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Human embryoid bodies as a novel system for genomic studies of functionally diverse cell types [article]

Katherine Rhodes, Kenneth A Barr, Joshua M Popp, Benjamin J Strober, Alexis Battle, Yoav Gilad
2021 bioRxiv   pre-print
et al. identified during the differentiation of iPSCs 361 to cardiomyocytes (Strober et al. 2019).  ...  . ; https://doi.org/10.1101/2021.06.16.448714 doi: bioRxiv preprint Moyerbrailean et al. 2016; 28 Strober et al. 2019; Aguet et al. 2017).  ... 
doi:10.1101/2021.06.16.448714 fatcat:kaqsvy2zangzjj6kyds3wil4fa

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
Rare genetic variants are abundant in humans yet their functional effects are often unknown and challenging to predict. 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 data. Here, we identify gene expression outliers, or individuals with extreme expression levels, across 44 human tissues, and characterize the contribution of rare variation to
more » ... hese large changes in expression. We find 58% of underexpression and 28% of overexpression outliers have underlying rare variants compared with 9% of non-outliers. Large expression effects are enriched for proximal loss-of-function, splicing, and structural variants, particularly variants near the TSS and at evolutionarily conserved sites. Known disease genes have expression outliers, underscoring that rare variants can contribute to genetic disease risk. To prioritize functional rare regulatory variants, we develop RIVER, a Bayesian approach that integrates RNA and whole genome sequencing data from the same individual. RIVER predicts functional variants significantly better than models using genomic annotations alone, and is an extensible tool for personal genome interpretation. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues with potential health consequences, and provide an integrative method for interpreting rare variants in individual genomes.
doi:10.1101/074443 fatcat:qlzvrwhpqrej3eob6h5dehpjcq

Human embryoid bodies as a novel system for genomic studies of functionally diverse cell types

Katherine Rhodes, Kenneth A Barr, Joshua M Popp, Benjamin J Strober, Alexis Battle, Yoav Gilad
2022 eLife  
We took a closer look at the 28 middle-dynamic eQTLs Strober et al. identified during the differentiation of iPSCs to cardiomyocytes (Strober et al., 2019) .  ...  Strober et al. reported that one of these middle-dynamic eQTLs was also found to overlap a GWAS variant associated with body mass index and red blood cell count.  ... 
doi:10.7554/elife.71361 pmid:35142607 pmcid:PMC8830892 fatcat:oudmocfvabbddoepqa7ro6mtxe

A method to predict the impact of regulatory variants from DNA sequence

Dongwon Lee, David U Gorkin, Maggie Baker, Benjamin J Strober, Alessandro L Asoni, Andrew S McCallion, Michael A Beer
2015 Nature Genetics  
Most variants implicated in common human disease by Genome-Wide Association Studies (GWAS) lie in non-coding sequence intervals. Despite the suggestion that regulatory element disruption represents a common theme, identifying causal risk variants within indicted genomic regions remains a significant challenge. Here we present a novel sequence-based computational method to predict the effect of regulatory variation, using a classifier (gkm-SVM) which encodes cell-specific regulatory sequence
more » ... bularies. The induced change in the gkm-SVM score, deltaSVM, quantifies the effect of variants. We show that deltaSVM accurately predicts the impact of SNPs on DNase I sensitivity in their native genomic context, and accurately predicts the results of dense mutagenesis of several enhancers in reporter assays. Previously validated GWAS SNPs yield large deltaSVM scores, and we predict novel risk SNPs for several autoimmune diseases. Thus, deltaSVM provides a powerful computational approach for systematically identifying functional regulatory variants. Sequence variation in DNA regulatory elements is hypothesized to contribute substantially to risk for common diseases. Variants associated with human disease by GWAS predominantly lie in non-coding genomic regions 1 and occur within putative regulatory Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
doi:10.1038/ng.3331 pmid:26075791 pmcid:PMC4520745 fatcat:y7ppmawn4rbdjkijulvlkg224i

Single-Cell Sequencing Reveals Lineage-Specific Dynamic Genetic Regulation of Gene Expression During Human Cardiomyocyte Differentiation [article]

