Neurochemical Research

, Volume 28, Issue 1, pp 73–82 | Cite as

Association of Seven Polymorphisms of the D2 Dopamine Receptor Gene with Brain Receptor-Binding Characteristics

Article

Abstract

Association of alleles at the Taql A, Taql B, intron 6, Taql D, exon 7, exon 8, and promoter-141C sites of the D2 dopamine receptor gene with D2 dopamine receptor binding characteristics in the caudate nucleus of Caucasian alcoholic and nonalcoholic subjects was determined. For the Taql D, exon 7, exon 8, and promoter-141C sites there were no significant allelic differences in Bmax (number of binding sites) or Kd (binding affinity) of the D2 dopamine receptors. However, subjects having the minor alleles at the Taql A, Taql B, and intron 6 sites had significantly lower Bmax than subjects not having them. None of these three polymorphisms had any significant effect on Kd. Highly significant linkage disequilibria were observed among the Taql A, Taql B, and intron 6 polymorphic sites, but linkage disequilibria between these three sites and each of the Taql D, exon 7, exon 8, and promoter-141C sites were of lesser or of no significance. Taken together, these findings suggest that the Taql A, Taql B, and intron 6 polymorphisms, but not the Taql D, exon 7, exon 8, and promoter-141C polymorphisms, are in linkage disequilibrium with a functional allelic variant that affects D2 dopamine receptor expression.

D2 dopamine receptor gene D2 dopamine receptor binding polymorphism alcoholism linkage disequilibrium allelic association 

