Skip to main content
SpringerLink
Log in

Alcohol dehydrogenase genes: restriction fragment length polymorphisms for ADH4 (π-ADH) and ADH5 (χ-ADH) and construction of haplotypes among different ADH classes

  • Original Investigations
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Of the five human alcohol dehydrogenase (ADH) genes located in the region q21–25 of chromosome 4, genetic markers have been reported previously only for class I enzymes, ADH1-3. Here, new restriction fragment length polymorphisms (RFLPs) are described for the genes of two other classes, ADH4 (π) and ADH5 (χ or formaldehyde dehydrogenase, FDH). The frequencies and modes of inheritance of these RFLPs were determined with DNA both from unrelated individuals and from families. A polymorphic PstI site is assigned to the fourth intron of the ADH4 gene. Pairwise linkage disequilibrium calculations for these new RFLPs and already known RFLPs at the ADH2 and ADH3 loci establish strong linkage disequilibria between polymorphic MspI and BstXI sites in the ADH5 gene as well as between XbaI and MspI sites in the ADH3 gene. Furthermore, linkage disequilibria were detected between RFLPs of the ADH2 and ADH3 genes as well as between those of the ADH4 and ADH5 genes. The latter disequilibrium implies a hitherto unknown physical proximity of two genes belonging to different ADH classes. The RFLPs were used to construct chromosomal haplotypes that include three ADH classes. Of the 16 possible haplotypes for four RFLP markers used here, 10 were experimentally detected. The potential application of the ADH RFLPs and haplotypes in linkage or association studies of inherited diseases such as familial “alcoholism” is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ackerman SJ (1992) Research on the genetics of alcoholism is still in ferment. J NIH Res 4:61–65

    Google Scholar 

  • Ausubel FM, Brent R Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (1987) Current protocols in molecular biology. Wiley, New York

    Google Scholar 

  • Bahr-Lindström H von, Jörnvall H, Höög J-O (1991) Cloning and characterization of the human ADH4 gene. Gene 103:269–274

    Google Scholar 

  • Buetow KH, Shiang R, Yang P, Nakamura Y, Lathrop GM, White R, Wasmuth JJ, Wood S, Berdahl LD, Leysens NJ, Ritty TM, Wise ME, Murray JC (1991) A detailed multi-point map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates. Am J Hum Genet 48:911–925

    Google Scholar 

  • Carlock L, Hiroshige S, Wasmuth J, Smith M (1985) Assignment of the ADH5 gene coding for class III ADH to human chromosome 4:4q21–4q25 (abstract). Cytogenet Cell Genet 40:598

    Google Scholar 

  • Chakravarti A, Buetow KH, Antonaraki SE, Waber PG, Boehm CD, Kazazian HH (1984) Nonuniform recombination within the human β-globin gene cluster. Am J Hum Genet 36:1239–1258

    Google Scholar 

  • Chakravarti A, Elbein SC, Perlmutt MA (1986) Evidence for increased recombination near the human insulin gene: implication for disease association studies. Proc Natl Acad Sci USA 83:1045–1049

    Google Scholar 

  • Chambers GK (1990) The genetics of human alcohol metabolism. Gen Pharmac 21:267–272

    Google Scholar 

  • Ciulla TA, Sklar RM, Hauser SL (1988) A simple method for DNA purification from peripheral blood. Anal Biochem 174:485–488

    Google Scholar 

  • Cloninger CR (1987) Neurogenetic adaptive mechanisms in alcoholism. Science 236:410–416

    CAS  PubMed  Google Scholar 

  • Comings DE, Muhlemann D, Dietz GW Jr, Donlon T (1991) Human tryptophan oxygenase localized to 4q 31:possible implications for alcoholism and other behavioural disorders. Genomics 9:301–308

    Google Scholar 

  • Devor EJ (1988) The relative efficiency of restriction enzymes: an update. Am J Hum Genet 42:179–182

    Google Scholar 

  • Duester G (1991) A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step. Alcohol Clin Exp Res 15:568–572

    Google Scholar 

  • Duester G, Hatfield GW, Smith M (1985) Molecular genetic analysis of human alcohol dehydrogenase. Alcohol 2:53–56