Reem Elorbany, Joshua M Popp, Katherine Rhodes, Benjamin J Strober, Kenneth Barr, Guanghao Qi, Yoav M Gilad, Alexis Battle
2021 bioRxiv   pre-print
Pearson correlation between 1049 single-cell pseudobulk data and bulk RNA-seq data (Strober et al 2019) for each individual; 1050 panels separated by differentiation day. .  ...  Pearson correlation 1054 between single-cell pseudobulk data and bulk RNA-seq data (Strober et al 2019) for each 1055 differentiation day; panels separated by individual. .  ... 
doi:10.1101/2021.06.03.446970 fatcat:rs22bvmzqndfxh5xgsupvkyfi4

Single-cell sequencing reveals lineage-specific dynamic genetic regulation of gene expression during human cardiomyocyte differentiation

Reem Elorbany, Joshua M. Popp, Katherine Rhodes, Benjamin J. Strober, Kenneth Barr, Guanghao Qi, Yoav Gilad, Alexis Battle, Mingyao Li
2022 PLoS Genetics  
,1000, j = 1,. . .,100 and i = 1,. . .  ...  Results We differentiated induced pluripotent stem cells (iPSCs) from 19 human cell lines into cardiomyocytes; these same cell lines were previously used for a cardiomyocyte time course study published in Strober  ...  (Bottom) Similar partial regression and partial residuals plots (respectively) for the nonlinear dynamic eQTL shown in Strober, Kenneth Barr, Guanghao Qi, Yoav Gilad, Alexis Battle.  ... 
doi:10.1371/journal.pgen.1009666 pmid:35061661 pmcid:PMC8809621 fatcat:doeabxftpra5hoyvdcmadulrni

Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning

A R Rezvani, A S Kanate, B Efron, S Chhabra, H E Kohrt, J A Shizuru, G G Laport, D B Miklos, J E Benjamin, L J Johnston, S Arai, W-K Weng (+3 others)
2015 Bone Marrow Transplantation  
We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG (anti-thymocyte globulin) conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma (n = 19), T-cell NHL (n = 6), mantle cell lymphoma (n = 4) or other B-cell subtypes (n = 3)), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1-11.9) years. The cumulative incidence of grade II-IV acute
more » ... vHD at day +100 was 12%, and the cumulative incidence of extensive chronic GvHD at 1 year was 36%. The 3-year cumulative incidences of overall survival (OS), PFS and non-relapse mortality (NRM) were 81%, 44% and 7%, respectively. Fifteen patients died (relapse, n = 10; NRM, n = 5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (41 year) CRs following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n = 24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GvHD, durable disease control and excellent OS (81% at 3 years).
doi:10.1038/bmt.2015.149 pmid:26146806 pmcid:PMC4699844 fatcat:h7zqhupfn5gtjojdh4rqcu7w5e

Long non-coding RNA gene regulation and trait associations across human tissues [article]

Olivia M. de Goede, Nicole M. Ferraro, Daniel C. Nachun, Abhiram Rao, François Aguet, Alvaro N. Barbeira, Stephane E Castel, Sarah Kim-Hellmuth, YoSon Park, Alexandra J. Scott, Benjamin J. Strober, Christopher D. Brown (+10 others)
2019 bioRxiv   pre-print
Maximilian Haeussler 75 , Thomas Juettemann 74 , W James Kent 75 , Christopher M Lee 75 , Conner C Powell 75 , Kate R Rosenbloom 75 , Magali Ruffier 74 , Dan Sheppard 74 , Kieron Taylor 74 , Stephen J  ...  Andrew D Skol 9,46 , Kevin S Smith 28 , Michael Snyder 19 , John Stamatoyannopoulos 81,85 , Barbara E Stranger 9,48 , Hua Tang 19 , Meng Wang 19 NIH program management: Philip A Branton 71 , Latarsha J  ... 
doi:10.1101/793091 fatcat:diepdlfutne2hco7awzhywufvq

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
We also thank J. Bonnie for providing comments on the manuscript and K. Tayeb for reviewing code.  ... 
doi:10.1101/786053 fatcat:tyc2dthbwfchtgxlnjvwawoosa

Predictors of longitudinal psychosocial functioning in bipolar youth transitioning to adults

