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Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines.
Ellrott K, Bailey MH, Saksena G, Covington KR, Kandoth C, Stewart C, Hess J, Ma S, Chiotti KE, McLellan M, Sofia HJ, Hutter C, Getz G, Wheeler D, Ding L, MC3 Working Group, Cancer Genome Atlas Research Network
(2018) Cell Syst 6: 271-281.e7
MeSH Terms: Algorithms, Exome, Genomics, High-Throughput Nucleotide Sequencing, Humans, Information Dissemination, Mutation, Neoplasms, Sequence Analysis, DNA, Software, Whole Exome Sequencing
Show Abstract · Added October 30, 2019
The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Calcium channel blockers as drug repurposing candidates for gestational diabetes: Mining large scale genomic and electronic health records data to repurpose medications.
Goldstein JA, Bastarache LA, Denny JC, Roden DM, Pulley JM, Aronoff DM
(2018) Pharmacol Res 130: 44-51
MeSH Terms: Adolescent, Adult, Calcium Channel Blockers, Data Mining, Diabetes, Gestational, Drug Repositioning, Electronic Health Records, Female, Genomics, Humans, Middle Aged, Polymorphism, Single Nucleotide, Pregnancy, Young Adult
Show Abstract · Added March 14, 2018
New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM). In parallel, we tested the association between drugs and glucose tolerance during pregnancy as measured by the glucose recorded during a routine 50-g glucose tolerance test (GTT). We found an association between GDM/DM2 and the genes targeted by 11 drug classes. In the EMR analysis, 6 drug classes were associated with changes in GTT. Two classes were identified in both analyses. L-type calcium channel blocking antihypertensives (CCBs), were associated with a 3.18 mg/dL (95% CI -6.18 to -0.18) decrease in glucose during GTT, and serotonin receptor type 3 (5HT-3) antagonist antinausea medications were associated with a 3.54 mg/dL (95% CI 1.86-5.23) increase in glucose during GTT. CCBs were identified as a class of drugs considered safe in pregnancy could have efficacy in treating or preventing GDM. 5HT-3 antagonists may be associated with worse glucose tolerance.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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An integrative functional genomics framework for effective identification of novel regulatory variants in genome-phenome studies.
Zhao J, Cheng F, Jia P, Cox N, Denny JC, Zhao Z
(2018) Genome Med 10: 7
MeSH Terms: Gene Regulatory Networks, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genomics, Humans, Molecular Sequence Annotation, Organ Specificity, Phenotype, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Transcription Factors
Show Abstract · Added March 14, 2018
BACKGROUND - Genome-phenome studies have identified thousands of variants that are statistically associated with disease or traits; however, their functional roles are largely unclear. A comprehensive investigation of regulatory mechanisms and the gene regulatory networks between phenome-wide association study (PheWAS) and genome-wide association study (GWAS) is needed to identify novel regulatory variants contributing to risk for human diseases.
METHODS - In this study, we developed an integrative functional genomics framework that maps 215,107 significant single nucleotide polymorphism (SNP) traits generated from the PheWAS Catalog and 28,870 genome-wide significant SNP traits collected from the GWAS Catalog into a global human genome regulatory map via incorporating various functional annotation data, including transcription factor (TF)-based motifs, promoters, enhancers, and expression quantitative trait loci (eQTLs) generated from four major functional genomics databases: FANTOM5, ENCODE, NIH Roadmap, and Genotype-Tissue Expression (GTEx). In addition, we performed a tissue-specific regulatory circuit analysis through the integration of the identified regulatory variants and tissue-specific gene expression profiles in 7051 samples across 32 tissues from GTEx.
RESULTS - We found that the disease-associated loci in both the PheWAS and GWAS Catalogs were significantly enriched with functional SNPs. The integration of functional annotations significantly improved the power of detecting novel associations in PheWAS, through which we found a number of functional associations with strong regulatory evidence in the PheWAS Catalog. Finally, we constructed tissue-specific regulatory circuits for several complex traits: mental diseases, autoimmune diseases, and cancer, via exploring tissue-specific TF-promoter/enhancer-target gene interaction networks. We uncovered several promising tissue-specific regulatory TFs or genes for Alzheimer's disease (e.g. ZIC1 and STX1B) and asthma (e.g. CSF3 and IL1RL1).
