bettina Stender, Stephan Janosch, Vinay K.J. Vikas, R.T. Krisnan, K. Aishwarya, Irene R.S. Ferreira, Radoslaw K. Ejsmont, Katja Finkl, Susanne Hasse, Philipp Kämpfer, Nicole Plewka, Elisabeth Vinis, Siegfried Schloissnig, Elisabeth Knust, Volker Hartenstein, Matthias Mann, Mani Ramaswami, K. VijayRaghavan, Pavel Tomancak, Frank Schnorrer
The Drosophila genome contains >13,000 protein coding genes, the majority of which remain poorly investigated. Important reasons include the lack of antibodies or reporter constructs to visualise these proteins. Here we present a genome-wide fosmid library of ≈10,000 GFP-tagged clones, comprising tagged genes and most of their regulatory information. For 880 tagged proteins we have created transgenic lines and for a total of 207 lines we have assessed protein expression and localisation in ovaries, embryos, pupae or adults by stainings and live imaging approaches. Importantly, we can visualise many proteins at endogenous expression levels and find a large fraction of them localising to subcellular compartments. Using complementation tests we demonstrate that two-thirds of the tagged proteins are fully functional. Moreover, our clones enable interaction proteomics from developing pupae and adult flies. Taken together, this resource will enable systematic analysis of protein expression and localisation in various cellular and developmental contexts.
5,334 downloads genomics
Normal human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While epigenomic landscapes of this process have been explored in immunophenotypically-defined populations, the single-cell regulatory variation that defines hematopoietic differentiation has been hidden by ensemble averaging. We generated single-cell chromatin accessibility landscapes across 8 populations of immunophenotypically-defined human hematopoietic cell types. Using bulk chromatin accessibility profiles to scaffold our single-cell data analysis, we constructed an epigenomic landscape of human hematopoiesis and characterized epigenomic heterogeneity within phenotypically sorted populations to find epigenomic lineage-bias toward different developmental branches in multipotent stem cell states. We identify and isolate sub-populations within classically-defined granulocyte-macrophage progenitors (GMPs) and use ATAC-seq and RNA-seq to confirm that GMPs are epigenomically and transcriptomically heterogeneous. Furthermore, we identified transcription factors and cis-regulatory elements linked to changes in chromatin accessibility within cellular populations and across a continuous myeloid developmental trajectory, and observe relatively simple TF motif dynamics give rise to a broad diversity of accessibility dynamics at cis-regulatory elements. Overall, this work provides a template for exploration of complex regulatory dynamics in primary human tissues at the ultimate level of granular specificity - the single cell.
5,306 downloads genomics
Mandeep Singh, Ghamdan Al-Eryani, Shaun Carswell, James M. Ferguson, James Blackburn, Kirston Barton, Daniel Roden, Fabio Luciani, Tri Phan, Simon Junankar, Katherine Jackson, Christopher C Goodnow, Martin Smith, Alexander Swarbrick
High-throughput single-cell RNA-Sequencing is a powerful technique for gene expression profiling of complex and heterogeneous cellular populations such as the immune system. However, these methods only provide short-read sequence from one end of a cDNA template, making them poorly suited to the investigation of gene-regulatory events such as mRNA splicing, adaptive immune responses or somatic genome evolution. To address this challenge, we have developed a method that combines targeted long-read sequencing with short-read based transcriptome profiling of barcoded single cell libraries generated by droplet-based partitioning. We use Repertoire And Gene Expression sequencing (RAGE-seq) to accurately characterize full-length T cell (TCR) and B cell (BCR) receptor sequences and transcriptional profiles of more than 7,138 lymphocytes sampled from the primary tumour and draining lymph node of a breast cancer patient. With this method we show that somatic mutation, alternate splicing and clonal evolution of T and B lymphocytes can be tracked across these tissue compartments. Our results demonstrate that RAGE-Seq is an accessible and cost-effective method for high-throughput deep single cell profiling, applicable to a wide range of biological challenges.
5,268 downloads genomics
Pervasive mutations in somatic cells generate a heterogeneous genomic population within an organism and may result in serious medical conditions. While cancer is the most studied disease associated with somatic variations, recent advances in single cell and ultra deep sequencing indicate that a number of phenotypes and pathologies are impacted by cell specific variants. Currently, the accurate identification of low allelic frequency somatic variants relies on a combination of deep sequencing coverage and multiple evidences of the presence of variants. However, in this study we show that false positive variants can account for more than 70% of identified somatic variations, rendering conventional detection methods inadequate for accurate determination of low allelic variants. Interestingly, these false positive variants primarily originate from mutagenic DNA damage which directly confounds determination of genuine somatic mutations. Furthermore, we developed and validated a simple metric to measure mutagenic DNA damage, and demonstrated that mutagenic DNA damage is the leading cause of sequencing errors in widely used resources including the 1000 Genomes Project and The Cancer Genome Atlas.
