Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals
Alexis Battle,Sara Mostafavi,Xiaowei Zhu,James B. Potash,Myrna M. Weissman,Courtney McCormick,Christian D. Haudenschild,Kenneth B. Beckman,Jianxin Shi,Rui Mei,Alexander E. Urban,Stephen B. Montgomery,Douglas F. Levinson,Daphne Koller +13 more
TLDR
This work provides a direct window into the regulatory consequences of genetic variation by sequencing RNA from 922 genotyped individuals, and presents a comprehensive description of the distribution of regulatory variation--by the specific expression phenotypes altered, the properties of affected genes, and the genomic characteristics of regulatory variants.Abstract:
Understanding the consequences of regulatory variation in the human genome remains a major challenge, with important implications for understanding gene regulation and interpreting the many disease-risk variants that fall outside of protein-coding regions. Here, we provide a direct window into the regulatory consequences of genetic variation by sequencing RNA from 922 genotyped individuals. We present a comprehensive description of the distribution of regulatory variation--by the specific expression phenotypes altered, the properties of affected genes, and the genomic characteristics of regulatory variants. We detect variants influencing expression of over ten thousand genes, and through the enhanced resolution offered by RNA-sequencing, for the first time we identify thousands of variants associated with specific phenotypes including splicing and allelic expression. Evaluating the effects of both long-range intra-chromosomal and trans (cross-chromosomal) regulation, we observe modularity in the regulatory network, with three-dimensional chromosomal configuration playing a particular role in regulatory modules within each chromosome. We also observe a significant depletion of regulatory variants affecting central and critical genes, along with a trend of reduced effect sizes as variant frequency increases, providing evidence that purifying selection and buffering have limited the deleterious impact of regulatory variation on the cell. Further, generalizing beyond observed variants, we have analyzed the genomic properties of variants associated with expression and splicing and developed a Bayesian model to predict regulatory consequences of genetic variants, applicable to the interpretation of individual genomes and disease studies. Together, these results represent a critical step toward characterizing the complete landscape of human regulatory variation.read more
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The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans
Kristin G. Ardlie,David S. DeLuca,Ayellet V. Segrè,Timothy J. Sullivan,Taylor Young,Ellen Gelfand,Casandra A. Trowbridge,Julian Maller,Taru Tukiainen,Monkol Lek,Lucas D. Ward,Pouya Kheradpour,Benjamin Iriarte,Yan Meng,Cameron D. Palmer,Tõnu Esko,Wendy Winckler,Joel N. Hirschhorn,Manolis Kellis,Daniel G. MacArthur,Gad Getz,Andrey A. Shabalin,Gen Li,Yi-Hui Zhou,Andrew B. Nobel,Ivan Rusyn,Fred A. Wright,Tuuli Lappalainen,Pedro G. Ferreira,Halit Ongen,Manuel A. Rivas,Alexis Battle,Sara Mostafavi,Jean Monlong,Michael Sammeth,Marta Melé,Ferran Reverter,Jakob M. Goldmann,Daphne Koller,Roderic Guigó,Mark I. McCarthy,Emmanouil T. Dermitzakis,Eric R. Gamazon,Hae Kyung Im,Anuar Konkashbaev,Dan L. Nicolae,Nancy J. Cox,Timothée Flutre,Xiaoquan Wen,Matthew Stephens,Jonathan K. Pritchard,Zhidong Tu,Bin Zhang,Tao Huang,Quan Long,Luan