Skip to main content
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1988 May 25;16(10):4437–4446.

Human tyrosine hydroxylase and insulin genes are contiguous on chromosome 11.

K L O'Malley 1, P Rotwein 1
PMCID: PMC336640  PMID: 2898127

Abstract

The gene for the catecholamine biosynthetic enzyme, tyrosine hydroxylase (TH), has been previously mapped to human chromosome 11 p15.5 in the vicinity of the loci for insulin (INS) and for the oncogene Harvey Ras 1 (HRAS). Here we show that gene probes derived from recombinant clones containing either human TH or INS cross-hybridize with each other. Direct DNA sequencing demonstrates that these genes are physically linked on chromosome 11. The TH gene is 5' to INS and is separated by only 2.7 kb of flanking DNA. Both genes have the same transcriptional polarity and form a head-to-tail linkage group with insulin-like growth factor 2 (IGF-2) in the order: 5' - TH - INS - IGF-2 - 3'. Because of the close physical proximity of these genes, previously described polymorphisms for INS are identical to those observed with TH. The localization of TH to the highly polymorphic INS locus provides four new restriction fragment length polymorphisms which should help determine rapidly whether defects in TH are responsible for bipolar affective disorder in the Old Order Amish and other populations.

Full text

PDF
4437

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bell G. I., Gerhard D. S., Fong N. M., Sanchez-Pescador R., Rall L. B. Isolation of the human insulin-like growth factor genes: insulin-like growth factor II and insulin genes are contiguous. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6450–6454. doi: 10.1073/pnas.82.19.6450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell G. I., Selby M. J., Rutter W. J. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature. 1982 Jan 7;295(5844):31–35. doi: 10.1038/295031a0. [DOI] [PubMed] [Google Scholar]
  4. Blundell T. L., Humbel R. E. Hormone families: pancreatic hormones and homologous growth factors. Nature. 1980 Oct 30;287(5785):781–787. doi: 10.1038/287781a0. [DOI] [PubMed] [Google Scholar]
  5. Brissenden J. E., Ullrich A., Francke U. Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor. 1984 Aug 30-Sep 5Nature. 310(5980):781–784. doi: 10.1038/310781a0. [DOI] [PubMed] [Google Scholar]
  6. Brown A. L., Graham D. E., Nissley S. P., Hill D. J., Strain A. J., Rechler M. M. Developmental regulation of insulin-like growth factor II mRNA in different rat tissues. J Biol Chem. 1986 Oct 5;261(28):13144–13150. [PubMed] [Google Scholar]
  7. Brown E. R., Coker G. T., 3rd, O'Malley K. L. Organization and evolution of the rat tyrosine hydroxylase gene. Biochemistry. 1987 Aug 11;26(16):5208–5212. doi: 10.1021/bi00390a046. [DOI] [PubMed] [Google Scholar]
  8. Chakravarti A., Elbein S. C., Permutt M. A. Evidence for increased recombination near the human insulin gene: implication for disease association studies. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1045–1049. doi: 10.1073/pnas.83.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen E. Y., Seeburg P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA. 1985 Apr;4(2):165–170. doi: 10.1089/dna.1985.4.165. [DOI] [PubMed] [Google Scholar]
  10. DiLella A. G., Kwok S. C., Ledley F. D., Marvit J., Woo S. L. Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry. 1986 Feb 25;25(4):743–749. doi: 10.1021/bi00352a001. [DOI] [PubMed] [Google Scholar]
  11. Egeland J. A., Gerhard D. S., Pauls D. L., Sussex J. N., Kidd K. K., Allen C. R., Hostetter A. M., Housman D. E. Bipolar affective disorders linked to DNA markers on chromosome 11. 1987 Feb 26-Mar 4Nature. 325(6107):783–787. doi: 10.1038/325783a0. [DOI] [PubMed] [Google Scholar]
  12. Elbein S. C., Corsetti L., Permutt M. A. New polymorphisms at the insulin locus increase its usefulness as a genetic marker. Diabetes. 1985 Nov;34(11):1139–1144. doi: 10.2337/diab.34.11.1139. [DOI] [PubMed] [Google Scholar]
  13. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  14. Gerald P. S., Miller O. J. Report of the committee on the genetic constitution of chromosomes 10, 11, and 12. Oslo Conference (1981): Sixth International Workshop on Human Gene Mapping. Cytogenet Cell Genet. 1982;32(1-4):153–160. doi: 10.1159/000131695. [DOI] [PubMed] [Google Scholar]
  15. Gray A., Tam A. W., Dull T. J., Hayflick J., Pintar J., Cavenee W. K., Koufos A., Ullrich A. Tissue-specific and developmentally regulated transcription of the insulin-like growth factor 2 gene. DNA. 1987 Aug;6(4):283–295. doi: 10.1089/dna.1987.6.283. [DOI] [PubMed] [Google Scholar]
