{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T13:40:45Z","timestamp":1772458845552,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2017,9,23]],"date-time":"2017-09-23T00:00:00Z","timestamp":1506124800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01GM109215-01"],"award-info":[{"award-number":["1R01GM109215-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"AHA","doi-asserted-by":"publisher","award":["14SDG20450118"],"award-info":[{"award-number":["14SDG20450118"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"AHA","doi-asserted-by":"publisher","award":["17PRE33460295"],"award-info":[{"award-number":["17PRE33460295"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>The majority of the human genome is composed of non-coding regions containing regulatory elements such as enhancers, which are crucial for controlling gene expression. Many variants associated with complex traits are in these regions, and may disrupt gene regulatory sequences. Consequently, it is important to not only identify true enhancers but also to test if a variant within an enhancer affects gene regulation. Recently, allele-specific analysis in high-throughput reporter assays, such as massively parallel reporter assays (MPRAs), have been used to functionally validate non-coding variants. However, we are still missing high-quality and robust data analysis tools for these datasets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We have further developed our method for allele-specific analysis QuASAR (quantitative allele-specific analysis of reads) to analyze allele-specific signals in barcoded read counts data from MPRA. Using this approach, we can take into account the uncertainty on the original plasmid proportions, over-dispersion, and sequencing errors. The provided allelic skew estimate and its standard error also simplifies meta-analysis of replicate experiments. Additionally, we show that a beta-binomial distribution better models the variability present in the allelic imbalance of these synthetic reporters and results in a test that is statistically well calibrated under the null. Applying this approach to the MPRA data, we found 602 SNPs with significant (false discovery rate 10%) allele-specific regulatory function in LCLs. We also show that we can combine MPRA with QuASAR estimates to validate existing experimental and computational annotations of regulatory variants. Our study shows that with appropriate data analysis tools, we can improve the power to detect allelic effects in high-throughput reporter assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>http:\/\/github.com\/piquelab\/QuASAR\/tree\/master\/mpra<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available online at Bioinformatics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btx598","type":"journal-article","created":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T15:18:11Z","timestamp":1505834291000},"page":"787-794","source":"Crossref","is-referenced-by-count":30,"title":["QuASAR-MPRA: accurate allele-specific analysis for massively parallel reporter assays"],"prefix":"10.1093","volume":"34","author":[{"given":"Cynthia A","family":"Kalita","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA"}]},{"given":"Gregory A","family":"Moyerbrailean","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA"}]},{"given":"Christopher","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA"}]},{"given":"Xiaoquan","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA"}]},{"given":"Francesca","family":"Luca","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA"},{"name":"Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA"}]},{"given":"Roger","family":"Pique-Regi","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI, USA"},{"name":"Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA"}]}],"member":"286","published-online":{"date-parts":[[2017,9,22]]},"reference":[{"key":"2023012712392737900_btx598-B1","doi-asserted-by":"crossref","first-page":"R106.","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol"},{"key":"2023012712392737900_btx598-B2","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1126\/science.1232542","article-title":"Genome-wide quantitative enhancer activity maps identified by STARR-seq","volume":"339","author":"Arnold","year":"2013","journal-title":"Science"},{"key":"2023012712392737900_btx598-B3","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc.Ser. B"},{"key":"2023012712392737900_btx598-B4","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1126\/science.1069516","article-title":"Genetic dissection of transcriptional regulation in budding yeast","volume":"296","author":"Brem","year":"2002","journal-title":"Science"},{"key":"2023012712392737900_btx598-B5","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/ng.3162","article-title":"Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins","volume":"47","author":"Buil","year":"2014","journal-title":"Nat. Genet"},{"key":"2023012712392737900_btx598-B6","doi-asserted-by":"crossref","first-page":"195.","DOI":"10.1186\/s13059-015-0762-6","article-title":"Tools and best practices for data processing in allelic expression analysis","volume":"16","author":"Castel","year":"2015","journal-title":"Genome Biol"},{"key":"2023012712392737900_btx598-B7","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/ng1094","article-title":"Natural variation