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Evolution of the rat kallikrein gene family: Gene conversion leads to functional diversity

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Summary

Kallikrein-like simple serine proteases are encoded by closely related members of a gene family in several mammalian species. Molecular cloning and genomic Southern blot analysis after conventional and pulsed-field gel electrophoresis indicate that the rat kallikrein gene family comprises 15–20 members, probably closely linked at a single locus. Determination of the nucleotide sequences of the rGK-3,-4, and-6 genes here completes sequence data for a total of nine rat kallikrein family members. Comparison of the rat gene sequences to each other and to those of human and mouse kallikrein family genes reveals patterns of relatedness indicative of concerted evolution. Analysis of nucleotide sequence variants in kallikrein family members shows that most sequence variants are shared by multiple family members; the patterns of shared variants are complex and indicate multiple short gene conversions between family members. Sequence exchanges between family members generate novel assortments of variants in amino acid coding regions that may affect substrate specificity and thereby contribute to the diversity of enzyme activity. Furthermore, small sequence exchanges also may play a role in generating the diverse patterns of tissue-specific expression of rat family members. These analyses indicate an important role for gene conversion in the evolution of the functional diversity of these duplicated genes.

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References

  • Arnheim N (1983) Concerted evolution of multigene families. In: Nei M, Koehn RK (eds) Evolution of genes and proteins. Sinauer, Sunderland MA pp 38–61

    Google Scholar 

  • Ashley PL, MacDonald RJ (1985a) Rat submaxillary gland kallikrein-related mRNAs: nucleotide sequences of four distinct types including tonin. Biochemistry 24:4512–4520

    PubMed  Google Scholar 

  • Ashley PL, MacDonald RJ (1985b) Tissue-specific expression of kallikrein-related genes in the rat. Biochemistry 24:4520–4527

    PubMed  Google Scholar 

  • Atchison M, Adesnik M (1986) Gene conversion in a cytochrome P-450 gene family. Proc Natl Acad Sci USA 83:2300–2304

    PubMed  Google Scholar 

  • Baker AR, Shine J (1985) Human kidney kallikrein: cDNA cloning and sequence analysis. DNA 4:445–450

    PubMed  Google Scholar 

  • Baltimore D (1981) Gene conversion: some implications for immunoglobulin genes. Cell 24:592–594

    PubMed  Google Scholar 

  • Bode W, Chen Z, Bartels K, Kutzbach C, Schmidt-Kastner G, Bartunik H (1983) Refined 2 Å X-ray crystal structure of porcine pancreatic kallikrein A, a specific trypsin-like serine proteinase. J Mol Biol 164:237–282

    PubMed  Google Scholar 

  • Boucher R, Asselin J, Genest J (1974) A new enzyme leading to the direct formation of angiotensin II. Circ Res 34[Suppl I]:203–209

    Google Scholar 

  • Bowcock AM, Fahnestock M, Goslin K, Shooter EM (1988) The NGF and kallikrein genes of mouse, the African ratMastomys natalensis and man: their distribution and mode of expression in the salivary gland. Mol Brain Res 3:165–172

    Google Scholar 

  • Brady JM, MacDonald RJ (1990) The expression of two kallikrein gene family members in the rat kidney. Arch Biochem Biophys 278:342–349

    PubMed  Google Scholar 

  • Brady JM, Wines DR, MacDonald RJ (1989) Expression of two kallikrein gene family members in the rat prostate. Biochemistry 28:5203–5210

    PubMed  Google Scholar 

  • Carle GF, Olson MV (1985) An electrophoretic karyotype for yeast. Proc Natl Acad Sci USA 82:3756–3760

    PubMed  Google Scholar 

  • Carroll MC, Alicot EM, Katzman PJ, Klickstein LB, Smith JA, Fearon DT (1988) Organization of genes encoding complement receptors type 1 and 2, decay-accelerating factor, and C4-binding protein in the RCA locus on human chromosome 1. J Exp Med 167:1271–1280

    PubMed  Google Scholar 

  • Chapdelaine P, Ho-Kim M, Tremblay RR, Dube JY (1988a) Nucleotide sequence of the androgen-dependent arginine esterase mRNA of canine prostate. FEBS Lett 232:187–192