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REFERENCES

  1. 1.
    Koob, Y. and LeMoal, M. 1997. Drug abuse: Hedonic homeostatic dysregulation. Science 278:52–58.Google Scholar
  2. 2.
    Tanda, G., Pontieri, F. E., and Di Chiara, G. 1997. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common μl opioid receptor mechanism. Science 276:2048–2050.Google Scholar
  3. 3.
    Blum, K., Noble, E. P., Sheridan, P. J., Montgomery, A., Ritchie, T., Jagadeeswaren, P., Nogami, H., Briggs, A. H., and Cohn, J. B. 1990. Allelic association of the human dopamine D2 receptor gene in alcoholism. J. Am. Med. Assoc. 263:2055-2060.Google Scholar
  4. 4.
    Amadéo, S., Abbar, M., Fourcade, M. L., Waksman, G., Leroux, M. G., Medec, A., Selin, M., Champiat, J.-C., Brethome, A., Leclair, Y., Castelnau, D., Venisse, J.-L., and Mallet, J. 1993. D2 dopamine receptor gene and alcoholism. J. Psychiatr. Res. 27:173-179.Google Scholar
  5. 5.
    Blum, K., Noble, E. P., Sheridan, P. J., Finley, O., Montgomery, A., Ritchie, T., Ozkaragoz, T., Fitch, R. J., Sadlack, F., Sheffield, D., Dahlmann, T., Halbardier, S., and Nogami, H. 1991. Association of the A1 allele of the human D2 dopamine receptor gene with severe alcoholism. Alcohol 8:409–416.Google Scholar
  6. 6.
    Comings, D. E., Comings, B. G., Muhleman, D., Dietz, G., Shahbahrami, B., Tast, D., Knell, E., Kocsis, P., Baumgarten, R., Kovacs, B. W., Levy, D. L., Smith, M., Borison, R. L., Evans, D. D., Klein, D. N., MacMurray, J., Tosk, J. F., Sverd, J., Gysin, R., and Flanagan, S. D. 1991. The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. J. Am. Med. Assoc. 266:1793–1800.Google Scholar
  7. 7.
    Hietala, J., Pohjalainen, T., Heikkila-Kallio, U., West, C., Salaspuro, M., and Syvälahti, E. 1997. Allelic association between D2 but not D1 dopamine receptor gene and alcoholism in Finland. Psychiat. Genet. 7:19–25.Google Scholar
  8. 8.
    Lawford, B. R., Young, R. M., Rowell, J. A., Gibson, J. N., Feeney, G. F. X., Ritchie, T. L., Syndulko, K., and Noble, E. P. 1997. Association of the D2 dopamine receptor A1 allele with alcoholism: Medical severity of alcoholism and type of controls. Biol. Psychiatry 41:386–393.Google Scholar
  9. 9.
    Neiswanger, K., Hill, S. Y., and Kaplan, B. B. 1995. Association and linkage studies of the Taql A allele of the dopamine D2 receptor gene in samples of female and male alcoholics. Am. J. Med. Genet. 60:267–271.Google Scholar
  10. 10.
    Noble, E. P., Syndulko, K., Fitch, R. J., Ritchie, T., Bohlman, M. C., Guth, P., Sheridan, P. J., Montegomery, A., Heinzmann, C., Sparkes, R. S., and Blum, K. 1994. D2 dopamine receptor Taql A alleles in medically ill alcoholic and nonalcoholic patients. Alcohol Alcohol. 29:729–744.Google Scholar
  11. 11.
    Ovchinnikov, I. V., Druzina, E., Ovchinnikova, O., Zagorovskaya, T., Nebrakova, T., Anokhina, I. P. 1999. Polymorphism of dopamine D2 and D4 receptor genes and Slavic-surnamed alcoholic patients. Addiction Biol. 4:399–404.Google Scholar
  12. 12.
    Parsian, A., Todd, R. D., Devor, E. J., O'Malley, K. L., Suarez, B. K., Reich, T., and Cloninger, C. R. 1991. Alcoholism and alleles of the human D2 receptor locus: Studies of association and linkage. Arch. Gen. Psychiatry 48:655–663.Google Scholar
  13. 13.
    Bolos, A. M., Dean, M., Lucase-Derse, S., Ramsburg, M., Brown, G. L., Goldman, D. 1990. Population and pedigree studies reveal a lack of association between dopamine D2 receptor gene and alcoholism. JAMA 264:3156–3160.Google Scholar
  14. 14.
    Cook, B. L., Wang, Z. W., Crowe, R. R., Hauser, R., and Freimer, M. 1992. Alcoholism and the D2 receptor gene. Alcohol. Clin. Exp. Res. 16:806–809.Google Scholar
  15. 15.
    Geijer, T., Neiman, J., Rydberg, U., Gyllander, A., Jöhnson, E., Sedvall, G., Valverius, P., and Terenius, L. 1994. Dopamine D2 receptor gene polymorphisms in Scandinavian chronic alcoholics. Eur. Arch. Psychiatry Clin. Neurosci. 244:26–32.Google Scholar
