title: Functional consequences of genetic variation in primates on tyrosine hydroxylase (TH) expression in vitro.
abstract: Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, is known to contain naturally occurring genetic variation in it's promoter region that associates with a number of neuropsychological disorders. As such, examining non-coding regions is important for understanding tyrosine hydroxylase function in human health and disease. We examined approximately 2 kb upstream of the translation start site within humans and non-human primates to obtain a fine resolution map of evolutionarily and functionally relevant cis-regulatory differences. Our study investigated Macaca mulatta, Pan troglodytes, Gorilla gorilla, and Homo sapiens haplotypes using transient dual-luciferase transfection in three neuroblastoma cell lines to assay the impact of naturally occurring sequence variation on expression level. In addition to trans effects between cell lines, there are several significant expression differences between primate species, but the most striking difference was seen between human haplotypes in one cell line. Underlying this variation are numerous sequence polymorphisms, two of which influence expression within humans in a non-additive and cell line-specific manner. This study highlights functional consequences of tyrosine hydroxylase genetic variation in primates. Additionally, the results emphasize the importance of examining more than one cell line, the existence of multiple functional variants in a given promoter region and the presence of non-additive cis-interactions.
authors: Institute for Genome Sciences & Policy, Duke University, Durham 27708, USA; Department of Biology, Duke University, Durham 27708, USA. lisa.r.warner@duke.edu
authors: Lisa R
authors: LR
authors: Warner
authors: Courtney C
authors: CC
authors: Babbitt
authors: Alex E
authors: AE
authors: Primus
authors: Tonya F
authors: TF
authors: Severson
authors: Ralph
authors: R
authors: Haygood
authors: Gregory A
authors: GA
authors: Wray
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006071:Gorilla gorilla; D006239:Haplotypes; D006801:Humans; D008253:Macaca mulatta; D009474:Neurons / Q000502:physiology; D002679:Pan troglodytes; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
chemical_list: D014446:Tyrosine 3-Monooxygenase