    Google Scholar 

  • Duester G, Smith M, Bilanchone V, Hatfield GW (1986) Molecular analysis of the human class I alcohol dehydrogenase gene family and nucleotide sequence of the gene encoding the β subunit. J Biol Chem 261:2027–2033

    Google Scholar 

  • Edman K, Maret W (1990) An MspI RFLP in the human ADH5 gene. Nucleic Acids Res 18:2836

    Google Scholar 

  • Giri RP, Krug JF, Kozak C, Moretti T, O'Brien SJ, Seuanez HN, Goldman D (1989) Cloning and comparative mapping of a human class III (χ) alcohol dehydrogenase cDNA. Biochem Biophys Res Commun 164:453–460

    Google Scholar 

  • Goldman D, Giri RP, Moretti TR, Krug JF, Kozak C, Dean M, Seuanez HN, O'Brien SJ (1989) Cloning and comparative mapping of a human class III ADH (abstract). Alcohol Clin Exp Res 13:332

    Google Scholar 

  • Groppi A, Begueret J, Iron A (1990) Improved methods for genotype determination of human alcohol dehydrogenase (ADH) at ADH2 and ADH3 loci by using polymerase chain reactiondirected mutagenesis. Clin Chem 36:1765–1768

    Google Scholar 

  • Gusella JF (1986) DNA polymorphism and human disease. Annu Rev Biochem 55:831–854

    Google Scholar 

  • Hill SY, Aston C, Rabin B (1988) Suggestive evidence of genetic linkage between alcoholism and the MNS blood group. Alcohol Clin Exp Res 12:811–814

    Google Scholar 

  • Höög J-O, Bahr-Lindström H von, Hedén L-O, Holmquist B, Larsson K, Hempel J, Vallee BL, Jörnvall H (1987) Structure of the class II enzyme of human liver alcohol dehydrogenase: combined cDNA and protein sequence determination of the π subunit. Biochemistry 26:1926–1932

    Google Scholar 

  • Kaiser R, Holmquist B, Hempel J, Vallee BL, Jörnvall H (1988) Class III human liver alcohol dehydrogenase: a novel structural type equidistantly related to the class I and class II enzymes. Biochemistry 27:1132–1140

    Google Scholar 

  • Koivusalo M, Baumann M, Uotila L (1989) Evidence for the identity of glutathione-dependent formaldehyde dehydrogenase and class III alcohol dehydrogenase. FEBS Lett 257:105–109

    Google Scholar 

  • Matsuo Y, Yokoyama S (1989) Molecular structure of the human alcohol dehydrogenase 1 gene. FEBS Lett 243:57–60

    Google Scholar 

  • Matsuo Y, Yokoyama S (1990) Cloning and sequencing of a processed pseudogene derived from a human class III alcohol dehydrogenase gene. Am J Hum Genet 46:85–91

    Google Scholar 

  • McPherson JD, Smith M, Wagner C, Wasmuth JJ, Höög J-O (1989) Mapping of the class II alcohol dehydrogenase gene locus to 4q22 (abstract). Cytogenet Cell Genet 51:1043

    Google Scholar 

  • Moreno A, Parés X (1991) Purification and characterization of a new alcohol dehydrogenase from human stomach. J Biol Chem 266:1128–1133

    Google Scholar 

  • Murray JC, Shiang R, Carlock LR, Smith M, Buetow KH (1987) Rapid RFLP screening procedure identifies new polymorphisms at albumin and alcohol dehydrogenase loci. Hum Genet 76:274–277

    Google Scholar 

  • Ott J (1985) Analysis of human genetic linkage. Johns Hopkins University Press, Baltimore

    Google Scholar 

  • Pandolfo M, Smith M (1988) A PvuII RFLP in the human ADH3 gene. Nucleic Acids Res 16:11857

    CAS  PubMed  Google Scholar 

  • Parés X, Cederlund E, Moreno A, Saubi N, Höög J-O, Jörnvall H (1992) Class IV alcohol dehydrogenase (the gastric enzyme). FEBS Lett 303:69–72

