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The impact of rare variation on gene expression across tissues [article]

Xin Li, Yungil Kim, Emily K. Tsang, Joe R. Davis, Farhan N. Damani, Colby Chiang, Zachary Zappala, Benjamin J. Strober, Alexandra J. Scott, Andrea Ganna, Jason Merker, Ira M. Hall (+2 others)
2016 bioRxiv   pre-print
Here, we identify gene expression outliers, or individuals with extreme expression levels, across 44 human tissues, and characterize the contribution of rare variation to these large changes in expression  ...  The Genotype-Tissue Expression (GTEx) project provides a unique opportunity to identify the functional impact of rare variants through combined analyses of whole genomes and multi-tissue RNA-sequencing  ...  However, it remains unknown which 51 categories of rare variation have the strongest impact on gene expression and how their consequences are 52 reflected across multiple tissues.  ... 
doi:10.1101/074443 fatcat:qlzvrwhpqrej3eob6h5dehpjcq

The impact of rare variation on gene expression across tissues

Xin Li, Yungil Kim, Emily K. Tsang, Joe R. Davis, Farhan N. Damani, Colby Chiang, Gaelen T. Hess, Zachary Zappala, Benjamin J. Strober, Alexandra J. Scott, Amy Li, Andrea Ganna (+244 others)
2017 Nature  
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  ...  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.  ...  We investigated the influence of rare genetic variation on extreme expression levels, focusing on the individuals of European ancestry with whole-genome sequencing data (1,144 multi-tissue outliers).  ... 
doi:10.1038/nature24267 pmid:29022581 pmcid:PMC5877409 fatcat:thl5q4fhgrayzams37kfedk45m

Diverse transcriptomic signatures across human tissues identify functional rare genetic variation [article]

Nicole M. Ferraro, Benjamin J. Strober, Jonah Einson, Xin Li, Francois Aguet, Alvaro N. Barbeira, Stephane E Castel, Joe R. Davis, Austin T. Hilliard, Bence Kotis, YoSon Park, Alexandra J. Scott (+11 others)
2019 bioRxiv   pre-print
Rare genetic variation is abundant in the human genome, yet identifying functional rare variants and their impact on traits remains challenging.  ...  Together, we provide a comprehensive analysis of the transcriptomic impact of rare variation and a framework to prioritize functional rare variants and assess their trait relevance.  ...  Bonnie for providing comments on the manuscript and K. Tayeb for reviewing code.  ... 
doi:10.1101/786053 fatcat:tyc2dthbwfchtgxlnjvwawoosa

Non-Coding Loss-of-Function Variation in Human Genomes

Zachary Zappala, Stephen B. Montgomery
2016 Human Heredity  
Whole genome and exome sequencing in human populations has revealed the tolerance of each gene for loss-of-function variation.  ...  In this review, we investigate recent studies of loss-of-function variation and emerging approaches for interpreting whole genome sequencing data to identify rare and impactful non-coding loss-of-function  ...  S.B.M. is supported by the National Institutes of Health through R01HG008150, R01MH101814 and U01HG007436.  ... 
doi:10.1159/000447453 pmid:28076858 pmcid:PMC5499665 fatcat:ab72c7hv3bcdpjtkuk35h35ck4

Measurement of selective constraint on human gene expression [article]

Emily C Glassberg, Ziyue Gao, Arbel Harpak, Xun Lan, Jonathan K Pritchard
2018 bioRxiv   pre-print
Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression levels.  ...  We estimate that, across all genes, singletons in a sample of 122 individuals have approximately 2.5 times greater effects on expression variance than common variants.  ...  ACKNOWLEDGEMENTS We thank the members of the Pritchard Lab for spirited conversations regarding this work. We also thank Lawrence Uricchio, Noah Zaitlen, and Ryan Hernandez for their comments.  ... 
doi:10.1101/345801 fatcat:upo2emfmy5h63c4a3kxanvv7wi

Evidence for Weak Selective Constraint on Human Gene Expression

Emily C. Glassberg, Ziyue Gao, Arbel Harpak, Xun Lan, Jonathan K. Pritchard
2018 Genetics  
We estimate that, across all genes, singletons in a sample of 122 individuals have ∼2.2× greater effects on expression variation than the average variant across allele frequencies.  ...  Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression.  ...  Acknowledgments We thank the members of the Pritchard Laboratory for spirited conversations regarding this work.  ... 
doi:10.1534/genetics.118.301833 pmid:30554168 pmcid:PMC6366908 fatcat:4dqeq7cjqzb5raftraayjq4n7m

Transcriptomic signatures across human tissues identify functional rare genetic variation

Nicole M Ferraro, Benjamin J Strober, Jonah Einson, Nathan S Abell, Francois Aguet, Alvaro N Barbeira, Margot Brandt, Maja Bucan, Stephane E Castel, Joe R Davis, Emily Greenwald, Gaelen T Hess (+27 others)
2020 Science  
Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge.  ...  Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs).  ...  The complete set of multitissue outlier statistics can be found on the GTEx portal (  ... 
doi:10.1126/science.aaz5900 pmid:32913073 pmcid:PMC7646251 fatcat:woalmwti2nayrpaz26kr6wxfam