CONCLUSIONS - This study offers powerful tools for exploring the functional consequences of variants generated from genome-phenome association studies in terms of their mechanisms on affecting multiple complex diseases and traits.
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Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species.
Lind AL, Wisecaver JH, Lameiras C, Wiemann P, Palmer JM, Keller NP, Rodrigues F, Goldman GH, Rokas A
(2017) PLoS Biol 15: e2003583
MeSH Terms: Alleles, Aspergillus fumigatus, Biological Evolution, Fungal Proteins, Fungi, Genetic Variation, Genome, Fungal, Genomics, Metabolic Networks and Pathways, Multigene Family, Mutation, Polymorphism, Genetic, Secondary Metabolism
Show Abstract · Added March 21, 2018
Filamentous fungi produce a diverse array of secondary metabolites (SMs) critical for defense, virulence, and communication. The metabolic pathways that produce SMs are found in contiguous gene clusters in fungal genomes, an atypical arrangement for metabolic pathways in other eukaryotes. Comparative studies of filamentous fungal species have shown that SM gene clusters are often either highly divergent or uniquely present in one or a handful of species, hampering efforts to determine the genetic basis and evolutionary drivers of SM gene cluster divergence. Here, we examined SM variation in 66 cosmopolitan strains of a single species, the opportunistic human pathogen Aspergillus fumigatus. Investigation of genome-wide within-species variation revealed 5 general types of variation in SM gene clusters: nonfunctional gene polymorphisms; gene gain and loss polymorphisms; whole cluster gain and loss polymorphisms; allelic polymorphisms, in which different alleles corresponded to distinct, nonhomologous clusters; and location polymorphisms, in which a cluster was found to differ in its genomic location across strains. These polymorphisms affect the function of representative A. fumigatus SM gene clusters, such as those involved in the production of gliotoxin, fumigaclavine, and helvolic acid as well as the function of clusters with undefined products. In addition to enabling the identification of polymorphisms, the detection of which requires extensive genome-wide synteny conservation (e.g., mobile gene clusters and nonhomologous cluster alleles), our approach also implicated multiple underlying genetic drivers, including point mutations, recombination, and genomic deletion and insertion events as well as horizontal gene transfer from distant fungi. Finally, most of the variants that we uncover within A. fumigatus have been previously hypothesized to contribute to SM gene cluster diversity across entire fungal classes and phyla. We suggest that the drivers of genetic diversity operating within a fungal species shown here are sufficient to explain SM cluster macroevolutionary patterns.
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13 MeSH Terms
Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas.
Cancer Genome Atlas Research Network. Electronic address: elizabeth.demicco@sinaihealthsystem.ca, Cancer Genome Atlas Research Network
(2017) Cell 171: 950-965.e28
MeSH Terms: Adult, Aged, Aged, 80 and over, Cluster Analysis, DNA Copy Number Variations, Epigenomics, Genome, Human, Genome-Wide Association Study, Humans, Middle Aged, Mutation, Sarcoma, Young Adult
Show Abstract · Added October 30, 2019
Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Landscape of X chromosome inactivation across human tissues.
Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, Aguirre M, Gauthier L, Fleharty M, Kirby A, Cummings BB, Castel SE, Karczewski KJ, Aguet F, Byrnes A, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Lappalainen T, Regev A, Ardlie KG, Hacohen N, MacArthur DG
(2017) Nature 550: 244-248
MeSH Terms: Chromosomes, Human, X, Female, Genes, X-Linked, Genome, Human, Genomics, Humans, Male, Organ Specificity, Phenotype, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome, X Chromosome Inactivation
Show Abstract · Added October 27, 2017
X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.
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13 MeSH Terms
The impact of rare variation on gene expression across tissues.