Lin,Jialiang Yang,Jun Zhu,Jun Liu,Amanda Brown,Bernadette Mestichelli,Denee Tidwell,Edmund Lo,Mike Salvatore,Saboor Shad,Jeffrey A. Thomas,John T. Lonsdale,Michael T. Moser,Bryan Gillard,Ellen Karasik,Kimberly Ramsey,Christopher Choi,Barbara A. Foster,John Syron,Johnell Fleming,Harold Magazine,Rick Hasz,Gary Walters,Jason Bridge,Mark Miklos,Susan L. Sullivan,Laura Barker,Heather M. Traino,Maghboeba Mosavel,Laura A. Siminoff,Dana R. Valley,Daniel C. Rohrer,Scott D. Jewell,Philip A. Branton,Leslie H. Sobin,Mary Barcus,Liqun Qi,Jeffrey McLean,Pushpa Hariharan,Ki Sung Um,Shenpei Wu,David Tabor,Charles Shive,Anna M. Smith,Stephen A. Buia,Anita H. Undale,Karna Robinson,Nancy Roche,Kimberly M. Valentino,Angela Britton,Robin Burges,Debra Bradbury,Kenneth W. Hambright,John Seleski,Greg E. Korzeniewski,Kenyon Erickson,Yvonne Marcus,Jorge Tejada,Mehran Taherian,Chunrong Lu,Margaret J. Basile,Deborah C. Mash,Simona Volpi,Jeffery P. Struewing,Gary F. Temple,Joy T. Boyer,Deborah Colantuoni,Roger Little,Susan E. Koester,Latarsha J. Carithers,Helen M. Moore,Ping Guan,Carolyn C. Compton,Sherilyn Sawyer,Joanne P. Demchok,Jimmie B. Vaught,Chana A. Rabiner,Nicole C. Lockhart +132 more
TL;DR: The landscape of gene expression across tissues is described, thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants are cataloged, complex network relationships are described, and signals from genome-wide association studies explained by eQTLs are identified.
Journal ArticleDOI
Genetic effects on gene expression across human tissues.
Enhancing GTEx (eGTEx) groups,Nih Common Fund,Nhgri,Biospecimen Core Resource—VARI,Elsi study,Genome Browser Data Integration Visualization—EBI,Lead analysts,Alexis Battle,Christopher D. Brown,Barbara E. Engelhardt,Stephen B. Montgomery +10 more
TL;DR: It is found that local genetic variation affects gene expression levels for the majority of genes, and inter-chromosomal genetic effects for 93 genes and 112 loci are identified, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
Journal ArticleDOI
A survey of best practices for RNA-seq data analysis
Ana Conesa,Pedro Madrigal,Pedro Madrigal,Sonia Tarazona,David Gomez-Cabrero,Alejandra Cervera,Andrew McPherson,Michał Wojciech Szcześniak,Daniel J. Gaffney,Laura L. Elo,Xuegong Zhang,Ali Mortazavi +11 more
TL;DR: All of the major steps in RNA-seq data analysis are reviewed, including experimental design, quality control, read alignment, quantification of gene and transcript levels, visualization, differential gene expression, alternative splicing, functional analysis, gene fusion detection and eQTL mapping.
Journal ArticleDOI
The GTEx Consortium atlas of genetic regulatory effects across human tissues
François Aguet,Alvaro N. Barbeira,Rodrigo Bonazzola,Andrew A. Brown,SE Castel,Brian Jo,Silva Kasela,Sarah Kim-Hellmuth,Yanyu Liang,Meritxell Oliva,Elise D. Flynn,Princy Parsana,Laure Fresard,Eric R. Gamazon,Andrew R. Hamel,Yuan He,Farhad Hormozdiari,Pejman Mohammadi,Manuel Muñoz-Aguirre,YoSon Park,Ashis Saha,Ayellet V. Segrè,Benjamin J. Strober,Xiaoquan Wen,Wucher,Kristin G. Ardlie,Alexis Battle,Christopher D. Brown,Nancy J. Cox,Souvik Das,Emmanouil T. Dermitzakis,Barbara E. Engelhardt,D Garrido-Martin,Gad Getz,Roderic Guigó,Robert E. Handsaker,Paul J. Hoffman,Hae Kyung Im,Seva Kashin,Alan Kwong,Lappalainen T,Xiao Li,Daniel G. MacArthur,Stephen B. Montgomery,John M. Rouhana,Matthew Stephens,Barbara E. Stranger,Ellen Todres,Ana Viñuela,Gao Wang,Yuxin Zou,Shankara Anand,S. Gabriel,Aaron Graubert,Kane