    PubMed  Google Scholar 

  • Chapdelaine P, Paradis G, Tremblay RR, Dube JY (1988b) High level of expression in the prostate of a human glandular kallikrein mRNA related to prostate-specific antigens. FEBS Lett 236:205–208

    PubMed  Google Scholar 

  • Chen Y-P, Chao J, Chao L (1988) Molecular cloning and characterization of two rat renal kallikrein genes. Biochemistry 27:7189–7196

    PubMed  Google Scholar 

  • Clements JA, Matheson BA, MacDonald RJ, Funder JW (1989) The expressions of the kallikrein gene family in the rat pituitary: oestrogen effects and the expression of an additional family member in the neurointermediate lobe. J Neuroendocrinol 1:199–203

    Google Scholar 

  • Craik CS, Choo Q, Swift GH, Quinto C, MacDonald RJ, Rutter WJ (1984) Structure of two related rat pancreatic trypsin genes. J Biol Chem 259:14255–14264

    PubMed  Google Scholar 

  • denDunnen JT, Moormann RJM, Lubsen NH, Schoenmakers JGG (1986) Concerted and divergent evolution within the rat γ-crystallin gene family. J Mol Biol 189:37–46

    PubMed  Google Scholar 

  • Digby M, Zhang X, Richards RI (1989) Human prostate specific antigen (PSA) gene: structure and linkage to the kallikrein-like gene hGK-1. Nucleic Acids Res 17:2137

    PubMed  Google Scholar 

  • Dover G (1982) Molecular drive: a cohesive mode of species evolution. Nature 299:111–117

    PubMed  Google Scholar 

  • Drinkwater CC, Evans BA, Richards RI (1987) Mouse glandular kallikrein genes: identification and characterization of the genes encoding the epidermal growth factor binding proteins. Biochemistry 26:6750–6756

    PubMed  Google Scholar 

  • Drinkwater CC, Richards RI (1987) Sequence of the mouse glandular kallikrein gene, mGK-5. Nucleic Acids Res 15:10052

    PubMed  Google Scholar 

  • Drinkwater CC, Evans BA, Richards RI (1988) Sequence and expression of mouse γ-renin. J Biol Chem 263:8565–8568

    PubMed  Google Scholar 

  • Dunbar JC, Bradshaw RA (1987) Amino acid sequence of guinea pig prostate kallikrein. Biochemistry 26:3471–3478

    PubMed  Google Scholar 

  • Eickbush TM, Burke WD (1986) The silkmoth late chorion locus II. Gradients of gene conversion in two paired multigene families. J Mol Biol 190:357–366

    Google Scholar 

  • Elmoujahed A, Butman N, Brillard M, Gauthier F (1990) Substrate specificity of two kallikrein family gene products isolated from the rat submaxillary gland. FEBS Lett 265:137–140

    PubMed  Google Scholar 

  • Evans BA, Richards RI (1985) Genes for the α and γ subunits of mouse nerve growth factor are contiguous. EMBO J 4:133–138

    PubMed  Google Scholar 

  • Evans BA, Drinkwater CC, Richards RI (1987) Mouse glandular kallikrein genes. Structure and partial sequence analysis of the kallikrein gene locus. J Biol Chem 262:8027–8034

    PubMed  Google Scholar 

  • Evans BA, Yun ZX, Close JA, Tregear GW, Kitamura N, Nakanishi S, Callen DF, Baker E, Hyland VJ, Sutherland GR, Richards RI (1988) Structure and chromosomal localization of the human renal kallikrein gene. Biochemistry 27:1324–1329

    Google Scholar 

  • Feinberg AP, Vogelstein B (1984) A technique for radiolabeling DNA restriction endonuclease fragments to high specificity. Anal Biochem 132:6–13

    Google Scholar 

  • Fiedler F (1979) Enzymology of glandular kallikreins. Handb Exp Pharmacol 25:103–161

    Google Scholar 

  • Flavell RA, Allen H, Burkly LC, Sherman DH, Waneck GL, Wildera G (1986) Molecular biology of the H-2 histocompatibility complex. Science 233:437–443

