Abstract
Cytochrome P450 genes from the CYP2A, CYP2B, and CYP2F subfamilies form a tight cluster which we have localized on the detailed physical map of human chromosome 19. The corresponding three gene subfamilies are also clustered in the mouse genome, on the region of chromosome 7 known to be syntenic to human chromosome 19. One hundred eight cosmid clones from the human P450 region were assembled into a single contig of 350 kb, restriction mapped, and probed with cDNAs from the three gene subfamilies. A total of 11 genes were identified in humans, including five from the 2A subfamily, three from the 2B subfamily, and three from the 2F subfamily; at least six of the 11 are pseudogenes. The organization of the genes, with members of the three subfamilies intermixed, indicates that the evolution of this gene cluster has been complex. The modern gene arrangement in humans is probably the result of a series of tandem duplications, plus at least one inverted duplication. The identification of all genes and pseudogenes in this cluster also makes it possible to determine the origins of some previously known variant P450 transcripts.
Similar content being viewed by others
References
Aida K, Moore R, Negishi M (1994) Lack of the steroid 15α-hydroxylase gene (Cyp2a-4) in wild mouse strain Mus spretus: rapid evolution of the P450 gene superfamily. Genomics 19:564–566
Bale AE, Mitchell AL, Gonzalez FJ, McBride OW (1991) Localization of CYP2F1 by multipoint linkage analysis and pulsed-field gel electrophoresis. Genomics 10:284–286
Boorstein WR, Vamakopoulos NC, Fiddes JC (1982) Human chorionic gonadotropin β-subunit is encoded by at least eight genes arranged in tandem and inverted pairs. Nature 300:419–422
Brandriff BF, Gordon LA, Trask BJ (1991) A new system for high-resolution DNA sequence mapping in interphase pronuclei. Genomics 10:75–82
Brandriff BF, Gordon LA, Tynan KM, Olsen A, Mohrenweiser HW, Carrano AV, Trask BJ (1992) Order, orientation, and estimates of genomic distances among members of the carcinoembryonic antigen (CEA) gene family determined by pronuclear and interphase fluorescence in situ hybridization. Genomics 12:773–779
Brandriff BF, Gordon LA, Fertitta A, Olsen AS, Christensen M, Ashworth LK, Nelson DO, Carrano AV, Mohrenweiser HW (1994) Human chromosome 19p: a fluorescence in situ hybridization map with genomic distance estimates for 79 intervals spanning 20 Mb. Genomics 23:582–591
Branscomb E, Slezak T, Pae R, Galas D, Carrano AV, Waterman M (1990) Optimizing restriction fragment fingerprinting methods for ordering large genomic libraries. Genomics 8:351–366
Carrano AV, Lamerdin J, Ashworth LK, Watkins B, Branscomb E, Slezak T, Raff M, de Jong PJ, Keith D, McBride L, Meister KS, Kronick M (1989) A high-resolution, fluorescence-based, semi-automated method for DNA fingerprinting. Genomics 4:129–136
De Jong PJ, Yokabata K, Chen C, Lohman F, Pederson L, McNinch J, Van Dilla M (1989) Human chromosome-specific partial digest libraries in lambda and cosmid vectors. Cytogenet Cell Genet 51: 985
Degtyarenko KN, Archakov AI (1993) Molecular evolution of P450 superfamily and P450-containing monooxygenase systems. FEBS Lett 332(1):1–8
Feinberg AP, Vogelstein B (1993) A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6–13
Fried M, Feo S, Heard E (1991) The role of inverted duplication in the generation of gene amplification in mammalian cells. Biochim Biophys Acta 1090:143–155
Gonzalez FJ, Nebert DW (1990) Evolution of the P450 gene superfamily: animal-plant “warfare,” molecular drive, and human genetic differences in drug oxidation. Trends Genet 6:182–186
Gotoh O (1992) Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J Biol Chem 267(1):83–90
Kant JA, Fornace AJ Jr, Saxe D, Simon MI, McBride OW, Crabtree GR (1985) Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci USA 82:2344–2248
Lamerdin JE, Carrano AV (1993) Automated fluorescence-based restriction fragment analysis. aBiotechniques 15:294–303