  16. Grenett H. E., Ledley F. D., Reed L. L., Woo S. L. Full-length cDNA for rabbit tryptophan hydroxylase: functional domains and evolution of aromatic amino acid hydroxylases. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5530–5534. doi: 10.1073/pnas.84.16.5530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kittur S. D., Hoppener J. W., Antonarakis S. E., Daniels J. D., Meyers D. A., Maestri N. E., Jansen M., Korneluk R. G., Nelkin B. D., Kazazian H. H., Jr Linkage map of the short arm of human chromosome 11: location of the genes for catalase, calcitonin, and insulin-like growth factor II. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5064–5067. doi: 10.1073/pnas.82.15.5064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ledley F. D., DiLella A. G., Kwok S. C., Woo S. L. Homology between phenylalanine and tyrosine hydroxylases reveals common structural and functional domains. Biochemistry. 1985 Jul 2;24(14):3389–3394. doi: 10.1021/bi00335a001. [DOI] [PubMed] [Google Scholar]
  19. Lidksy A. S., Robson K. J., Thirumalachary C., Barker P. E., Ruddle F. H., Woo S. L. The PKU locus in man is on chromosome 12. Am J Hum Genet. 1984 May;36(3):527–533. [PMC free article] [PubMed] [Google Scholar]
  20. Lund P. K., Moats-Staats B. M., Hynes M. A., Simmons J. G., Jansen M., D'Ercole A. J., Van Wyk J. J. Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues. J Biol Chem. 1986 Nov 5;261(31):14539–14544. [PubMed] [Google Scholar]
  21. Moss P. A., Davies K. E., Boni C., Mallet J., Reeders S. T. Linkage of tyrosine hydroxylase to four other markers on the short arm of chromosome 11. Nucleic Acids Res. 1986 Dec 22;14(24):9927–9932. doi: 10.1093/nar/14.24.9927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. O'Malley K. L., Anhalt M. J., Martin B. M., Kelsoe J. R., Winfield S. L., Ginns E. I. Isolation and characterization of the human tyrosine hydroxylase gene: identification of 5' alternative splice sites responsible for multiple mRNAs. Biochemistry. 1987 Nov 3;26(22):6910–6914. doi: 10.1021/bi00396a007. [DOI] [PubMed] [Google Scholar]
  23. Owerbach D., Aagaard L. Analysis of a 1963-bp polymorphic region flanking the human insulin gene. Gene. 1984 Dec;32(3):475–479. doi: 10.1016/0378-1119(84)90021-0. [DOI] [PubMed] [Google Scholar]
  24. Rotwein P., Chyn R., Chirgwin J., Cordell B., Goodman H. M., Permut M. A. Polymorphism in the 5'-flanking region of the human insulin gene and its possible relation to type 2 diabetes. Science. 1981 Sep 4;213(4512):1117–1120. doi: 10.1126/science.6267694. [DOI] [PubMed] [Google Scholar]
  25. Rotwein P., Naylor S. L., Chirgwin J. M. Human insulin-related DNA sequences map to chromosomes 2 and 11. Somat Cell Mol Genet. 1986 Nov;12(6):625–631. doi: 10.1007/BF01671947. [DOI] [PubMed] [Google Scholar]
  26. Rotwein P., Pollock K. M., Didier D. K., Krivi G. G. Organization and sequence of the human insulin-like growth factor I gene. Alternative RNA processing produces two insulin-like growth factor I precursor peptides. J Biol Chem. 1986 Apr 15;261(11):4828–4832. [PubMed] [Google Scholar]
  27. Rotwein P., Yokoyama S., Didier D. K., Chirgwin J. M. Genetic analysis of the hypervariable region flanking the human insulin gene. Am J Hum Genet. 1986 Sep;39(3):291–299. [PMC free article] [PubMed] [Google Scholar]
  28. Soares M. B., Ishii D. N., Efstratiadis A. Developmental and tissue-specific expression of a family of transcripts related to rat insulin-like growth factor II mRNA. Nucleic Acids Res. 1985 Feb 25;13(4):1119–1134. doi: 10.1093/nar/13.4.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ullrich A., Dull T. J., Gray A., Philips J. A., 3rd, Peter S. Variation in the sequence and modification state of the human insulin gene flanking regions. Nucleic Acids Res. 1982 Apr 10;10(7):2225–2240. doi: 10.1093/nar/10.7.2225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wahl G. M., Stern M., Stark G. R. Efficient transfer of large DNA fragments from agarose gels to diazobenzyloxymethyl-paper and rapid hybridization by using dextran sulfate. Proc Natl Acad Sci U S A. 1979 Aug;76(8):3683–3687. doi: 10.1073/pnas.76.8.3683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zabel B. U., Kronenberg H. M., Bell G. I., Shows T. B. Chromosome mapping of genes on the short arm of human chromosome 11: parathyroid hormone gene is at 11p15 together with the genes for insulin, c-Harvey-ras 1, and beta-hemoglobin. Cytogenet Cell Genet. 1985;39(3):200–205. doi: 10.1159/000132135. [DOI] [PubMed] [Google Scholar]
  32. de Pagter-Holthuizen P., Jansen M., van Schaik F. M., van der Kammen R., Oosterwijk C., Van den Brande J. L., Sussenbach J. S. The human insulin-like growth factor II gene contains two development-specific promoters. FEBS Lett. 1987 Apr 20;214(2):259–264. doi: 10.1016/0014-5793(87)80066-2. [DOI] [PubMed] [Google Scholar]
  33. de Pagter-Holthuizen P., van Schaik F. M., Verduijn G. M., van Ommen G. J., Bouma B. N., Jansen M., Sussenbach J. S. Organization of the human genes for insulin-like growth factors I and II. FEBS Lett. 1986 Jan 20;195(1-2):179–184. doi: 10.1016/0014-5793(86)80156-9. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES