Human Molecular Genetics, 2003, Vol. 12, No. 3 205-216
© 2003 Oxford University Press
Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor
1Schizophrenia Genetics Research Program, Department of Psychiatry, The University of Chicago, Jules F. Knapp Medical Research Center, Chicago, IL 60637, USA, 2Division of Pediatric Neurology, Northwestern University Medical School, Children's Memorial Hospital, Chicago, IL 60614, USA, 3Department of Biological Sciences, Center for Comparative Genomics, University of Iowa, Iowa City, IA 52242, USA, 4Division of Population Genetics, National Institute of Genetics, Mishima, Japan and 5Department of Psychiatry, Yale University School of Medicine, West Haven, CT 06516, USA
Received August 15, 2002; Accepted November 19, 2002
Although changes in nucleotide sequence affecting the composition and the structure of proteins are well known, functional changes resulting from nucleotide substitutions cannot always be inferred from simple analysis of DNA sequence. Because a strong synonymous codon usage bias in the human DRD2 gene, suggesting selection on synonymous positions, was revealed by the relative independence of the G+C content of the third codon positions from the isochoric G+C frequencies, we chose to investigate functional effects of the six known naturally occurring synonymous changes (C132T, G423A, T765C, C939T, C957T, and G1101A) in the human DRD2. We report here that some synonymous mutations in the human DRD2 have functional effects and suggest a novel genetic mechanism. 957T, rather than being ‘silent’, altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed dopamine-induced up-regulation of DRD2 expression. 1101A did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1101A, demonstrating that combinations of synonymous mutations can have functional consequences drastically different from those of each isolated mutation. C957T was found to be in linkage disequilibrium in a European-American population with the -141C Ins/Del and TaqI ‘A’ variants, which have been reported to be associated with schizophrenia and alcoholism, respectively. These results call into question some assumptions made about synonymous variation in molecular population genetics and gene-mapping studies of diseases with complex inheritance, and indicate that synonymous variation can have effects of potential pathophysiological and pharmacogenetic importance.
* To whom correspondence should be addressed at: Schizophrenia Genetics Research Program, Department of Psychiatry, The University of Chicago, Jules F. Knapp Medical Research Center, 924 East 57th Street, Room R-010, Chicago, IL 60637, USA; Tel: +1 7738343060; Fax: +1 7738342970. Email: pgejman{at}delphi.bsd.uchicgao.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. L. Bauer DuMont, N. D. Singh, M. H. Wright, and C. F. Aquadro Locus-Specific Decoupling of Base Composition Evolution at Synonymous Sites and Introns along the Drosophila melanogaster and Drosophila sechellia Lineages Gen Biol Evol, June 22, 2009; 2009(0): 67 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. G. Johnson, P. D. Sherrington, A. Carter, K. Lin, T. Liloglou, J. K. Field, and A. R. Pettitt A Novel Type of p53 Pathway Dysfunction in Chronic Lymphocytic Leukemia Resulting from Two Interacting Single Nucleotide Polymorphisms within the p21 Gene Cancer Res., June 15, 2009; 69(12): 5210 - 5217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Psychiatric GWAS Consortium Coordinating Committee Genomewide Association Studies: History, Rationale, and Prospects for Psychiatric Disorders Am J Psychiatry, May 1, 2009; 166(5): 540 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kudla, A. W. Murray, D. Tollervey, and J. B. Plotkin Coding-Sequence Determinants of Gene Expression in Escherichia coli Science, April 10, 2009; 324(5924): 255 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Beuten, J. A.L. Gelfond, J. J. Byrne, I. Balic, A. C. Crandall, T. L. Johnson-Pais, I. M. Thompson, D. K. Price, and R. J. Leach CYP1B1 variants are associated with prostate cancer in non-Hispanic and Hispanic Caucasians Carcinogenesis, September 1, 2008; 29(9): 1751 - 1757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ponce, J. Hoenicka, M. A. Jimenez-Arriero, R. Rodriguez-Jimenez, M. Aragues, N. Martin-Sune, E. Huertas, and T. Palomo DRD2 and ANKK1 genotype in alcohol-dependent patients with psychopathic traits: association and interaction study The British Journal of Psychiatry, August 1, 2008; 193(2): 121 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-M. Brand-Herrmann Where Do We Go for Atherothrombotic Disease Genetics? Stroke, April 1, 2008; 39(4): 1070 - 1075. [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Lehnerdt, P. Franz, A. Zaqoul, K. J. Schmitz, S. Grehl, S. Lang, K. W. Schmid, W. Siffert, K. Jahnke, and U. H. Frey Overall and Relapse-Free Survival in Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma Are Associated with Genotypes of T393C Polymorphism of the GNAS1 Gene Clin. Cancer Res., March 15, 2008; 14(6): 1753 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, A. Bertolino, L. Fazio, G. Blasi, A. Rampino, R. Romano, M.