  16. 16.
    Gelernter, J., O'Malley, S., Risch, N., Kranzler, H. R., Krystal, J., Merikangas, K., Kennedy, J. F., and Kidd, K. K. 1991. No association between an allele of the D2 dopamine receptor gene (DRD2) and alcoholism. JAMA 266:1801–1807.Google Scholar
  17. 17.
    Goldman, D., Dean, M., Brown, G. L., Bolos, A. N., Tokola, R., Virkkunen, M., and Linnoila, M. 1992. D2 dopamine receptor genotype and cerebral spinal fluid homovanillic acid, 5-hydroxy-indoleacetic acid and 3-methoxy-4-hydroxyphenylglycol in alcoholics in Finland and the United States. Acta Psychiatr. Scand. 86:351–357.Google Scholar
  18. 18.
    Heintz, A., Sander, T., Harms, H., Finckh, U., Kuhn, S., Dufeu, P., Dettling, M., Gräf, K., Rolfs, A., Rommelspacher, H., and Schmidt, L. G. 1996. Lack of allelic association of dopamine D1 and D2 (Taql A) receptor gene polymorphisms with reduced dopaminergic sensitivity in alcoholism. Alcohol. Clin. Exp. Res. 20:1109–1113.Google Scholar
  19. 19.
    Sander, T., Murat, L., Samochowiec, J., Finckh, U., Romelspacher, H., and Schmidt, L. G. 1999. Lack of an allelic association between polymorphisms of the dopamine D2 receptor gene and alcohol dependence in the German population. Alcohol. Clin. Exp. Res. 23:578–581.Google Scholar
  20. 20.
    Suarez, B. K., Parsian, A., Hampe, C. L., Todd, R. D., Reich, T., and Cloninger, C. R. 1994. Linkage disequilibria and the D2 dopamine receptor locus (DRD2) in alcoholics and controls. Genomics 19:12–20.Google Scholar
  21. 21.
    Blum, K., Sheridan, P. J., Wood, R. C., Braverman, E. R., Chen, I. J. H., and Comings, D. E. 1995. Dopamine D2 receptor gene variants: Association and linkage studies in impulsive-addictive-compulsive behavior. Pharmacogenetics 5:121–141.Google Scholar
  22. 22.
    Cloninger, C. R. 1991. D2 dopamine receptor gene is associated but not linked with alcoholism. JAMA 266:1833–1834.Google Scholar
  23. 23.
    Cook, C. C. H. and Gurling, H. M. D. 1994. The D2 dopamine receptor gene and alcoholism: A genetic effect on the liability for alcoholism. J. R. Soc. Med. 87:400–402.Google Scholar
  24. 24.
    Gorwood, P., Ades, J., and Feingold, J. 1994. Are genes coding for dopamine receptors implicated in alcoholism? Eur. Psychiatry 9:63–69.Google Scholar
  25. 25.
    Noble, E. P. 2000. The DRD2 gene in psychiatric and neurological disorders and its phenotypes. Pharmacogenomics 1:309–333.Google Scholar
  26. 26.
    Pato, C. N., Macciardi, F., Pato, M. T., Verga, M., and Kennedy, H. 1993. Review of the putative association of dopamine D2 receptor and alcoholism: A meta-analysis. Am. J. Med. Genet. 48:78–82.Google Scholar
  27. 27.
    Uhl, G., Blum, K., Noble, E., and Smith, S. 1993. Substance abuse vulnerability and D2 receptor gene. Trends Neurosci. 16: 83–88.Google Scholar
  28. 28.
    Gelernter, J., Goldman, D., and Risch, N. 1993. The A1 allele of the D2 dopamine receptor gene and alcoholism. JAMA 268: 1673–1677.Google Scholar
  29. 29.
    Noble, E. P. and Blum, K. 1993. Alcoholism and the D2 receptor gene [letter]. JAMA 270:1547.Google Scholar
  30. 30.
    Smith, S. S., O'Hara, B. F., Persico, A. M., Gorelick, D. A., Newlin, D. B., Vlahov, D., Solomon, L., Pickens, R., and Uhl, G. R. 1992. Genetic vulnerability to drug abuse: The D2 dopamine receptor Taql B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers. Arch. Gen. Psychiatry 49:723–727.Google Scholar
  31. 31.
    O'Hara, B. F., Smith, S. S., Bird, G., Persico, A. M., Suarez, B. K., Cutting, G. R., and Uhl, G. R. 1993. Dopamine D2 receptor RFLPs, haplotypes and their association with substance use in black and caucasian research volunteers. Hum. Hered. 43: 209–218.Google Scholar
  32. 32.
    Comings, D. E., Muhleman, D., Ahn, C., Gysin, R., and Flanagan, S. D. 1994. The dopamine D2 receptor gene: A genetic risk factor in substance abuse. Drug Alcohol Depend. 34:175–180.Google Scholar
