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Volume 64, Issue 4


Positive selection of three chitinase genes of the family 18 of glycoside hydrolases in mammals

Beibei He / Li Wang / Jinhong Wang / Gang Li / Shuyi Zhang
Published Online: 2009-07-17 | DOI: https://doi.org/10.2478/s11756-009-0117-4


The digestive enzyme chitinase degrades chitin, and is found in a wide range of organisms, from prokaryotes to eukaryotes. Although mammals cannot synthesize or assimilate chitin, several proteins of the glycoside hydrolase (GH) chitinase family GH18, including some with enzymatic activity, have recently been identified from mammalian genomes. Consequently, there is growing interest in molecular evolution of this family of proteins. Here we report on the use of maximum likelihood methods to test for evidence of positive selection in three genes of the chitinase family GH18, all of which are found in mammals. These focal genes are CHIA, CHIT1 and CHI3L1, which encode the chitinase proteins acidic mammalian chitinase, chitotriosidase and cartilage protein 39, respectively. The results of our analyses indicate that each of these genes has undergone independent selective pressure in their evolution. Additionally, we have found evidence of a signature of positive natural selection, with most sites identified as being subject to adaptive evolution located in the catalytic domain. Our results suggest that positive selection on these genes stems from their function in digestion and/or immunity.

Keywords: protein evolution; glycoside hydrolase family GH18; chitinase; positive selection

  • [1] Altschul S.F., Madden T.L., Schäffer A.A., Zhang J., Zhang Z., Miller W. & Lipman D.J. 1997. Gapped BLAST and PSIBLAST: a new generation of protein database search programs. Nucleic Acids Res. 25: 3389–3402. http://dx.doi.org/10.1093/nar/25.17.3389CrossrefGoogle Scholar

  • [2] Baeten D., Boots A.M., Steenbakkers P.G., Elewaut D., Bos E., Verheijden G.F., Berheijden G., Miltenburg A.M., Rijnders A.W., Veys E.M. & De Keyser F. 2000. Human cartilage gp-39+,CD16+ monocytes in peripheral blood and synovium: correlation with joint destruction in rheumatoid arthritis. Arthritis Rheum. 43: 1233–1243. http://dx.doi.org/10.1002/1529-0131(200006)43:6<1233::AID-ANR6>3.0.CO;2-9Google Scholar

  • [3] Bleau G., Massicotte F., Merlen Y. & Boisvert C. 1999. Mammalian chitinase-like proteins. EXS 87: 211–221. Google Scholar

  • [4] Benson D.A., Karsch-Mizrachi I., Lipman D.J., Ostell J. & Wheeler D.L. 2008. GenBank. Nucleic Acids Res. 36(Database issue): D25–D30. Google Scholar

  • [5] Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N. & Bourne P.E. 2000. The Protein Data Bank. Nucleic Acids Res. 28: 235–242. http://dx.doi.org/10.1093/nar/28.1.235CrossrefGoogle Scholar

  • [6] Boot R.G., Blommaart E.F., Swart E., Ghauharali-van der Vlugt K., Bijl N., Moe C., Place A. & Aerts J.M. 2001. Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J. Biol. Chem. 276: 6770–6778. http://dx.doi.org/10.1074/jbc.M009886200CrossrefGoogle Scholar

  • [7] Boot R.G., Renkema G.H., Strijland A., van Zonneveld A.J. & Aerts J.M. 1995. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J. Biol. Chem. 270: 26252–26256. http://dx.doi.org/10.1074/jbc.270.5.2198CrossrefGoogle Scholar

  • [8] Boot R.G., Renkema G.H., Verhoek M., Strijland A., Bliek J., de Meulemeester T.M., Mannens M.M. & Aerts J.M. 1998. The human chitotriosidase gene. Nature of inherited enzyme deficiency. J. Biol. Chem. 273: 25680–25685. http://dx.doi.org/10.1074/jbc.273.40.25680CrossrefGoogle Scholar

