{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:34:40Z","timestamp":1772138080476,"version":"3.50.1"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"4","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Motivation: The majority of disease-associated variants identified in genome-wide association studies reside in noncoding regions of the genome with regulatory roles. Thus being able to interpret the functional consequence of a variant is essential for identifying causal variants in the analysis of genome-wide association studies.<\/jats:p>\n                  <jats:p>Results: We present GERV (generative evaluation of regulatory variants), a novel computational method for predicting regulatory variants that affect transcription factor binding. GERV learns a k-mer-based generative model of transcription factor binding from ChIP-seq and DNase-seq data, and scores variants by computing the change of predicted ChIP-seq reads between the reference and alternate allele. The k-mers learned by GERV capture more sequence determinants of transcription factor binding than a motif-based approach alone, including both a transcription factor\u2019s canonical motif and associated co-factor motifs. We show that GERV outperforms existing methods in predicting single-nucleotide polymorphisms associated with allele-specific binding. GERV correctly predicts a validated causal variant among linked single-nucleotide polymorphisms and prioritizes the variants previously reported to modulate the binding of FOXA1 in breast cancer cell lines. Thus, GERV provides a powerful approach for functionally annotating and prioritizing causal variants for experimental follow-up analysis.<\/jats:p>\n                  <jats:p>Availability and implementation: The implementation of GERV and related data are available at http:\/\/gerv.csail.mit.edu\/.<\/jats:p>\n                  <jats:p>Contact: \u00a0gifford@mit.edu<\/jats:p>\n                  <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btv565","type":"journal-article","created":{"date-parts":[[2015,10,17]],"date-time":"2015-10-17T21:38:30Z","timestamp":1445117910000},"page":"490-496","source":"Crossref","is-referenced-by-count":40,"title":["GERV: a statistical method for generative evaluation of regulatory variants for transcription factor binding"],"prefix":"10.1093","volume":"32","author":[{"given":"Haoyang","family":"Zeng","sequence":"first","affiliation":[{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02142, USA and"}]},{"given":"Tatsunori","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02142, USA and"}]},{"given":"Daniel D.","family":"Kang","sequence":"additional","affiliation":[{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02142, USA and"}]},{"given":"David K.","family":"Gifford","sequence":"additional","affiliation":[{"name":"1 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02142, USA and"},{"name":"2 Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, Cambridge, MA 02138, USA"}]}],"member":"286","published-online":{"date-parts":[[2015,10,17]]},"reference":[{"key":"2023020110321795800_btv565-B1","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1371\/journal.pcbi.0040005","article-title":"In silico detection of sequence variations modifying transcriptional regulation","volume":"4","author":"Andersen","year":"2008","journal-title":"PLoS Comput. Biol."},{"key":"2023020110321795800_btv565-B2","doi-asserted-by":"crossref","first-page":"7605","DOI":"10.4049\/jimmunol.179.11.7605","article-title":"Peptide-mediated disruption of NFkappaB\/NRF interaction inhibits IL-8 gene activation by IL-1 or Helicobacter pylori","volume":"179","author":"Bartels","year":"2007","journal-title":"J. Immunol."},{"key":"2023020110321795800_btv565-B3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cell.2005.05.008","article-title":"Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1","volume":"122","author":"Carroll","year":"2005","journal-title":"Cell"},{"key":"2023020110321795800_btv565-B4","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/ng1901","article-title":"Genome-wide analysis of estrogen receptor binding sites","volume":"38","author":"Carroll","year":"2006","journal-title":"Nat. Genet."},{"key":"2023020110321795800_btv565-B5","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1038\/ng.2416","article-title":"Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression","volume":"44","author":"Cowper-Sal Lari","year":"2012","journal-title":"Nat. Genet."},{"key":"2023020110321795800_btv565-B6","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1101\/gad.1446006","article-title":"A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer","volume":"20","author":"Eeckhoute","year":"2006","journal-title":"Genes Dev."},{"key":"2023020110321795800_btv565-B7","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nrg2554","article-title":"Human genetic variation and its contribution to complex traits","volume":"10","author":"Frazer","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"2023020110321795800_btv565-B8","first-page":"7806","article-title":"NF-\u03baB and AP-1 connection: mechanism of NF- \u03ba B-dependent regulation of AP-1 activity","volume":"24","author":"Fujioka","year":"2004","journal-title":"Society"},{"key":"2023020110321795800_btv565-B9","doi-asserted-by":"crossref","first-page":"e1003711","DOI":"10.1371\/journal.pcbi.1003711","article-title":"Enhanced regulatory sequence prediction using gapped k-mer features","volume":"10","author":"Ghandi","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2023020110321795800_btv565-B10","doi-asserted-by":"crossref","first-page":"e1002638","DOI":"10.1371\/journal.pcbi.1002638","article-title":"High resolution genome wide binding event finding and motif discovery reveals transcription factor spatial binding constraints","volume":"8","author":"Guo","year":"2012","journal-title":"PLoS Comput. Biol."},{"key":"2023020110321795800_btv565-B11","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/ng.545","article-title":"Nucleosome dynamics define transcriptional enhancers","volume":"42","author":"He","year":"2010","journal-title":"Nat. Genet."