Hadley,Katherine H. Huang,Meier,Jared L. Nedzel,Duyen T. Nguyen,Brunilda Balliu,Donald F. Conrad,Daniel J. Cotter,OM deGoede,Jonah Einson,Eskin E,Tiffany Eulalio,Nicole M. Ferraro,Michael J. Gloudemans,Lei Hou,Serghei Mangul,Daniel Nachun,Andrew B. Nobel,Abhiram Rao,Ferran Reverter,Chiara Sabatti,Andrew D Skol,Nicole A. Teran,Fred A. Wright,Pedro G. Ferreira,Gen Li,Marta Melé,Esti Yeger-Lotem,Mary Barcus,Debra Bradbury,T Krubit,Jeffrey McLean,Liqun Qi,Karna Robinson,Nancy Roche,Anna M. Smith,David E. Tabor,Anita H. Undale,Jason Bridge,Lori E. Brigham,Barbara A. Foster,Bryan Gillard,Rick Hasz,Marcus Hunter,Christopher Johns,Mark H. Johnson,Ellen Karasik,Gene Kopen,William F. Leinweber,Alisa McDonald,Mike Moser,Kevin Myer,Kimberly Ramsey,Bruce A. Roe,Saboor Shad,Jeffrey A. Thomas,Gary Walters,Michael Washington,Jessica Wheeler,Scott D. Jewell,Daniel C. Rohrer,David A. Davis,Deborah C. Mash,Leslie H. Sobin,Laura Barker,HM Gardiner,Maghboeba Mosavel,Laura A. Siminoff,Paul Flicek,Maximilian Haeussler,Thomas Juettemann,W. J. Kent,Christopher Lee,CC Powell,Kate R. Rosenbloom,Magali Ruffier,Dan Sheppard,Kieron Taylor,Stephen J. Trevanion,Zerbino,Nathan S. Abell,Joshua M. Akey,Lin Chen,Kathryn Demanelis,Jennifer A. Doherty,Andrew P. Feinberg,Kasper D. Hansen,Peter Hickey,Farzana Jasmine,Lihua Jiang,Rajinder Kaul,Manolis Kellis,Muhammad G. Kibriya,Jin Billy Li,Qin Li,Shin Lin,Sandra Linder,Brandon L. Pierce,Lindsay F. Rizzardi,Kevin S. Smith,Michael Snyder,John A. Stamatoyannopoulos,Hua Tang,Meng Wang,Phillip Branton,Latarsha J. Carithers,Ping Guan,Susan E. Koester,AR Little,Helen M. Moore,Concepcion R. Nierras,Abhi Rao,Jimmie B. Vaught,Simona Volpi +167 more
Journal ArticleDOI
A Gene-Based Association Method for Mapping Traits Using Reference Transcriptome Data
Eric R. Gamazon,Heather E. Wheeler,Kaanan P. Shah,Sahar V. Mozaffari,Keston Aquino-Michaels,Robert J. Carroll,Anne E. Eyler,Joshua C. Denny,Dan L. Nicolae,Nancy J. Cox,Nancy J. Cox,Hae Kyung Im +11 more
TL;DR: The results demonstrate that PrediXcan can detect known and new genes associated with disease traits and provide insights into the mechanism of these associations.
References
More filters
Journal ArticleDOI
Maximum likelihood from incomplete data via the EM algorithm
Journal ArticleDOI
BEDTools: a flexible suite of utilities for comparing genomic features
Aaron R. Quinlan,Ira M. Hall +1 more
TL;DR: A new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format, which allows the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks.
Journal ArticleDOI
An integrated encyclopedia of DNA elements in the human genome
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Journal ArticleDOI
Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation
Cole Trapnell,Cole Trapnell,Brian A. Williams,Geo Pertea,Ali Mortazavi,Gordon Kwan,Marijke J. van Baren,Steven L. Salzberg,Barbara J. Wold,Lior Pachter +9 more
TL;DR: The results suggest that Cufflinks can illuminate the substantial regulatory flexibility and complexity in even this well-studied model of muscle development and that it can improve transcriptome-based genome annotation.
Journal ArticleDOI
Mapping and quantifying mammalian transcriptomes by RNA-Seq.
TL;DR: Although >90% of uniquely mapped reads fell within known exons, the remaining data suggest new and revised gene models, including changed or additional promoters, exons and 3′ untranscribed regions, as well as new candidate microRNA precursors.
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