  • [9] Boot R.G., van Achterberg T.A., van Aken B.E., Renkema G.H., Jacobs M.J., Aerts J.M. & de Vries C.J. 1999. Strong induction of members of the chitinase family of proteins in atherosclerosis: chitotriosidase and human cartilage gp-39 expressed in lesion macrophages. Arterioscler. Thromb. Vasc. Biol. 19: 687–694. CrossrefGoogle Scholar

  • [10] Bussink A.P., Speijer D., Aerts J.M. & Boot R.G. 2007. Evolution of mammalian chitinase(-like) members of family 18 glycosyl hydrolases. Genetics 177: 959–970. http://dx.doi.org/10.1534/genetics.107.075846CrossrefGoogle Scholar

  • [11] Bussink A.P., van Eijk M., Renkema G.H., Aerts J.M. & Boot R.G. 2006. The biology of the Gaucher cell: the cradle of human chitinases. Int. Rev. Cytol. 252: 71–128. http://dx.doi.org/10.1016/S0074-7696(06)52001-7CrossrefGoogle Scholar

  • [12] Bussink A.P., Vreede J., Aerts J.M. & Boot R.G. 2008. A single histidine residue modulates enzymatic activity in acidic mammalian chitinase. FEBS Lett. 582: 931–935. http://dx.doi.org/10.1016/j.febslet.2008.02.032CrossrefGoogle Scholar

  • [13] Elias J.A., Homer R.J., Hamid Q. & Lee C.G. 2005. Chitinases and chitinase-like proteins in T(H)2 inflammation and asthma. J. Allergy Clin. Immunol. 116: 497–500. http://dx.doi.org/10.1016/j.jaci.2005.06.028CrossrefGoogle Scholar

  • [14] Flach J., Pilet P.E. & Jolles P. 1992. What’s new in chitinase research? Experientia 48: 701–716. http://dx.doi.org/10.1007/BF02124285CrossrefGoogle Scholar

  • [15] Flicek P., Aken B.L., Beal K., Ballester B., Caccamo M., Chen Y., Clarke L., Coates G., Cunningham F., Cutts T., Down T., Dyer S.C., Eyre T., Fitzgerald S., Fernandez-Banet J., Gräf S., Haider S., Hammond M., Holland R., Howe K.L., Howe K., Johnson N., Jenkinson A., Kähäri A., Keefe D., Kokocinski F., Kulesha E., Lawson D., Longden I., Megy K., Meidl P., Overduin B., Parker A., Pritchard B., Prlic A., Rice S., Rios D., Schuster M., Sealy I., Slater G., Smedley D., Spudich G., Trevanion S., Vilella A.J., Vogel J., White S., Wood M, Birney E., Cox T., Curwen V., Durbin R., Fernandez-Suarez X.M., Herrero J., Hubbard T.J., Kasprzyk A., Proctor G., Smith J., Ureta-Vidal A. & Searle S. 2008. Ensembl 2008. Nucleic Acids Res. 36(Database issue): D707–D714 Google Scholar

  • [16] Fujimoto W., Kimura K. & Iwanaga T. 2002. Cellular expression of the gut chitinase in the stomach of frogs Xenopus laevis and Rana catesbeiana. Biomed. Res. 23: 91–99. CrossrefGoogle Scholar

  • [17] Fukamizo T. 2000. Chitinolytic enzymes: catalysis, substrate binding, and their application. Curr. Protein Pept. Sci. 1: 105–124. http://dx.doi.org/10.2174/1389203003381450CrossrefGoogle Scholar

  • [18] Funkhouser J.D. & Aronson N.N., Jr. 2007. Chitinase family GH18: evolutionary insights from the genomic history of a diverse protein family. BMC Evol. Biol. 7: 96. http://dx.doi.org/10.1186/1471-2148-7-96CrossrefGoogle Scholar