  33. 33.
    Noble, E. P., Blum, K., Khalsa, M. E., Ritchie, T., Montgomery, A., Wood, R. D., Fitch, R. J., Ozkaragoz, T., Sheridan, P. J., Anglin, M. D., Parades, A., Treiman, L. J., and Sparkes, R. S. 1993. Allelic association of the D2 dopamine receptor gene with cocaine dependence. Drug Alcohol Depend. 33:271–285.Google Scholar
  34. 34.
    Persico, A. M., Bird, G., Gabbay, F. H., and Uhl, G. R. 1996. D2 dopamine receptor gene Taql A1 and B1 restriction fragment length polymorphism: Enhanced frequencies in psychostimulant-preferring polysubstance abusers. Biol. Psychiatry 40:776–784.Google Scholar
  35. 35.
    Noble, E. P., St Jeor, S. T., Ritchie, T., Syndulco, K., St Jeor, S. C., Fitch, R. J., Brunner, R. L., and Sparkes, R. S. 1994. D2 dopamine receptor gene and cigarette smoking: A reward gene? Med. Hypotheses 42:257–260.Google Scholar
  36. 36.
    Comings, D. E., Ferry, L., Bradshaw-Robinson, S., Burghette, R., Chiu, C., and Muhleman, D. 1996. The dopamine D2 receptor (DRD2) gene: A genetic risk factor in smoking. Pharmacogenetics 6:73–79.Google Scholar
  37. 37.
    Spitz, M. R., Shi, H., Yang, F., Hudmon, K. S., Jiang, H., Chamberlain, R. M., Amos, C. I., and Wan, Y. 1998. Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients. J. Natl. Cancer Inst. 90:358–363.Google Scholar
  38. 38.
    Lawford, B. R., Young, R. McD., Noble, E. P., Sargent, J., Rowell, J., Shadforth, S., Zhang, X., and Ritchie, T. 2000. The D2 dopamine receptor A1 allele and opioid dependence: Association with heroin use and response to methadone treatment. Am. J. Med. Genet. (Neuropsychiat. Genet.) 96:592–598.Google Scholar
  39. 39.
    Comings, D. E., Flanagan, S. D., Dietz, G., Muhleman, D., Knell, E., and Gysin, R. 1993. The dopamine D2 receptor (DRD2) as a major gene in obesity and weight. Biochem. Med. Metabol. Biol. 50:176–185.Google Scholar
  40. 40.
    Noble, E. P., Noble, R. E., Ritchie, T., Syndulko, K., Bohlman, M. C., Noble, L. A., Zhang, Y., Sparkes, R. S., and Grandy, D. K. 1994. Allelic association of the human D2 dopamine receptor gene and obesity. Int. J. Eat. Disord. 15:205–217.Google Scholar
  41. 41.
    Comings, D. E., Gade, R., MacMurray, J. P., Muhleman, D., and Peters, W. R. 1996. Genetic variants of the human obesity (OB) gene: Association with body mass index in young women, psychiatric symptoms, and interaction with the dopamine D2 receptor (DRD2) gene. Molec. Psychiatry 1:325–335.Google Scholar
  42. 42.
    Spitz, M. R., Detry, M. A., Pillow, P., Hu, Y. H., Amos, C. I., Hong, W. K., and Wu, X. F. 2000. Variant alleles of the D2 dopamine receptor gene and obesity. Nutri. Res. 20:371–380.Google Scholar
  43. 43.
    Noble, E. P., Zhang, X., Ritchie, T. L., and Sparkes, R. S. 2000. Haplotypes at the DRD2 locus and severe alcoholism. Am. J. Med. Genet. (Neuropsychiat. Genet.) 96:622–631.Google Scholar
  44. 44.
    Blum, K., Noble, E. P., Sheridan, P. J., Montgomery, A., Ritchie, T., Ozkaragoz, T., Fitch, R. J., Wood, R., Finley, O., and Sadlack, F. 1993. Genetic predisposition in alcoholism: Association of the D2 dopamine receptor Taql B RFLP in severe alcoholics. Alcohol 10:59-67.Google Scholar
  45. 45.
    Noble, E. P., Blum, K., Ritchie, T., Montgomery, A., and Sheridan, P. J. 1991. Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch. Gen. Psychiatry 48:648-654.Google Scholar
  46. 46.
    Thompson, J., Thomas, N., Singleton, A., Piggott, M., Lloyd, S., Perry, E. K., Morris, C. M., Perry, R. H., Ferrier, I. N., and Court, J. A. 1997. D2 dopamine receptor gene (DRD2) Taql A polymorphism: Reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 7:479–484.Google Scholar
  47. 47.
    Pohjalainen, T., Rinne, J. O., Nåagren, K., Lehikoinen, P., Anttila, K., Syvälahti, E. K. G., and Hietala, J. 1998. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Molec. Psychiatry 3:256–260.Google Scholar
  48. 48.
    Jönsson, E. G., Nöthen, M. M., Grünhage, F., Farde, L., Nakashima, Y., Propping, P., and Sedvall, G. C. 1999. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molec. Psychiatry 4:290–296.Google Scholar
  49. 49.
    Saiki, R. K., Gelfand, D. H., Stoffel, S., Scharf, S. J., Higuchi, R., Horn, G. T., Mullins, K. B., and Erlich, H. A. 1988. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491.Google Scholar
  50. 50.
    Grandy, D. K., Zhang, Y., and Civelli, O. 1993. PCR detection of the Taql A RFLP at the DRD2 locus. Hum. Mol. Genet. 2: 2197.Google Scholar
  51. 51.
    Castiglione, C. M., Deinard, A. S., Speed, W. C., Sirugo, G., Rosenbaum, H. C., Zhang, Y., Grandy, D. K., Grigorenko, E. L., Bonne-Tamir, B., Pakstis, A. J., Kidd, J. R., and Kidd, K. K. 1995. Evolution of haplotypes at the DRD2 locus. Am. J. Hum. Genet. 57:1445–1456.Google Scholar
  52. 52.
    Sarkar, G. and Sommer, S. S. 1991. Haplotyping by double PCR amplification of specific alleles. Biotechniques 10:436–440.Google Scholar
  53. 53.
    Kidd, K. K., Pakstis, A. J., Castiglione, C. M., Kid, J. R., Speed, W. C., Goldman, D., Knowler, W. C., Lu, R.-B., and Bonne-Tamir, B. 1996. DRD2 haplotypes containing the Taql A1 allele: Implications for alcoholism research. Alcohol. Clin. Exp. Res. 20:697–705.Google Scholar
  54. 54.
    Arinami, T., Gao, M., Hamaguchi, H., and Toru, M. 1997. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum. Mol. Genetic. 6:577–582.Google Scholar
  55. 55.
    Samochowiec, J., Ladehoff, M., Pelz, J., Smolka, M., Schmidt, L. G., Rommelspacher, H., and Finckh, U. 2000. Predominant influence of the 3′-region of dopamine D2 receptor gene (DRD2) on the clinical phenotype in German alcoholics. Pharmacogenetics 10:471–475.Google Scholar
  56. 56.
    Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurement with the folin phenol reagent. J. Biol. Chem. 193:265–275.Google Scholar
  57. 57.
    Munson, P. J. and Rodbard, D. 1980. LIGAND: A versatile computerized approach for characterization for ligand-binding systems. Anal. Biochem. 107:220–239.Google Scholar
  58. 58.
    Weir, B. S. 1996. Genetic data analysis II: Methods for discrete population genetic data. Sinauer Associates, Sunderland, Massachusetts.Google Scholar
  59. 59.
    Weir, B. S. and Cockerham, C. C. 1989. Complete characterization of disequilibrium at two loci. Pages 86–110, in Feldman, M. E. (ed.), Mathematical Evolutionary Theory, Princeton University Press, New Jersey.Google Scholar
  60. 60.
    Seeman, P., Ulpian, C., Bergeron, C., Riederer, P., Jellinger, K., Gabriel, E., Reynolds, G. P., and Tourtellotte, W. W. 1984. Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science 225:728–730.Google Scholar
  61. 61.
    De Keyser, J., Walraevens, H., De Backer, J.-P., Ebinger, G., and Vauquelin, G. 1989. D2 dopamine receptors in the human brain: Heterogeneity based on differences in guanine nucleotide effect on agonist binding, and their presence on corticostriatal nerve terminals. Brain Res. 484:36–42.Google Scholar
  62. 62.
    Severson, J. A., Marcusson, J., Winblad, B., and Finch, C. E. 1982. Age-correlated loss of dopaminergic binding sites in human basal ganglia. J. Neurochem. 39:1623–1631.Google Scholar
  63. 63.
    Laruelle, M., Gelernter, J., and Innis, R. B. 1998. D2 receptors binding potential is not affected by Taql polymorphism at the D2 receptor gene. Mol. Psychiatry 3:261–265.Google Scholar
  64. 64.
    Hitzemann, R. J. 1998. The regulation of D2 dopamine receptor expression. Mol. Psychiatry 3:198–203.Google Scholar
  65. 65.
    Silvestri, S., Seeman, M. V., Negrete, J.-C., Houle, S., Shammi, C. M., Remington, G. J., Kupar, S., Zipursky, R. B., Wilson, A. A., Christensen, B. K., and Seeman, P. 2000. Increased dopamine D2 receptor binding after long-term treatment antipsychotics in humans: A clinical PET study. Psychopharmacology 152:174–180.Google Scholar