Miles JS, McLaren AW, Gonzalez FJ, Wolf CR (1990a) Alternative splicing in the human cytochrome P450IIB6 gene: use of a cryptic exon within intron 3 and splice acceptor site within exon 4. Nucleic Acids Res 18(1):189
Miles JS, Moss JE, Meehan RR, Wolf CR (1990b) Close linkage of the cytochrome P450HA gene subfamily (Cyp2a) to CYP2b and Coh on mouse chromosome 7. Genomics 7:445–448
Negishi M, Lindberg R, Burkhart B, Ichikawa T, Honkakoski P, Lang M (1989) Mouse steroid 15α-hydroxylase family: identification of the type II P45015α as coumarin 7-hydroxylase. Biochemistry 28: 4169–4172
Nelson DR, Kamataki T, Waxman DJ, Guengerich FP, Estabrook RW, Feyereisen R, Gonzalez FJ, Coon MJ, Gunsalus IC, Gotoh O, Okuda K, Nebert DW (1993) The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 12(1):1–51
Nhamburo PT, Kimura S, McBride OW, Kozak CA, Gelboin HV, Gonzalez FJ (1990) The human CYP2F gene subfamily: identification of a cDNA encoding a new cytochrome P450, cDNA-directed expression, and chromosome mapping. Biochemistry 29: 5491–5499
Ohm T (1989) Role of gene duplication in evolution. Genome 31:304–310
Ohta T (1991) Multigene families and the evolution of complexity. J Mol Evol 33:34–41
Olsen AS, Combs J, Garcia E, Elliott J, Amemiya C, de Jong PJ, Threadgill G (1993) Automated production of high density cosmid and YAC colony filters with a robotic workstation. Biotechniques 14:116–123
Olsen AS, Teglund S, Nelson D, Gordon L, Copeland A, Georgescu A, Carrano AV, Hammarström S (1994) Gene organization of the pregnancy-specific glycoprotein region on human chromosome 19: assembly and analysis of a 700 kb cosmid contig spanning the region. Genomics 23:659–668
Passananti C, Davies B, Ford M, Fried M (1987) Structure of an inverted duplication formed as a first step in a gene amplification event: implications for a model of gene amplification. EMBO 6(6): 1697–1703
Pearce R, Greenway D, Parkinson A (1992) Species differences and inter-ndividual variation in liver microsomal cytochrome P450 2A enzymes: effects on coumarin, dicumarol, and testosterone oxidation. Arch Biochem Biophys 298(1):211–225
Phillips IR, Shephard EA, Povey S, Davis MB, Kelsey G, Monteiro M, West LF (1985) A cytochrome P450 gene family mapped to human chromosome 19. Ann Hum Genet 49:267–274
Ritter JK, Owens IS, Negishi M, Nagata K, Sheen YY, Gillette JR, Sasame HA (1991) Mouse pulmonary cytochrome P450 naphthalene hydroxylase: cDNA cloning, sequence, and expression in Saccharomyces cerevisiae. Biochemistry 30:11430–11437
Santisteban I, Povey S, Shephard EA, Phillips IR (1988) The major phenobarbital-inducible cytochrome P-450 gene subfamily (P450IIB) mapped to the long arm of human chromosome 19. Ann Hum Genet 52:129–135
Trask B, Massa H, Kenwrick S, Gitschier J (1991) Mapping of human chromosome Xg28 by two-color flourescence in situ hybridization of DNA sequences to interphase cell nuclei. Am J Hum Genet 48:1–15
Tynan KM, Olsen A, Trask B, de Jong PJ, Branscomb E, Thompson J, Zimmermann W, Mohrenweise HW (1992) Assembly of a cosmid contig map in the CEA-gene family region of human chromosome 19. Nucleic Acids Res 7:1629–1636
Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, Kalow W, Gelboin HV, McBride OW, Gonzalez FJ (1989) cDNA cloning and sequence and cDNA-directed expression of human P450IIB 1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. Biochemistry 28:7340–7348
Yamano S, Tatsuno J, Gonzalez FJ (1990) The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry 29:1322–1329
Author information
Authors and Affiliations
Additional information
Correspondence to: H.W. Mohrenweiser
Rights and permissions
About this article
Cite this article
Hoffman, S.M.G., Fernandez-Salguero, P., Gonzalez, F.J. et al. Organization and evolution of the cytochrome P450 CYP2A-2B-2F subfamily gene cluster on human chromosome 19. J Mol Evol 41, 894–900 (1995). https://doi.org/10.1007/BF00173169
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00173169