-L. T. Lee, T. Xiao, A. Papp, D. Wang, et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory PNAS, December 18, 2007; 104(51): 20552 - 20557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-Z. Yang, H. R. Kranzler, H. Zhao, J. R. Gruen, X. Luo, and J. Gelernter Association of haplotypic variants in DRD2, ANKK1, TTC12 and NCAM1 to alcohol dependence in independent case control and family samples Hum. Mol. Genet., December 1, 2007; 16(23): 2844 - 2853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ghoussaini, V. Vatin, C. Lecoeur, V. Abkevich, A. Younus, C. Samson, C. Wachter, B. Heude, M. Tauber, P. Tounian, et al. Genetic Study of the Melanin-Concentrating Hormone Receptor 2 in Childhood and Adulthood Severe Obesity J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4403 - 4409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Frank, A. A. Moustafa, H. M. Haughey, T. Curran, and K. E. Hutchison Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning PNAS, October 9, 2007; 104(41): 16311 - 16316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Rexrode, P. M. Ridker, H. H. Hegener, J. E. Buring, J. E. Manson, and R. Y.L. Zee Polymorphisms and Haplotypes of the Estrogen Receptor-{beta} Gene (ESR2) and Cardiovascular Disease in Men and Women Clin. Chem., October 1, 2007; 53(10): 1749 - 1756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Thorleifsson, K. P. Magnusson, P. Sulem, G. B. Walters, D. F. Gudbjartsson, H. Stefansson, T. Jonsson, A. Jonasdottir, A. Jonasdottir, G. Stefansdottir, et al. Common Sequence Variants in the LOXL1 Gene Confer Susceptibility to Exfoliation Glaucoma Science, September 7, 2007; 317(5843): 1397 - 1400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E Fidler, K. van Oers, P. J Drent, S. Kuhn, J. C Mueller, and B. Kempenaers Drd4 gene polymorphisms are associated with personality variation in a passerine bird Proc R Soc B, July 22, 2007; 274(1619): 1685 - 1691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhou, J. G. H. Hickford, Q. Fang, and S. O. Byun Short Communication: Identification of Allelic Variation at the Bovine DRA Locus by Polymerase Chain Reaction-Single Strand Conformational Polymorphism J Dairy Sci, April 1, 2007; 90(4): 1943 - 1946. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Armando, X. Wang, V. A. M. Villar, J. E. Jones, L. D. Asico, C. Escano, and P. A. Jose Reactive Oxygen Species-Dependent Hypertension in Dopamine D2 Receptor-Deficient Mice Hypertension, March 1, 2007; 49(3): 672 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tanaka, H. Hirata, Z. Chen, N. Kikuno, K. Kawamoto, S. Majid, T. Tokizane, S. Urakami, H. Shiina, K. Nakajima, et al. Polymorphisms of Catechol-O-Methyltransferase in Men with Renal Cell Cancer Cancer Epidemiol. Biomarkers Prev., January 1, 2007; 16(1): 92 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Nackley, S. A. Shabalina, I. E. Tchivileva, K. Satterfield, O. Korchynskyi, S. S. Makarov, W. Maixner, and L. Diatchenko Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure Science, December 22, 2006; 314(5807): 1930 - 1933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gelernter, Y. Yu, R. Weiss, K. Brady, C. Panhuysen, B.-z. Yang, H. R. Kranzler, and L. Farrer Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations Hum. Mol. Genet., December 15, 2006; 15(24): 3498 - 3507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bhatti, D. M. Church, J. L. Rutter, J. P. Struewing, and A. J. Sigurdson Candidate Single Nucleotide Polymorphism Selection using Publicly Available Tools: A Guide for Epidemiologists Am. J. Epidemiol., October 15, 2006; 164(8): 794 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Meletiadis, S. Chanock, and T. J. Walsh Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy Clin. Microbiol. Rev., October 1, 2006; 19(4): 763 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Cebrian, P. D. Pharoah, S. Ahmed, S. Ropero, M. F. Fraga, P. L. Smith, D. Conroy, R. Luben, B. Perkins, D. F. Easton, et al. Genetic variants in epigenetic genes and breast cancer risk Carcinogenesis, August 1, 2006; 27(8): 1661 - 1669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Schattner and M. Diekhans Regions of extreme synonymous codon selection in mammalian genes Nucleic Acids Res., March 23, 2006; 34(6): 1700 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Parmley, J. V. Chamary, and L. D. Hurst Evidence for Purifying Selection Against Synonymous Mutations in Mammalian Exonic Splicing Enhancers Mol. Biol. Evol., February 1, 2006; 23(2): 301 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Lesueur, A. Cebrian, M. Robledo, P. Niccoli-Sire, K.-A. Svensson, S. Pinson, J. Leyland, J. Whittaker, P. D. Pharoah, and B. A.J. Ponder Polymorphisms in RET and Its Coreceptors and Ligands as Genetic Modifiers of Multiple Endocrine Neoplasia Type 2A Cancer Res., January 15, 2006; 66(2): 1177 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Shabalina, A. Y. Ogurtsov, and N. A. Spiridonov A periodic pattern of mRNA secondary structure created by the genetic code. Nucleic Acids Res., January 1, 2006; 34(8): 2428 - 2437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P K Lovelock, S Healey, W Au, E Y M Sum, A Tesoriero, E M Wong, S Hinson, R Brinkworth, A Bekessy, O Diez, et al. Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants J. Med. Genet., January 1, 2006; 43(1): 74 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Comeron and T. B. Guthrie Intragenic Hill-Robertson Interference Influences Selection Intensity on Synonymous Mutations in Drosophila Mol. Biol. Evol., December 1, 2005; 22(12): 2519 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Sadee and Z. Dai Pharmacogenetics/genomics and personalized medicine Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R207 - R214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, D. Wang, A. D. Johnson, A. C. Papp, and W. Sadee Allelic Expression Imbalance of Human mu Opioid Receptor (OPRM1) Caused by Variant A118G J. Biol. Chem., September 23, 2005; 280(38): 32618 - 32624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Vallet, B. A. Freking, K. A. Leymaster, and R. K. Christenson Allelic variation in the secreted folate binding protein gene is associated with uterine capacity in swine J Anim Sci, August 1, 2005; 83(8): 1860 - 1867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. H. Frey, H. Alakus, J. Wohlschlaeger, K. J. Schmitz, G. Winde, H. G. van Calker, K.-H. Jockel, W. Siffert, and K. W. Schmid GNAS1 T393C Polymorphism and Survival in Patients with Sporadic Colorectal Cancer Clin. Cancer Res., July 15, 2005; 11(14): 5071 - 5077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gemignani, S. Landi, V. Moreno, L. Gioia-Patricola, A. Chabrier, E. Guino, M. Navarro, M. Cambray, G. Capella, F. Canzian, et al. Polymorphisms of the Dopamine Receptor Gene DRD2 and Colorectal Cancer Risk Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1633 - 1638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Webb and J. Zhang FoxP2 in Song-Learning Birds and Vocal-Learning Mammals J. Hered., May 1, 2005; 96(3): 212 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. H. Frey, A. Eisenhardt, G. Lummen, H. Rubben, K.-H. Jockel, K. W. Schmid, and W. Siffert The T393C Polymorphism of the G{alpha}s Gene (GNAS1) Is a Novel Prognostic Marker in Bladder Cancer Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 871 - 877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Burwinkel, M. Wirtenberger, R. Klaes, R. K. Schmutzler, E. Grzybowska, A. Forsti, B. Frank, J. L. Bermejo, P. Bugert, B. Wappenschmidt, et al. Association of NCOA3 Polymorphisms with Breast Cancer Risk Clin. Cancer Res., March 15, 2005; 11(6): 2169 - 2174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Kreek, G. Bart, C. Lilly, K. S. Laforge, and D. A. Nielsen Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments Pharmacol. Rev., March 1, 2005; 57(1): 1 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Diatchenko, G. D. Slade, A. G. Nackley, K. Bhalang, A. Sigurdsson, I. Belfer, D. Goldman, K. Xu, S. A. Shabalina, D. Shagin, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition Hum. Mol. Genet., January 1, 2005; 14(1): 135 - 143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Capon, M. H. Allen, M. Ameen, A. D. Burden, D. Tillman, J. N. Barker, and R. C. Trembath A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups Hum. Mol. Genet., October 1, 2004; 13(20): 2361 - 2368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. McD. YOUNG, B. R. LAWFORD, M. BARNES, S. C. BURTON, T. RITCHIE, W. K. WARD, and E. P. NOBLE Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele The British Journal of Psychiatry, August 1, 2004; 185(2): 147 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Mas, N Taske, S Deutsch, M Guipponi, P Thomas, A Covanis, M Friis, M J Kjeldsen, G P Pizzolato, J-G Villemure, et al. Association of the connexin36 gene with juvenile myoclonic epilepsy J. Med. Genet., July 1, 2004; 41(7): e93 - e93. [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Comeron Selective and Mutational Patterns Associated With Gene Expression in Humans: Influences on Synonymous Composition and Intron Presence Genetics, July 1, 2004; 167(3): 1293 - 1304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-V. Chamary and L. D. Hurst Similar Rates but Different Modes of Sequence Evolution in Introns and at Exonic Silent Sites in Rodents: Evidence for Selectively Driven Codon Usage Mol. Biol. Evol., June 1, 2004; 21(6): 1014 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. B. DuMont, J. C. Fay, P. P. Calabrese, and C. F. Aquadro DNA Variability and Divergence at the Notch Locus in Drosophila melanogaster and D. simulans: A Case of Accelerated Synonymous Site Divergence Genetics, May 1, 2004; 167(1): 171 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wacholder, S. Chanock, M. Garcia-Closas, L. El ghormli, and N. Rothman Assessing the Probability That a Positive Report is False: An Approach for Molecular Epidemiology Studies J Natl Cancer Inst, March 17, 2004; 96(6): 434 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. W. Harries, A. T. Hattersley, and S. Ellard Messenger RNA Transcripts of the Hepatocyte Nuclear Factor-1{alpha} Gene Containing Premature Termination Codons Are Subject to Nonsense-Mediated Decay Diabetes, February 1, 2004; 53(2): 500 - 504. [Abstract] [Full Text]
|
|