in human gene expression assessed in lymphoblastoid cells","volume":"33","author":"Cheung","year":"2003","journal-title":"Nature Genet"},{"key":"2023012712392737900_btx598-B8","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Consortium","year":"2012","journal-title":"Nature"},{"key":"2023012712392737900_btx598-B9","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans","volume":"348","author":"Consortium","year":"2015","journal-title":"Science"},{"key":"2023012712392737900_btx598-B10","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature10808","article-title":"DNaseI sensitivity QTLs are a major determinant of human expression variation","volume":"482","author":"Degner","year":"2012","journal-title":"Nature"},{"key":"2023012712392737900_btx598-B11","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nrg3115","article-title":"Cellular genomics for complex traits","volume":"13","author":"Dermitzakis","year":"2012","journal-title":"Nat. Rev. Genet"},{"key":"2023012712392737900_btx598-B12","doi-asserted-by":"crossref","first-page":"R7","DOI":"10.1186\/gb-2012-13-1-r7","article-title":"Dissecting the regulatory architecture of gene expression QTLs","volume":"13","author":"Gaffney","year":"2012","journal-title":"Genome Biol"},{"key":"2023012712392737900_btx598-B13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1000952","article-title":"Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain","volume":"6","author":"Gibbs","year":"2010","journal-title":"PLoS Genet"},{"key":"2023012712392737900_btx598-B14","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1093\/bioinformatics\/btu802","article-title":"QuASAR: quantitative allele specific analysis of reads","volume":"31","author":"Harvey","year":"2014","journal-title":"Bioinformatics"},{"key":"2023012712392737900_btx598-B15","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1093\/nar\/gks1284","article-title":"Integrative annotation of chromatin elements from ENCODE data","volume":"41","author":"Hoffman","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2023012712392737900_btx598-B16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1004722","article-title":"Integrating functional data to prioritize causal variants in statistical fine-mapping studies","volume":"10","author":"Kichaev","year":"2014","journal-title":"PLoS Genet"},{"key":"2023012712392737900_btx598-B17","doi-asserted-by":"crossref","first-page":"744.","DOI":"10.1126\/science.1242463","article-title":"Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription","volume":"342","author":"Kilpinen","year":"2013","journal-title":"Science"},{"key":"2023012712392737900_btx598-B18","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/nmeth.4298","article-title":"Allele-specific expression reveals interactions between genetic variation and environment","volume":"14","author":"Knowles","year":"2017","journal-title":"Nat. Methods"},{"key":"2023012712392737900_btx598-B19","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/ng.3467","article-title":"Fine-mapping cellular QTLs with RASQUAL and ATAC-seq","volume":"48","author":"Kumasaka","year":"2016","journal-title":"Nat. Genet"},{"key":"2023012712392737900_btx598-B20","article-title":"Fine-mapping cellular QTLs with RASQUAL and ATAC-seq","author":"Kumasaka","year":"2015","journal-title":"Nature Genet"},{"key":"2023012712392737900_btx598-B21","first-page":"19498","author":"Kwasnieski","year":"2012"},{"key":"2023012712392737900_btx598-B22","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1101\/gr.173518.114","article-title":"High-throughput functional testing of ENCODE segmentation predictions","volume":"24","author":"Kwasnieski","year":"2014","journal-title":"Genome Res"},{"key":"2023012712392737900_btx598-B23","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/nature12531","article-title":"Transcriptome and genome sequencing uncovers functional variation in humans","volume":"501","author":"Lappalainen","year":"2013","journal-title":"Nature"},{"key":"2023012712392737900_btx598-B24","author":"Lea","year":"2017"},{"key":"2023012712392737900_btx598-B25","first-page":"955","article-title":"A method to predict the impact of regulatory variants from DNA sequence","volume":"47","author":"Lee","year":"2015","journal-title":"Nature"},{"key":"2023012712392737900_btx598-B26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1000358","article-title":"Learning a prior on regulatory potential from eQTL data","volume":"5","author":"Lee","year":"2009","journal-title":"PLoS Genet"},{"key":"2023012712392737900_btx598-B27","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1038\/ng.3432","article-title":"Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo","volume":"47","author":"Maurano","year":"2015","journal-title":"Nat. Genet"},{"key":"2023012712392737900_btx598-B28","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/nbt.2137","article-title":"Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay","volume":"30","author":"Melnikov","year":"2012","journal-title":"Nat. Biotechnol"},{"key":"2023012712392737900_btx598-B29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1000072","article-title":"A genome-wide association study identifies protein quantitative trait loci (pQTLs)","volume":"4","author":"Melzer","year":"2008","journal-title":"PLoS Genet"},{"key":"2023012712392737900_btx598-B30","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1101\/gr.209759.116","article-title":"High-throughput