Diagnosing rare diseases after the exome

Laure Frésard, Stephen B. Montgomery
2018 Molecular Case Studies  
When applied to individuals with rare genetic diseases, these approaches have greatly accelerated gene discovery and patient diagnosis.  ...  Over the past decade, exome sequencing has emerged as a comprehensive and cost-effective approach to identify pathogenic variants in the protein-coding regions of the genome.  ...  Wheeler, Craig Smail, and anonymous reviewers for their critical review of the manuscript.  ... 
doi:10.1101/mcs.a003392 pmid:30559314 pmcid:PMC6318767 fatcat:yobxbt5yk5b6pi6aeoryeplpju

From the Literature

Tracy Hampton
2018 Circulation  
One specifically examined rare variants' effects on gene expression, with a focus on individuals with extremely high or extremely low expression of a particular gene compared with the population.  ...  Ongoing Studies Examine Tissue-Specific Gene Expression to Provide Insights on Health and Disease Scientists working on a far-reaching collaborative project to understand how variation in individuals'  ...  World Wide Web at: The online version of this article, along with updated information and services, is located on the  ... 
doi:10.1161/circulationaha.117.033109 fatcat:teis7pskqnahdj2nbinn5pm6ay

Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues

Kimberly R. Kukurba, Rui Zhang, Xin Li, Kevin S. Smith, David A. Knowles, Meng How Tan, Robert Piskol, Monkol Lek, Michael Snyder, Daniel G. MacArthur, Jin Billy Li, Stephen B. Montgomery (+1 others)
2014 PLoS Genetics  
By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which  ...  rare deleterious coding alleles are consistently expressed across tissues.  ...  These results demonstrate the extent to which regulatory variation can modify the functional impact of protein-coding variation across tissues, as well as the importance of using ASE for the interpretation  ... 
doi:10.1371/journal.pgen.1004304 pmid:24786518 pmcid:PMC4006732 fatcat:ibddft34wfhmzd6odzsaygku6i

Structural variants are a major source of gene expression differences in humans and often affect multiple nearby genes [article]

Alexandra J Scott, Colby Chiang, Ira M Hall
2021 bioRxiv   pre-print
Remarkably, both common and rare noncoding SVs often show strong regional effects on the expression of multiple genes: SV-eQTLs affect an average of 1.82 nearby genes compared to 1.09 genes affected by  ...  SNV- and indel-eQTLs, and 21.34% of rare expression-altering SVs show strong effects on 2-9 different genes.  ...  ACKNOWLEDGMENTS The authors thank E.J. Gardner for advice on MELT and R.E. Handsaker for advice on Genome STRiP. This work was supported by a Mr. and Mrs. Spencer T.  ... 
doi:10.1101/2021.03.06.434233 fatcat:i4ofcjdd2zb6jpsltf4s7qj75m

Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders

Patrick F. Sullivan, Daniel H. Geschwind
2019 Cell  
regulatory processes that influence gene expression and the functional coordination of genes that control biological processes.  ...  Studies of the genetics of psychiatric disorders have become one of the most exciting and fast-moving areas in human genetics.  ...  Work in progress on the functional architecture and cellular/ tissue architecture will, we believe, yield the needed insights. The impact of rare variation is less studied.  ... 
doi:10.1016/j.cell.2019.01.015 pmid:30901538 pmcid:PMC6432948 fatcat:u5q2vzrpnncvfhwecow3pcqfua

Data resources for human functional genomics

Kristin G. Ardlie, Roderic Guigó
2017 Current Opinion in Systems Biology  
These large-scale efforts have produced concerted genome wide maps of these elements as well as initial insights on the impact of genetic variation on functional variation.  ...  One of the most pressing needs in medical and evolutionary genomes is characterizing and interpreting the function of the millions of genetic variants in the human genome, most of which are rare, and many  ...  The Genotype Tissue Expression (GTEx) project expands on these efforts and was specifically established to characterize the role of genetic variation on gene expression variation across a wide range of  ... 
doi:10.1016/j.coisb.2016.12.019 pmid:28989986 pmcid:PMC5625631 fatcat:4767mb5b5bhgbhctuartvgt23i

Patterns of genic intolerance of rare copy number variation in 59,898 human exomes

Douglas M Ruderfer, Tymor Hamamsy, Monkol Lek, Konrad J Karczewski, David Kavanagh, Kaitlin E Samocha, Mark J Daly, Daniel G MacArthur, Menachem Fromer, Shaun M Purcell
2016 Nature Genetics  
On average, individuals possessed 0.81 deleted and 1.75 duplicated genes, and most (70%) carried at least one rare genic CNV.  ...  Copy number variation (CNV) impacting protein-coding genes contributes significantly to human diversity and disease.  ...  Work at the Icahn School of Medicine at Mount Sinai was supported by the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department  ... 
doi:10.1038/ng.3638 pmid:27533299 pmcid:PMC5042837 fatcat:fxalnidkujejnbgssezf3vz3qy

Evolutionary Constraint and Disease Associations of Post-Translational Modification Sites in Human Genomes

Jüri Reimand, Omar Wagih, Gary D. Bader, Chris Cotsapas
2015 PLoS Genetics  
This work aids understanding of the selective forces acting on protein-coding genome sequence and provides an integrative framework for predicting variant function in population and disease.  ...  We highlight 152 genes where disease mutations significantly accumulate in PTM regions, and integrate these with pharmacological information of PTM enzymes to predict new drug candidates to diseases.  ...  Shaheena Bashir, Maris Laan, Leopold Parts, Changjiang Xu, and the anonymous reviewers for their comments and advice on the manuscript.  ... 
doi:10.1371/journal.pgen.1004919 pmid:25611800 pmcid:PMC4303425 fatcat:wdi7pg4z6fad5cj3ma4pga4zcy
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