    Google Scholar 

  • Parsian A, Burgess AK, Khan MA, Devor EJ (1989) PvuII RFLP detected by human β-ADH cDNA probe. Nucleic Acids Res 17:10145

    Google Scholar 

  • Parsian A, Cloninger CR, Todd RD, Devor EJ (1990) Molecular genetic studies of alcohol subtypes β- and γ-alcohol dehydrogenases (ADH) (abstract). Alcohol Clin Exp Res 14:326

    Google Scholar 

  • Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY

    Google Scholar 

  • Shah T, Macpherson AJS, Ward RJ, Peters TJ, Yoshida A (1989) A PvuII RFLP in the human ADH2 gene. Nucleic Acids Res 17:7549

    Google Scholar 

  • Sharma CP, Fox EA, Holmquist B, Jörnvall H, Vallee BL (1989) cDNA sequence of human class III alcohol dehydrogenase. Biochem Biophys Res Commun 164:631–637

    Google Scholar 

  • Smith M (1986) Genetics of human alcohol and aldehyde dehydrogenase. Adv Hum Genet 15:249–290

    Google Scholar 

  • Smith M (1988) Molecular genetic studies on alcohol and aldehyde dehydrogenase: individual variation, gene mapping and analysis of regulation. Biochem Soc Trans 16:227–230

    Google Scholar 

  • Smith M, Duester G, Carlock L, Wasmuth J (1985) Assignment of ADH1, ADH2, and ADH3 genes (class I ADH) to human chromosome 4q21–4q25, through use of DNA probes (abstract). Cytogenet Cell Genet 40:748

    Google Scholar 

  • Smith M, Yoshiyama K, Kew M (1989) Evidence for chromosome 4q deletions in human hepatomas (abstract). Cytogenet Cell Genet 51:1081

    Google Scholar 

  • Sokol RJ, Smith M, Ernhart CB, Baumann R, Martier SS, Ager JW, Morrow-Tlucak M (1989) A genetic basis for alcohol-related birth defects (abstract)? Alcohol Clin Exp Res 13:343

    Google Scholar 

  • Thomasson HR, Edenberg HJ, Crabb DW, Mai X-L, Jerome RE, Li T-LK, Wang S-P, Lin Y-T, Lu R-B, Yin S-J (1991) Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet 48:677–681

    Google Scholar 

  • Vallee BL, Bazzone TJ (1983) Isozymes of human liver alcohol dehydrogenase. In: Rattazzi MC, Scandalios JG, Witt GS (eds) Isozymes: current topics in biological and medical research, vol 8. Liss, New York, pp 219–244

    Google Scholar 

  • Wijsman EM (1984) Optimizing selection of restriction enzymes in the search for DNA variants. Nucleic Acids Res 12:9209–9226

    Google Scholar 

  • Yasunami M, Kikuchi I, Sarapata D, Yoshida A (1990) The human class I alcohol dehydrogenase gene cluster: three genes are tandemly organized in an 80-kb-long segment of the genome. Genomics 7:152–158

    Google Scholar 

  • Yasunami M, Chen C-S, Yoshida A (1991) A human alcohol dehydrogenase gene (ADH6) encoding an additional class of isozyme. Proc Natl Acad Sci USA 88:7610–7614

    Google Scholar 

  • Yokoyama S, Yokoyama R, Rotwein P (1987) Molecular characterization of cDNA clones encoding the human alcohol dehydrogenase β, and the evolutionary relationship to the other class I subunits α and γ. Jpn J Genet 62:241–256

    Google Scholar 

Download references

Author information

Author notes

  1. Kjell Edman

    Present address: Department of Natural Sciences, University College of Kalmar, S-39129, Kalmar, Sweden

Authors and Affiliations

  1. Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, 02115, Boston, MA, USA

    Kjell Edman & Wolfgang Maret

Authors
  1. Kjell Edman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wolfgang Maret
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Edman, K., Maret, W. Alcohol dehydrogenase genes: restriction fragment length polymorphisms for ADH4 (π-ADH) and ADH5 (χ-ADH) and construction of haplotypes among different ADH classes. Hum Genet 90, 395–401 (1992). https://doi.org/10.1007/BF00220466

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00220466

Keywords

Search

Navigation