Li X, Kim Y, Tsang EK, Davis JR, Damani FN, Chiang C, Hess GT, Zappala Z, Strober BJ, Scott AJ, Li A, Ganna A, Bassik MC, Merker JD, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Hall IM, Battle A, Montgomery SB
(2017) Nature 550: 239-243
MeSH Terms: Bayes Theorem, Female, Gene Expression Profiling, Genetic Variation, Genome, Human, Genomics, Genotype, Humans, Male, Models, Genetic, Organ Specificity, Sequence Analysis, RNA
Show Abstract · Added October 27, 2017
Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.
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12 MeSH Terms
Identifying -mediators for -eQTLs across many human tissues using genomic mediation analysis.
Yang F, Wang J, GTEx Consortium, Pierce BL, Chen LS
(2017) Genome Res 27: 1859-1871
MeSH Terms: Databases, Genetic, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Selection, Genetic, Tissue Distribution
Show Abstract · Added November 29, 2017
The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (-eQTLs). More research is needed to identify effects of genetic variation on distant genes (-eQTLs) and understand their biological mechanisms. One common -eQTLs mechanism is "mediation" by a local () transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are "-mediators" of -eQTLs, including those "-hubs" involved in regulation of many -genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying -eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study -mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of -hubs and -eQTL regulation across tissue types.
© 2017 Yang et al.; Published by Cold Spring Harbor Laboratory Press.
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Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma.
Cancer Genome Atlas Research Network. Electronic address: andrew_aguirre@dfci.harvard.edu, Cancer Genome Atlas Research Network
(2017) Cancer Cell 32: 185-203.e13
MeSH Terms: Carcinoma, Pancreatic Ductal, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Humans, Mutation, Pancreatic Neoplasms, Proteome, Proto-Oncogene Proteins p21(ras), Transcriptome
Show Abstract · Added October 30, 2019
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Controlling the signal: Practical privacy protection of genomic data sharing through Beacon services.
Wan Z, Vorobeychik Y, Kantarcioglu M, Malin B
(2017) BMC Med Genomics 10: 39
MeSH Terms: Computer Security, Gene Frequency, Genomics, Humans, Information Dissemination
Show Abstract · Added April 10, 2018
BACKGROUND - Genomic data is increasingly collected by a wide array of organizations. As such, there is a growing demand to make summary information about such collections available more widely. However, over the past decade, a series of investigations have shown that attacks, rooted in statistical inference methods, can be applied to discern the presence of a known individual's DNA sequence in the pool of subjects. Recently, it was shown that the Beacon Project of the Global Alliance for Genomics and Health, a web service for querying about the presence (or absence) of a specific allele, was vulnerable. The Integrating Data for Analysis, Anonymization, and Sharing (iDASH) Center modeled a track in their third Privacy Protection Challenge on how to mitigate the Beacon vulnerability. We developed the winning solution for this track.
METHODS - This paper describes our computational method to optimize the tradeoff between the utility and the privacy of the Beacon service. We generalize the genomic data sharing problem beyond that which was introduced in the iDASH Challenge to be more representative of real world scenarios to allow for a more comprehensive evaluation. We then conduct a sensitivity analysis of our method with respect to several state-of-the-art methods using a dataset of 400,000 positions in Chromosome 10 for 500 individuals from Phase 3 of the 1000 Genomes Project. All methods are evaluated for utility, privacy and efficiency.
RESULTS - Our method achieves better performance than all state-of-the-art methods, irrespective of how key factors (e.g., the allele frequency in the population, the size of the pool and utility weights) change from the original parameters of the problem. We further illustrate that it is possible for our method to exhibit subpar performance under special cases of allele query sequences. However, we show our method can be extended to address this issue when the query sequence is fixed and known a priori to the data custodian, so that they may plan stage their responses accordingly.
CONCLUSIONS - This research shows that it is possible to thwart the attack on Beacon services, without substantially altering the utility of the system, using computational methods. The method we initially developed is limited by the design of the scenario and evaluation protocol for the iDASH Challenge; however, it can be improved by allowing the data custodian to act in a staged manner.
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