  • [19] Fusetti F., Pijning T., Kalk K.H., Bos E. & Dijkstra B.W. 2003. Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J. Biol. Chem. 278: 37753–37760. http://dx.doi.org/10.1074/jbc.M303137200Google Scholar

  • [20] Fusetti F., von Moeller H., Houston D., Rozeboom H.J., Dijkstra B.W., Boot R.G., Aerts J.M. & van Aalten D.M. 2002. Structure of human chitotriosidase. Implications for specific inhibitor design and function of mammalian chitinase-like lectins. J. Biol. Chem. 277: 25537–25544. http://dx.doi.org/10.1074/jbc.M201636200CrossrefGoogle Scholar

  • [21] Hakala B.E., White C. & Recklies A.D. 1993. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J. Biol. Chem. 268: 25803–25810. Google Scholar

  • [22] Henrissat B. 1991. A classification of glycosyl hydrolases based on amino acid sequence similarities. Biochem. J. 280: 309–316. Google Scholar

  • [23] Henrissat B. 1999. Classification of chitinases modules. EXS 87: 137–156. Google Scholar

  • [24] Houston D.R., Recklies A.D., Krupa J.C. & van Aalten D.M. 2003. Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes. J. Biol. Chem. 278: 30206–30212. http://dx.doi.org/10.1074/jbc.M303371200CrossrefGoogle Scholar

  • [25] Jansa S.A., Lundrigan B.L. & Tucker P.K. 2003. Tests for positive selection on immune and reproductive genes in closely related species of the murine genus mus. J. Mol. Evol. 56: 294–307. http://dx.doi.org/10.1007/s00239-002-2401-6CrossrefGoogle Scholar

  • [26] Johansen J.S., Baslund B., Garbarsch C., Hansen M., Stoltenberg M., Lorenzen I. & Price P.A. 1999. YKL-40 in giant cells and macrophages from patients with giant cell arteritis. Arthritis Rheum. 42: 2624–2630. http://dx.doi.org/10.1002/1529-0131(199912)42:12<2624::AID-ANR17>3.0.CO;2-KCrossrefGoogle Scholar

  • [27] Johansen J.S., Christoffersen P., Moller S., Price P.A., Henriksen J.H., Garbarsch C. & Bendtsen F. 2000. Serum YKL-40 is increased in patients with hepatic fibrosis. J. Hepatol. 32: 911–920. http://dx.doi.org/10.1016/S0168-8278(00)80095-1CrossrefGoogle Scholar

  • [28] Johansen J.S., Olee T., Price P.A., Hashimoto S., Ochs R.L. & Lotz M. 2001. Regulation of YKL-40 production by human articular chondrocytes. Arthritis Rheum. 44: 826–837. http://dx.doi.org/10.1002/1529-0131(200104)44:4<826::AID-ANR139>3.0.CO;2-UCrossrefGoogle Scholar

  • [29] Junker N., Johansen J.S., Andersen C.B. & Kristjansen P.E. 2005. Expression of YKL-40 by peritumoral macrophages in human small cell lung cancer. Lung Cancer 48: 223–231. http://dx.doi.org/10.1016/j.lungcan.2004.11.011CrossrefGoogle Scholar

  • [30] Kasprzewska A. 2003. Plant chitinases — regulation and function. Cell. Mol. Biol. Lett. 8: 809–824. Google Scholar

  • [31] Kawasaki M., Hasegawa Y., Kondo S. & Iwata H. 2001. Concentration and localization of YKL-40 in hip joint diseases. J. Rheumatol. 28: 341–345. Google Scholar

  • [32] Kirkpatrick R.B., Emery J.G., Connor J.R., Dodds R., Lysko P.G. & Rosenberg M. 1997. Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages. Exp. Cell. Res. 237: 46–54. http://dx.doi.org/10.1006/excr.1997.3764CrossrefGoogle Scholar

