RESEARCH Exploring the relationship between polymorphic (TG/CA)n repeats in intron 1 regions and gene expression Wei Zhang,1 Lijun He,1 Wanqing Liu,1 Chang Sun2 and Mark J. Ratain1,3,4* 1Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA 2Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA 3Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL 60637, USA 4Cancer Research Center, University of Chicago, Chicago, IL 60637, USA *Correspondence to: Tel: þ1: 773 702 4400; Fax: þ1 773 702 3969; E-mail: mratain@medicine.bsd.uchicago.edu Date received (in revised form): 6th January, 2009 Abstract The putative role of (TG/CA)n repeats in the regulation of transcription has recently been reported for several cancer- and disease-related genes, including the genes encoding the epidermal growth factor receptor (EGFR), hydroxysteroid (11-beta) dehydrogenase 2 (HSD11B2) and interferon-gamma (IFNG). These studies indicated a correlation between gene expression levels and the presence or length of (TG/CA)n repeats in their intron 1 regions. A genome-wide search for genes with similar features may provide evidence of whether these dinucleo- tide repeats represent a class of universal regulators of gene expression, which has recently begun to be investi- gated as a quantitative complex phenotype. Using a public database of simple repeats, we identiﬁed 330 genes containing potentially polymorphic long (TG/CA)n repeats (n 12) in their intron 1 regions. One known physio- logical pathway, the calcium signalling pathway, was found to be enriched among the genes containing long repeats. In addition, certain biological processes, such as cation transport, signal transduction and ion transport, were found to be enriched in these genes. Genotyping of the long repeats showed that the majority of these dinucleotide repeats were polymorphic in the HapMap CEU (Caucasians from Utah, USA) samples of northern and western European ancestry. Evidence for a signiﬁcant association between these repeats and gene expression was not observed in the genes selected based on their expression proﬁles in the HapMap CEU samples. Our current ﬁndings, therefore, do not support a role for these repeats as a class of universal gene expression regulators. A more comprehensive evaluation of the relationship between these repeats and gene expression, potentially in other tissues, may be necessary to illustrate their roles in gene regulation in the future. Keywords: CA repeat, intron, polymorphism, gene expression, pathway Introduction Microsatellite sequences that consist of repeating units of two to ﬁve base pairs with different lengths and complexities are dispersed along the human genome and exhibit extensive length polymorph- ism, a feature widely used in genetic mapping.1– 3 Among the dinucleotide repeats, (TG/CA)n (CA-) repeats represent the most common class of micro- satellites in vertebrates, including humans.4 Because of their structure of alternating purine/pyrimidine sequences, CA- repeats have a tendency to form Z-DNA under physiological conditions, sug- gesting a possible role for such Z elements in chromatin activation or genome rearrangements.5 236 # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 3. NO. 3. 236–245 APRIL 2009