{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T03:04:36Z","timestamp":1780110276929,"version":"3.54.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"17","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Studies of gene expression quantitative trait loci (eQTL) in different organisms have shown the existence of eQTL hot spots: each being a small segment of DNA sequence that harbors the eQTL of a large number of genes. Two questions of great interest about eQTL hot spots arise: (1) which gene within the hot spot is responsible for the linkages, i.e. which gene is the quantitative trait gene (QTG)? (2) How does a QTG affect the expression levels of many genes linked to it? Answers to the first question can be offered by available biological evidence or by statistical methods. The second question is harder to address. One simple situation is that the QTG encodes a transcription factor (TF), which regulates the expression of genes linked to it. However, previous results have shown that TFs are not overrepresented in the eQTL hot spots. In this article, we consider the scenario that the propagation of genetic perturbation from a QTG to other linked genes is mediated by the TF activity. We develop a procedure to detect the eQTL modules (eQTL hot spots together with linked genes) that are compatible with this scenario.<\/jats:p><jats:p>Results: We first detect 27 eQTL modules from a yeast eQTL data, and estimate TF activity profiles using the method of Yu and Li (2005). Then likelihood ratio tests (LRTs) are conducted to find 760 relationships supporting the scenario of TF activity mediation: (DNA polymorphism \u2192 cis-linked gene \u2192 TF activity \u2192 downstream linked gene). They are organized into 4 eQTL modules: an amino acid synthesis module featuring a cis-linked gene LEU2 and the mediating TF Leu3; a pheromone response module featuring a cis-linked gene GPA1 and the mediating TF Ste12; an energy-source control module featuring two cis-linked genes, GSY2 and HAP1, and the mediating TF Hap1; a mitotic exit module featuring four cis-linked genes, AMN1, CSH1, DEM1 and TOS1, and the mediating TF complex Ace2\/Swi5. Gene Ontology is utilized to reveal interesting functional groups of the downstream genes in each module.<\/jats:p><jats:p>Availability: Our methods are implemented in an R package: eqtl.TF, which includes source codes and relevant data. It can be freely downloaded at http:\/\/www.stat.ucla.edu\/~sunwei\/software.htm<\/jats:p><jats:p>Abbreviations: eQTL (expression Quantitative Trait Loci); TF (Transcription Factor); QTG (Quantitative Trait Gene); SNP (Single Nucleotide Polymorphism); FDR (False Discovery Rate); SGD (Saccharomyces Genome Database); LRT (Likelihood Ratio Test).<\/jats:p><jats:p>Contact: \u00a0kcli@stat.ucla.edu<\/jats:p><jats:p>Supplementary information: \u00a0http:\/\/www.stat.ucla.edu\/~sunwei\/yeast_eQTL_TF\/supplementary.pdf<\/jats:p>","DOI":"10.1093\/bioinformatics\/btm327","type":"journal-article","created":{"date-parts":[[2007,6,29]],"date-time":"2007-06-29T00:25:06Z","timestamp":1183076706000},"page":"2290-2297","source":"Crossref","is-referenced-by-count":28,"title":["Detection of eQTL modules mediated by activity levels of transcription factors"],"prefix":"10.1093","volume":"23","author":[{"given":"Wei","family":"Sun","sequence":"first","affiliation":[{"name":"1 Department of Statistics, University of California at Los Angeles, Los Angeles, California, 2Department of Biostatistics, Emory University, Atlanta, Georgia, USA and 3Institute of Statistical Science, Academia Sinica, Taipei, Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianwei","family":"Yu","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, University of California at Los Angeles, Los Angeles, California, 2Department of Biostatistics, Emory University, Atlanta, Georgia, USA and 3Institute of Statistical Science, Academia Sinica, Taipei, Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ker-Chau","family":"Li","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, University of California at Los Angeles, Los Angeles, California, 2Department of Biostatistics, Emory University, Atlanta, Georgia, USA and 3Institute of Statistical Science, Academia Sinica, Taipei, Taiwan, ROC"},{"name":"1 Department of Statistics, University of California at Los Angeles, Los Angeles, California, 2Department of Biostatistics, Emory University, Atlanta, Georgia, USA and 3Institute of Statistical Science, Academia Sinica, Taipei, Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2007,6,28]]},"reference":[{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"8059","DOI":"10.1016\/S0021-9258(17)39688-6","article-title":"Yeast LEU2. Repression of mRNA levels by leucine and primary structure of the gene product","volume":"259","author":"Andreadis","year":"1984","journal-title":"J. Bio. Chem"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene Ontology: tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nature Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1534\/genetics.105.041103","article-title":"Genetical genomics analysis of a yeast segregant population for transcription network inference","volume":"170","author":"Bing","year":"2005","journal-title":"Genetics"},{"key":"2023041105574890700_","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":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1073\/pnas.0408709102","article-title":"The landscape of genetic complexity across 5,700 gene expression traits in yeast","volume":"102","author":"Brem","year":"2005","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nature03865","article-title":"Genetic interactions between polymorphisms that affect gene expression in yeast","volume":"436","author":"Brem","year":"2005","journal-title":"Nature"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/ng1518","article-title":"Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function","volume":"37","author":"Chesler","year":"2005","journal-title":"Nat. Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1128\/MCB.16.4.1746","article-title":"Role of negative regulation in promoter specificity of the homologous transcriptional activators Ace2p and Swi5p","volume":"16","author":"Dohrmann","year":"1996","journal-title":"Mol. Cell. Biol"},{"key":"2023041105574890700_","first-page":"2690","article-title":"LEU3 of Saccharomyces cerevisiae activates multiple genes for branched-chain amino acid biosynthesis by binding to a common decanucleotide core sequence","volume":"8","author":"Friden","year":"1988","journal-title":"Mol. Cell. Biol"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S1097-2765(03)00307-1","article-title":"The yeast G protein alpha subunit Gpa1 transmits a signal through an RNA binding effector protein Scp160","volume":"12","author":"Guo","year":"2003","journal-title":"Mol. Cell"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature02800","article-title":"Transcriptional regulatory code of a eukaryotic genome","volume":"431","author":"Harbison","year":"2004","journal-title":"Nature"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/415180a","article-title":"Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry","volume":"415","author":"Ho","year":"2002","journal-title":"Nature"},{"key":"2023041105574890700_","article-title":"Saccharomyces Genome Database","author":"Hong","year":"2007"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1534\/genetics.104.037143","article-title":"The heme activator protein Hap1 represses transcription by a heme-independent mechanism in Saccharomyces cerevisiae","volume":"169","author":"Hon","year":"2005","journal-title":"Genetics"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/nature04670","article-title":"Global landscape of protein complexes in the yeast Saccharomyces cerevisiae","volume":"440","author":"Krogan","year":"2006","journal-title":"Nature"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/1471-2164-7-125","article-title":"Causal inference of regulator-target pairs by gene mapping of expression phenotypes","volume":"7","author":"Kulp","year":"2006","journal-title":"BMC Genomics"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"15522","DOI":"10.1073\/pnas.2136632100","article-title":"Network component analysis: reconstruction of regulatory signals in biological systems","volume":"100","author":"Liao","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nature02797","article-title":"Genetic analysis of genome-wide variation in human gene expression","volume":"430","author":"Morley","year":"2004","journal-title":"Nature"},{"key":"2023041105574890700_","first-page":"e172","article-title":"Heritability and tissue specificity of expression quantitative trait loci","volume":"2","author":"Petretto","year":"2006","journal-title":"Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0092-8674(89)90903-3","article-title":"Functional dissection and sequence of yeast HAP1 activator","volume":"56","author":"Pfeifer","year":"1989","journal-title":"Cell"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nrg1964","article-title":"Genetics of global gene expression","volume":"7","author":"Rockman","year":"2006","journal-title":"Nat. Rev. Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"e25","DOI":"10.1371\/journal.pgen.0010025","article-title":"Local regulatory variation in Saccharomyces cerevisiae","volume":"1","author":"Ronald","year":"2005","journal-title":"PLoS Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/ng1377","article-title":"Periodic gene expression program of the fission yeast cell cycle","volume":"36","author":"Rustici","year":"2005","journal-title":"Nat. Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nature01434","article-title":"Genetics of gene expression surveyed in maize, mouse and man","volume":"422","author":"Schadt","year":"2003","journal-title":"Nature"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/ng1589","article-title":"An integrative genomics approach to infer causal associations between gene expression and disease","volume":"37","author":"Schadt","year":"2005","journal-title":"Nat. Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1371\/journal.pgen.0010078","article-title":"Genome-wide asssociations of gene expression variation in humans","volume":"1","author":"Stranger","year":"2005","journal-title":"PLoS Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1002\/yea.739","article-title":"Yeast 14-3-3 proteins","volume":"18","author":"van Hemert","year":"2001","journal-title":"Yeast"},{"key":"2023041105574890700_","first-page":"254","article-title":"Gene networks as a tool to understand transcriptional regulation","volume":"5","author":"Veiga","year":"2006","journal-title":"Genet. Mol. Res"},{"key":"2023041105574890700_","first-page":"347","article-title":"No amplifications of hypoxia-inducible factor-1alpha gene in invasive breast cancer: a tissue microarray study","volume":"26","author":"Vleugel","year":"2004","journal-title":"Cell. Oncol"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"307","DOI":"10.2307\/1912557","article-title":"Likelihood ratio test for model selection and non-nested hypotheses","volume":"57","author":"Vuong","year":"1989","journal-title":"Econometrica"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1126\/science.1104568","article-title":"Pheromone signaling mechanisms in yeast: a prototypical sex machine","volume":"306","author":"Wang","year":"2004","journal-title":"Science"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1371\/journal.pgen.0020015","article-title":"Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity","volume":"2","author":"Wang","year":"2006","journal-title":"PLoS Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0092-8674(03)00121-1","article-title":"Exit from exit: resetting the cell cycle through Amn1 inhibition of G protein signaling","volume":"112","author":"Wang","year":"2003","journal-title":"Cell"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"4033","DOI":"10.1093\/bioinformatics\/bti656","article-title":"Inference of transcriptional regulatory network by two-stage constrained space factor analysis","volume":"21","author":"Yu","year":"2005","journal-title":"Bioinformatics"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/ng1222","article-title":"Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors","volume":"35","author":"Yvert","year":"2003","journal-title":"Nat. Genet"},{"key":"2023041105574890700_","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1159\/000078209","article-title":"An integrative genomics approach to the reconstruction of gene networks in segregating populations","volume":"105","author":"Zhu","year":"2004","journal-title":"Cytogenet. Genome Res"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/23\/17\/2290\/49816653\/bioinformatics_23_17_2290.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/23\/17\/2290\/49816653\/bioinformatics_23_17_2290.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T18:53:23Z","timestamp":1683917603000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/23\/17\/2290\/261204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,6,28]]},"references-count":36,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2007,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btm327","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2007,9,1]]},"published":{"date-parts":[[2007,6,28]]}}}