allele-specific expression across 250 environmental conditions","volume":"26","author":"Moyerbrailean","year":"2016","journal-title":"Genome Res"},{"key":"2023012712392737900_btx598-B31","doi-asserted-by":"crossref","first-page":"e1005875","DOI":"10.1371\/journal.pgen.1005875","article-title":"Which genetics variants in DNase-seq footprints are more likely to alter binding?","volume":"12","author":"Moyerbrailean","year":"2016","journal-title":"PLoS Genet"},{"key":"2023012712392737900_btx598-B32","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nbt.2136","article-title":"Massively parallel functional dissection of mammalian enhancers in vivo","volume":"30","author":"Patwardhan","year":"2012","journal-title":"Nat. Biotechnol"},{"key":"2023012712392737900_btx598-B33","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.ajhg.2014.03.004","article-title":"Joint analysis of functional genomic data and genome-wide association studies of 18 human traits","volume":"94","author":"Pickrell","year":"2014","journal-title":"Am. J. Hum. Genet"},{"key":"2023012712392737900_btx598-B34","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1101\/gr.112623.110","article-title":"Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data","volume":"21","author":"Pique-Regi","year":"2011","journal-title":"Genome Res"},{"key":"2023012712392737900_btx598-B35","doi-asserted-by":"crossref","first-page":"9.","DOI":"10.1186\/s12920-015-0084-2","article-title":"ASEQ: fast allele-specific studies from next-generation sequencing data","volume":"8","author":"Romanel","year":"2015","journal-title":"BMC Med. Genomics"},{"key":"2023012712392737900_btx598-B36","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/nbt.2205","article-title":"Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters","volume":"30","author":"Sharon","year":"2012","journal-title":"Nat. Biotechnol"},{"key":"2023012712392737900_btx598-B37","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1101\/gr.119784.110","article-title":"A powerful and flexible statistical framework for testing hypotheses of allele-specific gene expression from RNA-seq data","volume":"21","author":"Skelly","year":"2011","journal-title":"Genome Res"},{"key":"2023012712392737900_btx598-B38","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/ng2142","article-title":"Population genomics of human gene expression","volume":"39","author":"Stranger","year":"2007","journal-title":"Nat. Genet"},{"key":"2023012712392737900_btx598-B39","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/j.cell.2016.04.027","article-title":"Direct identification of hundreds of expression-modulating variants using a multiplexed reporter assay","volume":"165","author":"Tewhey","year":"2016","journal-title":"Cell"},{"key":"2023012712392737900_btx598-B40","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1016\/j.cell.2016.04.048","article-title":"Systematic functional dissection of common genetic variation affecting red blood cell traits","volume":"165","author":"Ulirsch","year":"2016","journal-title":"Cell"},{"key":"2023012712392737900_btx598-B41","author":"van de Geijn","year":"2014"},{"key":"2023012712392737900_btx598-B42","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nmeth.3582","article-title":"WASP: allele-specific software for robust molecular quantitative trait locus discovery","volume":"12","author":"van de Geijn","year":"2015","journal-title":"Nat. Methods"},{"key":"2023012712392737900_btx598-B43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1000214","article-title":"High-resolution mapping of expression-QTLs yields insight into human gene regulation","volume":"4","author":"Veyrieras","year":"2008","journal-title":"PLoS Genet"},{"key":"2023012712392737900_btx598-B44","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1101\/gr.190090.115","article-title":"Massively parallel quantification of the regulatory effects of non-coding genetic variation in a human cohort","volume":"25","author":"Vockley","year":"2015","journal-title":"Genome Res"},{"key":"2023012712392737900_btx598-B45","first-page":"1","volume-title":"PLoS Genet","author":"Wen","year":"2015"},{"key":"2023012712392737900_btx598-B46","article-title":"Genomic inflation factors under polygenic inheritance","volume":"16","author":"Yang","year":"2011","journal-title":"Eur. J. Hum. Genet"},{"key":"2023012712392737900_btx598-B47","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nmeth.3547","article-title":"Predicting effects of noncoding variants with deep learningbased sequence model","volume":"12","author":"Zhou","year":"2015","journal-title":"Nat. Methods"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/34\/5\/787\/48913902\/bioinformatics_34_5_787.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/34\/5\/787\/48913902\/bioinformatics_34_5_787.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T22:24:56Z","timestamp":1719440696000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/34\/5\/787\/4209990"}},"subtitle":[],"editor":[{"given":"Oliver","family":"Stegle","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2017,9,22]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btx598","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/105627","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,3,1]]},"published":{"date-parts":[[2017,9,22]]}}}