5,267 downloads genomics
Yinping Jiao, Paul Peluso, Jinghua Shi, Tiffany Liang, Michelle C Stitzer, Bo Wang, Michael S. Campbell, Joshua C Stein, Xuehong Wei, Chen-Shan Chin, Katherine Guill, Michael Regulski, Sunita Kumari, Andrew Olson, Jonathan Gent, Kevin L Schneider, Thomas K Wolfgruber, Michael R May, Nathan M Springer, Eric Antoniou, Richard McCombie, Gernot G Presting, Michael McMullen, Jeffrey Ross-Ibarra, R. Kelly Dawe, Alex Hastie, David R Rank, Doreen Ware
Complete and accurate reference genomes and annotations provide fundamental tools for characterization of genetic and functional variation. These resources facilitate elucidation of biological processes and support translation of research findings into improved and sustainable agricultural technologies. Many reference genomes for crop plants have been generated over the past decade, but these genomes are often fragmented and missing complex repeat regions. Here, we report the assembly and annotation of maize, a genetic and agricultural model species, using Single Molecule Real-Time (SMRT) sequencing and high-resolution optical mapping. Relative to the previous reference genome, our assembly features a 52-fold increase in contig length and significant improvements in the assembly of intergenic spaces and centromeres. Characterization of the repetitive portion of the genome revealed over 130,000 intact transposable elements (TEs), allowing us to identify TE lineage expansions unique to maize. Gene annotations were updated using 111,000 full-length transcripts obtained by SMRT sequencing. In addition, comparative optical mapping of two other inbreds revealed a prevalence of deletions in the low gene density region and maize lineage-specific genes.
5,265 downloads genomics
Åshild J. Vågene, Michael G. Campana, Nelly M. Robles García, Christina Warinner, Maria A. Spyrou, Aida Andrades Valtueña, Daniel Huson, Noreen Tuross, Alexander Herbig, Kirsten I. Bos, Johannes Krause
Indigenous populations of the Americas experienced high mortality rates during the early contact period as a result of infectious diseases, many of which were introduced by Europeans. Most of the pathogenic agents that caused these outbreaks remain unknown. Using a metagenomic tool called MALT to search for traces of ancient pathogen DNA, we were able to identify Salmonella enterica in individuals buried in an early contact era epidemic cemetery at Teposcolula-Yucundaa, Oaxaca in southern Mexico. This cemetery is linked to the 1545-1550 CE epidemic locally known as 'cocoliztli', the cause of which has been debated for over a century. Here we present two reconstructed ancient genomes for Salmonella enterica subsp. enterica serovar Paratyphi C, a bacterial cause of enteric fever. We propose that S. Paratyphi C contributed to the population decline during the 1545 cocoliztli outbreak in Mexico.
5,265 downloads genomics
For the first time, a complete genome of an RNA virus has been sequenced in its original form. Previously, RNA was sequenced by the chemical degradation of radiolabelled RNA, a difficult method that produced only short sequences. Instead, RNA has usually been sequenced indirectly by copying it into cDNA, which is often amplified to dsDNA by PCR and subsequently analyzed using a variety of DNA sequencing methods. We designed an adapter to short highly conserved termini of the influenza virus genome to target the (-) sense RNA into a protein nanopore on the Oxford Nanopore MinION sequencing platform. Utilizing this method and total RNA extracted from the allantoic fluid of infected chicken eggs, we demonstrate successful sequencing of the complete influenza virus genome with 100% nucleotide coverage, 99% consensus identity, and 99% of reads mapped to influenza. By utilizing the same methodology we can redesign the adapter in order to expand the targets to include viral mRNA and (+) sense cRNA, which are essential to the viral life cycle. This has the potential to identify and quantify splice variants and base modifications, which are not practically measurable with current methods.
5,260 downloads genomics
The past five years have witnessed a tremendous growth of single-cell RNA-seq methodologies. Currently, there are three major commercial platforms for single-cell RNA-seq: Fluidigm C1, Clontech iCell8 (formerly Wafergen) and 10x Genomics Chromium. Here, we provide a systematic comparison of the throughput, sensitivity, cost and other performance statistics for these three platforms using single cells from primary human islets. The primary human islets represent a complex biological system where multiple cell types coexist, with varying cellular abundance, diverse transcriptomic profiles and differing total RNA contents. We apply standard pipelines optimized for each system to derive gene expression matrices. We further evaluate the performance of each system by benchmarking single-cell data with bulk RNA-seq data from sorted cell fractions. Our analyses can be generalized to a variety of complex biological systems and serve as a guide to newcomers to the field of single-cell RNA-seq when selecting platforms.
5,140 downloads genomics
The assay for transposase-accessible chromatin using sequencing (ATAC-seq) is widely used to identify regulatory regions throughout the genome. However, very few studies have been performed at the single cell level (scATAC-seq) due to technical challenges. Here we developed a simple and robust plate-based scATAC-seq method, combining upfront bulk tagmentation with single-nuclei sorting. By profiling over 3,000 splenocytes, we identify distinct immune cell types and reveal cell type-specific regulatory regions and related transcription factors.
5,138 downloads genomics
Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they can have drastically different effects depending on both the precise location and specific amino acid substitution of the variant. In order to better evaluate missense variation, we leveraged the exome sequencing data of 60,706 individuals from the Exome Aggregation Consortium (ExAC) dataset to identify sub-genic regions that are depleted of missense variation. We further used this depletion as part of a novel missense deleteriousness metric named MPC. We applied MPC to de novo missense variants and identified a category of de novo missense variants with the same impact on neurodevelopmental disorders as truncating mutations in intolerant genes, supporting the value of incorporating regional missense constraint in variant interpretation.
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