    PubMed  Google Scholar 

  • Fukushima D, Kitamura N, Nakanishi S (1985) Nucleotide sequence of cloned cDNA for human pancreatic kallikrein. Biochemistry 24:8037–8043

    PubMed  Google Scholar 

  • Fuller PJ, Verity K, Matheson BA, Clements JA (1989) Kallikrein-gene expression in the rat gastrointestinal tract. Biochem J 264:133–136

    PubMed  Google Scholar 

  • Geliebter J, Nathenson SG (1987) Recombination and the concerted evolution of the murine MHC. Trends Genet 3:107–112

    Google Scholar 

  • Gerald WL, Chao J, Chao L (1986) Immunological identification of rat tissue kallikrein cDNA and characterization of the kallikrein gene family. Biochim Biophys Acta 866:1–14

    PubMed  Google Scholar 

  • Gorski J, Mach B (1986) Polymorphism of human Ia antigens: gene conversion between two DR β loci results in a new HLA-D/DR specificity. Nature 322:67–70

    PubMed  Google Scholar 

  • Greer J (1981) Comparative model-building of the mammalian serine proteases. J Mol Biol 153:1027–1042

    PubMed  Google Scholar 

  • Hess JF, Schmid C, Shen C (1984) A gradient of sequence divergence in the human adult α-globin duplication units. Science 226:67–70

    PubMed  Google Scholar 

  • Hill AUS, Nicholls RD, Thein SL, Higgs DR (1985) Recombination within the human embryonic zeta-globin locus: a common zeta-zeta chromosome produced by gene conversion of the pseudo-zeta gene. Cell 42:809–819

    PubMed  Google Scholar 

  • Howles PN, Dickinson DP, DiCaprio LL, Woodworth-Gutai M, Gross KW (1984) Use of a cDNA recombinant for the γ-subunit of mouse nerve growth factor to localize members of this multigene family near the TAM-1 locus on chromosome 7. Nucleic Acids Res 12:2791–2805

    PubMed  Google Scholar 

  • Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning. A laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor NY

    Google Scholar 

  • Mason AJ, Evans BA, Cox DR, Shine, J, Richards RI (1983) Structure of mouse kallikrein gene family suggests a role in specific processing of biologically active peptides. Nature 303: 300–307

    PubMed  Google Scholar 

  • Matsunaga E, Umeno M, Gonzalez FJ (1990) The rat P450 subfamily: complete sequences of four closely linked genes and evidence that gene conversions maintained sequence homogeneity at the heme-binding region of the cytochrome P450 active site. J Mol Evol 30:155–169

    PubMed  Google Scholar 

  • McIntyre KR, Seidman JG (1984) Nucleotide sequence of mutant I-Aβbm 12 gene is evidence for genetic exchange between mouse immune response genes. Nature 308:551–553

    PubMed  Google Scholar 

  • Mortimer RK, Schild D (1985) Genetic map ofSaccharomyces cerevisiae, edition 9. Microbiol Rev 49:181–213

    PubMed  Google Scholar 

  • Ohta T (1980) Evolution and variation of multigene families. Lecture notes in biomathematics, vol 37. Springer-Verlag, New York

    Google Scholar 

  • Ohta T (1983) On the evolution of multigene families. Theor Pop Biol 23:216–240

    Google Scholar 

  • Powers PA, Smithies O (1986) Short gene conversions in the human fetal globin gene region: a by-product of chromosome pairing during meiosis? Genetics 112:343–358

    PubMed  Google Scholar 

  • Pritchett DB, Roberts JL (1987) Dopamine regulates expression of the glandular-type kallikrein gene at the transcriptional level in the pituitary. Proc Natl Acad Sci USA 84:5545–5549

    PubMed  Google Scholar 

  • Reynaud C, Anquez U, Grimal H, Weill J (1987) A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 48:379–388

    PubMed  Google Scholar 

  • Riegman PHJ, Vlietstra RJ, van der Korput J, Romijn JC, Trapman J (1989) Characterization of the prostate-specific antigen gene: a novel human kallikrein-like gene. Biochem Biophys Res Commun 159:95–102