  66. 66.
    Pohjalainen, T., Nåagren, K., Syvälahti, E. K., and Hietala, J. 1999. The dopamine D2 receptor 5′-flanking variant,-141C Ins/Del, is not associated with reduced dopamine D2 receptor density in vivo. Pharmacogenetics 9:505–509.Google Scholar
  67. 67.
    Gelernter, J., Kranzler, H., Cubells, J. F., Ichimose, H., and Nagatsu, T. 1998. DRD2 allele frequencies and linkage disequilibria, including the-141C Ins/Del promoter polymorphism, in European-American, African-American and Japanese subjects. Genomics 51:21–26.Google Scholar
  68. 68.
    Ishiguro, H., Arinami, T., Saito, T., Akazawa, S., Enomoto, M., Mitushio, H., Fujishiro, H., Tada, K., Akimoto, Y., Mifune, H., Shioduka, S., Hamaguchi, H., Toru, M., and Shibuya, H. 1998. Association study between the-141C Ins/Del and Taql A polymorphisms of the doamine D2 receptor gene and alcoholism. Alcoholism Clin. Exp. Res. 22:845–848.Google Scholar
  69. 69.
    Parsian, A., Cloninger, C. R., and Zhang, Z. H. 2000. Functional variant in the DRD2 receptor promoter region and subtypes of alcoholism. Am. J. Med. Genet. 96:407–411.Google Scholar
  70. 70.
    Kidd, K. K., Bharati, M., Castiglione, C. M., Zhao, H., Pakstis, A. J., Speed, W. C., Bonne-Tamir, B., Lu, R.-B., Goldman, D., Lee, C., Nam, Y. S., Grandy, D. K., Jenkins, T., and Kidd, J. R. 1998. A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus. Hum. Genet. 103:211–227.Google Scholar
  71. 71.
    Hietala, J., West, C., Syvälahti, E., Någren, K., Lehikoinen, P., Sonninen, P., and Ruotsalainen, U. 1994. Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology 116:285–290.Google Scholar
  72. 72.
    Volkow, N. D., Wang, G.-J., Fowler, J. S., Logan, J., Hitzemann, R., Ding, Y.-S., Pappas, N., Shea, C., and Piscani, K. 1996. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol. Clin. Exp. Res. 20:1594–1598.Google Scholar
  73. 73.
    Thanos, P. K., Volkow, N. D., Freimuth, P., Umegaki, H., Ikari, H., Roth, G., Ingram, D. K., and Hitzemann, R. 2001. Over-expression of dopamine D2 receptors reduces alcohol self-administration. J. Neurochem. 78:1094–1103.Google Scholar
  74. 74.
    Noble, E. P. 1996. The gene that rewards alcoholism. Sci. Am. Sci. Med. 3:52–61.Google Scholar
  75. 75.
    Gandelman, K. Y., Harmon, S., Todd, R. D., and O'Malley, K. L. 1991. Analysis of the structure and expression of the human dopamine D2 A receptor gene. J. Neurochem. 56:1024–1029.Google Scholar
  76. 76.
    Eubanks, J., Djabali, M., Selleri, L., Grandy, D. K., Civelli, O., McElligott, D. L., and Evans, G. A. 1992. Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23. Genomics 14:1010–1018.Google Scholar
  77. 77.
    Carswell, S. and Alwine, J. C. 1989. Efficiency of utilization of the simian virus 40 late polyadenylation site: Effects of upstream sequences. Mol. Cell. Biol. 9:4248–4258.Google Scholar
  78. 78.
    Rotondaro, L., Mele, A., and Rovera, G. 1996. Efficacy of different viral promoters in directing gene expression in mammalian cells: Effect of 3′-untranslated sequences. Gene 168:195–198.Google Scholar
  79. 79.
    Mammès, O., Betoulle, D., Aubert, R., Giraud, V., Tuset, S., Petiet, A., Colas-Linhart, N., and Fumeron, F. 1998. Novel polymorphisms in the 5′ region of the LEP gene: Association with leptin levels and response to low-calorie diet in human obesity. Diabetes 47:487–489.Google Scholar
  80. 80.
    Cooper, D. N. 1992. Regulatory mutations and human genetic disease. Ann. Med. 24:427–437.Google Scholar
  81. 81.
    Bedell, M. A., Jenkins, N. A., and Copeland, N. G. 1996. Good genes in bad neighbourhoods. Nat. Genet. 12:229–232.Google Scholar

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© Plenum Publishing Corporation 2003

Authors and Affiliations

  1. 1.Department of Psychiatry and Biobehavioral SciencesUniversity of CaliforniaLos Angeles

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