Heather Hower, Erica J. Lee, Richard N. Jones, Boris Birmaher, Michael Strober, Benjamin I. Goldstein, John Merranko, Martin B. Keller, Tina R. Goldstein, Lauren M. Weinstock, Daniel P. Dickstein, Jeffrey I. Hunt (+5 others)
2019 Journal of Affective Disorders  
J Affect Disord. Author manuscript; available in PMC 2020 March 01. Hower et al.  ...  MDE: Major Depressive Episode C-GAS: Children's Global Assessment Scale WASI: Wechsler Abbreviated Scale of Intelligence (including Vocabulary and Matrix Reasoning Subtests) IQ: Intelligence Quotient J  ... 
doi:10.1016/j.jad.2018.12.108 pmid:30605876 pmcid:PMC6363880 fatcat:7kpi5wppkne4bhax5pocdpvlci

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  
Briefly, For a given LeafCutter cluster in a given tissue, we defined a matrix, X (dim NxJ), where each row corresponds to one of N samples, each column corresponding to one of J exon-exon junctions mapped  ... 
doi:10.1126/science.aaz5900 pmid:32913073 pmcid:PMC7646251 fatcat:woalmwti2nayrpaz26kr6wxfam

Identification of rare-disease genes in diverse undiagnosed cases using whole blood transcriptome sequencing and large control cohorts [article]

Laure Fresard, Craig Smail, Kevin S. Smith, Nicole M. Ferraro, Nicole A. Teran, Kristin D. Kernohan, Devon Bonner, Xin Li, Shruti Marwaha, Zachary Zappala, Brunilda Balliu, Joe R. Davis (+21 others)
2018 bioRxiv   pre-print
Beggs; Babak Behnam; Hugo J. Bellen; Jonathan A. Bernstein; Gerard T. Berry; Anna Bican; David P. Bick; Camille L. Birch; Devon Bonner; 15 .  ...  In this case, two sisters exhibited profound global developmental delay, neonatal-onset seizures, acquired microcephaly, hypotonia, G-/J-tube dependence, and progressive scoliosis and had undergone a diagnostic  ... 
doi:10.1101/408492 fatcat:iztgwrzwzrechnej23gb4onc7q

Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts

Laure Frésard, Craig Smail, Nicole M. Ferraro, Nicole A. Teran, Xin Li, Kevin S. Smith, Devon Bonner, Kristin D. Kernohan, Shruti Marwaha, Zachary Zappala, Brunilda Balliu, Joe R. Davis (+22 others)
2019 Nature Medicine  
It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9,
more » ... nd cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
doi:10.1038/s41591-019-0457-8 pmid:31160820 pmcid:PMC6634302 fatcat:e7szwhhldzfcvfslnq4r5tzd6e

Local genetic effects on gene expression across 44 human tissues [article]

Francois Aguet, Andrew A Brown, Stephane Castel, Joe R Davis, Pejman Mohammadi, Ayellet V Segre, Zachary Zappala, Nathan S Abell, Laure Fresard, Eric R Gamazon, Ellen Gelfand, Machael J Gloudemans (+38 others)
2016 bioRxiv   pre-print
In each tier, any the same gene, the P -value of that tissue's tier j genome-wide significant variant was used in the Benjamini-Hochberg procedure.  ...  J. Med. 373, 895-907 (2015). 684 24. Harismendy, O. et al. 9p21 DNA variants associated with coronary artery disease impair 685 interferon-γ signalling response. Nature 470, 264-268 (2011).  ... 
doi:10.1101/074450 fatcat:ps7qztxbt5f7ba454x2s7hg2ia

The GTEx Consortium atlas of genetic regulatory effects across human tissues [article]

François Aguet, Alvaro N Barbeira, Rodrigo Bonazzola, Andrew Brown, Stephane E Castel, Brian Jo, Silva Kasela, Sarah Kim-Hellmuth, Yanyu Liang, Meritxell Oliva, Princy E Parsana, Elise Flynn (+41 others)
2019 biorxiv/medrxiv   pre-print
The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost
more » ... l genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
doi:10.1101/787903 fatcat:lio7wugkyjhwlk6akssbybi46e
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