    PubMed  Google Scholar 

  • Schachter M (1980) Kallikreins (kininogenases)—a group of serine proteases with bioregulatory actions. Pharmacol Rev 31:1–17

    Google Scholar 

  • Schechter I, Berger A (1967) On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun 27:157–162

    PubMed  Google Scholar 

  • Schedlich LJ, Bennetts BH, Morris BJ (1987) Primary structure of a human glandular kallikrein gene. DNA 6:429–437

    PubMed  Google Scholar 

  • Seemann GHA, Rein RS, Brown CS, Ploegh HL (1986) Gene conversion-like mechanisms may generate polymorphism in human class I genes. EMBO J 5:547–552

    PubMed  Google Scholar 

  • Slightom JL, Blechl AE, Smithies O (1980) Human fetalGγ− and^γ−-globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes}. Cell 21:627–638

    PubMed  Google Scholar 

  • Smithies O, Powers P (1986) Gene conversions and their relation to homologous chromosome pairing. Phil Trans R Soc Lond B 312:291–302

    Google Scholar 

  • Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517

    PubMed  Google Scholar 

  • Swift GH, Dagorn J-C, Ashley PL, Cummings SW, MacDonald RJ (1982) Rat pancreatic kallikrein mRNA: nucleotide sequence and amino acid sequence of the encoded preproenzyme. Proc Natl Acad Sci USA 79:7263–7267

    PubMed  Google Scholar 

  • Swift GH, Craik CS, Stary SJ, Quinto C, Lahaie RG, Rutter WJ, MacDonald RJ (1984) Structure of two related elastase genes in the rat pancreas. J Biol Chem 259:14271–14278

    PubMed  Google Scholar 

  • Thibault G, Genest J (1981) Tonin, an esteroprotease from rat submaxillary gland. Biochim Biophys Acta 660:23–29

    PubMed  Google Scholar 

  • Tschesche H, Mair G, Godec G, Fiedler F, Ehret W, Hirschauer C, Lemon M, Fritz H, Schmidt-Kastner G, Kutzback K (1979) The primary structure of porcine glandular kallikrein. In: Fujii S, Moriya H, Suzuki T (eds) Advances in experimental medicine and biology, 120A. Kinins II. Plenum, New York, pp 245–260

    Google Scholar 

  • van Leeuwen BH, Evans BA, Tregear GW, Richards RI (1986) Mouse glandular kallikrein genes. Identification, structure and expression of the renal kallikrein gene. J Biol Chem 261:5529–5535

    PubMed  Google Scholar 

  • Walsh JB (1987) Sequence-dependent gene conversion: can duplicated genes diverge fast enough to escape conversion? Genetics 117:543–557

    PubMed  Google Scholar 

  • Wines DR (1989) The rat kallikrein gene family: structure and evolution. PhD thesis, University of Texas Southwestern Medical Center, Dallas

    Google Scholar 

  • Wines DR, Brady JM, Pritchett DB, Roberts JL, MacDonald RJ (1989) Organization and expression of the rat kallikrein gene family. J Biol Chem 264:7653–7662

    PubMed  Google Scholar 

  • Woodley CM, Chao J, Margolius HS, Chao L (1985) Specific identification of tissue kallikrein in exocrine tissues and in cell-free translation products with monoclonal antibodies. Biochem J 231:721–728

    PubMed  Google Scholar 

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  1. Debora R. Wines

    Present address: Fred Hutchinson Cancer Research Center, 98104, Seattle, WA, USA

Authors and Affiliations

  1. Department of Biochemistry, The University of Texas Southwestern Medical Center, 75235-9038, Dallas, TX, USA

    Debora R. Wines, James M. Brady, E. Michelle Southard & Raymond J. MacDonald

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  1. Debora R. Wines
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Wines, D.R., Brady, J.M., Michelle Southard, E. et al. Evolution of the rat kallikrein gene family: Gene conversion leads to functional diversity. J Mol Evol 32, 476–492 (1991). https://doi.org/10.1007/BF02102650

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  • DOI: https://doi.org/10.1007/BF02102650

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