},{"key":"2023020110321795800_btv565-B12","doi-asserted-by":"crossref","first-page":"9362","DOI":"10.1073\/pnas.0903103106","article-title":"Potential etiologic and functional implications of genome-wide association loci for human diseases and traits","volume":"106","author":"Hindorff","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023020110321795800_btv565-B13","doi-asserted-by":"crossref","first-page":"9607","DOI":"10.1073\/pnas.1219099110","article-title":"Systematic functional regulatory assessment of disease-associated variants","volume":"110","author":"Karczewski","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023020110321795800_btv565-B14","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/ng.3331","article-title":"A method to predict the impact of regulatory variants from DNA sequence","volume":"47","author":"Lee","year":"2015","journal-title":"Nat. Genet."},{"key":"2023020110321795800_btv565-B15","doi-asserted-by":"crossref","first-page":"e1001002","DOI":"10.1371\/journal.pgen.1001002","article-title":"Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium","volume":"6","author":"Long","year":"2010","journal-title":"PLoS Genet."},{"key":"2023020110321795800_btv565-B16","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.cell.2008.01.018","article-title":"FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription","volume":"132","author":"Lupien","year":"2008","journal-title":"Cell"},{"key":"2023020110321795800_btv565-B17","doi-asserted-by":"crossref","first-page":"i524","DOI":"10.1093\/bioinformatics\/btq378","article-title":"is-rSNP: a novel technique for in silico regulatory SNP detection","volume":"26","author":"Macintyre","year":"2010","journal-title":"Bioinformatics"},{"key":"2023020110321795800_btv565-B18","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1093\/nar\/gkm272","article-title":"STAMP: a web tool for exploring DNA-binding motif similarities","volume":"35","author":"Mahony","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2023020110321795800_btv565-B19","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1002\/humu.21209","article-title":"Quantifying the effect of sequence variation on regulatory interactions","volume":"31","author":"Manke","year":"2010","journal-title":"Hum. Mutat."},{"key":"2023020110321795800_btv565-B20","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1056\/NEJMra0905980","article-title":"Genomewide association studies and assessment of the risk of disease","volume":"363","author":"Manolio","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"2023020110321795800_btv565-B21","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nrg2344","article-title":"Genome-wide association studies for complex traits: consensus, uncertainty and challenges","volume":"9","author":"McCarthy","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"2023020110321795800_btv565-B22","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/humu.22299","article-title":"Identification of functional cis-regulatory polymorphisms in the human genome","volume":"34","author":"Molineris","year":"2013","journal-title":"Hum. Mut."},{"key":"2023020110321795800_btv565-B23","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2023020110321795800_btv565-B24","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1186\/1471-2164-13-S4-S7","article-title":"Large-scale computational identification of regulatory SNPs with rSNP-MAPPER","volume":"13","author":"Riva","year":"2012","journal-title":"BMC Genomics"},{"key":"2023020110321795800_btv565-B25","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/msb.2011.54","article-title":"AlleleSeq: analysis of allele-specific expression and binding in a network framework","volume":"7","author":"Rozowsky","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"2023020110321795800_btv565-B26","doi-asserted-by":"crossref","first-page":"3632","DOI":"10.1128\/JVI.00599-07","article-title":"IRF-1 is required for full NF-kappaB transcriptional activity at the human immunodeficiency virus type 1 long terminal repeat enhancer","volume":"82","author":"Sgarbanti","year":"2008","journal-title":"J. Virol."},{"key":"2023020110321795800_btv565-B27","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1534\/genetics.110.120907","article-title":"Progress and promise of genome-wide association studies for human complex trait genetics","volume":"187","author":"Stranger","year":"2011","journal-title":"Genetics"},{"key":"2023020110321795800_btv565-B28","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1093\/bioinformatics\/bts275","article-title":"Regsnps: a strategy for prioritizing regulatory single nucleotide substitutions","volume":"28","author":"Teng","year":"2012","journal-title":"Bioinformatics"},{"key":"2023020110321795800_btv565-B29","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1038\/sj.onc.1201125","article-title":"ETS1, NFkappaB and AP1 synergistically transactivate the human GM-CSF promoter","volume":"14","author":"Thomas","year":"1997","journal-title":"Oncogene"},{"key":"2023020110321795800_btv565-B30","doi-asserted-by":"crossref","first-page":"D930","DOI":"10.1093\/nar\/gkr917","article-title":"HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants","volume":"40","author":"Ward","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023020110321795800_btv565-B31","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1038\/nbt.2422","article-title":"Interpreting noncoding genetic variation in complex traits and human disease","volume":"30","author":"Ward","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"2023020110321795800_btv565-B32","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1093\/bioinformatics\/btv328","article-title":"atSNP: transcription factor binding affinity testing for regulatory SNP detection","volume":"31","author":"Zuo","year":"2015","journal-title":"Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/4\/490\/49017474\/bioinformatics_32_4_490.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/4\/490\/49017474\/bioinformatics_32_4_490.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T16:54:20Z","timestamp":1675270460000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/32\/4\/490\/1743515"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,17]]},"references-count":32,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2016,2,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btv565","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/017392","asserted-by":"object"}]},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,2,15]]},"published":{"date-parts":[[2015,10,17]]}}}