  • [33] Kumar S., Tamura K. & Nei M. 2004. MEGA3: integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief. Bioinform. 5: 150–163. http://dx.doi.org/10.1093/bib/5.2.150CrossrefGoogle Scholar

  • [34] Kzhyshkowska J., Mamidi S., Gratchev A., Kremmer E., Schmuttermaier C., Krusell L., Haus G., Utikal J., Schledzewski K., Scholtze J. & Goerdt S. 2006. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 107: 3221–3228. http://dx.doi.org/10.1182/blood-2005-07-2843CrossrefGoogle Scholar

  • [35] Nei M., Gu X. & Sitnikova T. 1997. Evolution by the birth-and-death process in multigene families of the vertebrate immune system. Proc. Natl. Acad. Sci. USA 94: 7799–7806. http://dx.doi.org/10.1073/pnas.94.15.7799CrossrefGoogle Scholar

  • [36] Rehli M., Krause S.W. & Andreesen R. 1997. Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation. Genomics 43: 221–225. http://dx.doi.org/10.1006/geno.1997.4778CrossrefGoogle Scholar

  • [37] Rehli M., Niller H.H., Ammon C., Langmann S., Schwarzfischer L., Andreesen R. & Krause S.W. 2003. Transcriptional regulation of CHI3L1, a marker gene for late stages of macrophage differentiation. J. Biol. Chem. 278: 44058–44067. http://dx.doi.org/10.1074/jbc.M306792200CrossrefGoogle Scholar

  • [38] Renkema G.H., Boot R.G., Au F.L., Donker-Koopman W.E., Strijland A., Muijsers A.O., Hrebicek M. & Aerts J.M. 1998. Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur. J. Biochem. 251: 504–509. http://dx.doi.org/10.1046/j.1432-1327.1998.2510504.xCrossrefGoogle Scholar

  • [39] Saito A., Ozaki K., Fujiwara T., Nakamura Y. & Tanigami A. 1999. Isolation and mapping of a human lung-specific gene, TSA1902, encoding a novel chitinase family member. Gene 239: 325–331. http://dx.doi.org/10.1016/S0378-1119(99)00394-7CrossrefGoogle Scholar

  • [40] Stam M.R., Blanc E., Coutinho P.M. & Henrissat B. 2005. Evolutionary and mechanistic relationships between glycosidases acting on α- and β-bonds. Carbohydr. Res. 340: 2728–2734 http://dx.doi.org/10.1016/j.carres.2005.09.018CrossrefGoogle Scholar

  • [41] Suzuki M., Fujimoto W., Goto M., Morimatsu M., Syuto B. & Iwanaga T. 2002. Cellular expression of gut chitinase mRNA in the gastrointestinal tract of mice and chickens. J. Histochem. Cytochem. 50: 1081–1089. CrossrefGoogle Scholar

  • [42] Swanson W.J., Yang Z., Wolfner M.F. & Aquadro C.F. 2001. Positive Darwinian selection drives the evolution of several female reproductive proteins in mammals. Proc. Natl. Acad. Sci. USA 98: 2509–2514. http://dx.doi.org/10.1073/pnas.051605998CrossrefGoogle Scholar

  • [43] Tharanathan R.N. & Kittur F.S. 2003. Chitin — the undisputed biomolecule of great potential. Crit. Rev. Food Sci. Nutr. 43: 61–87. http://dx.doi.org/10.1080/10408690390826455CrossrefGoogle Scholar

  • [44] Tjoelker L.W., Gosting L., Frey S., Hunter C.L., Trong H.L., Steiner B., Brammer H. & Gray P.W. 2000. Structural and functional definition of the human chitinase chitin-binding domain. J. Biol. Chem. 275: 514–520. http://dx.doi.org/10.1074/jbc.275.1.514CrossrefGoogle Scholar

  • [45] van Aalten D.M., Komander D., Synstad B., Gaseidnes S., Peter M.G. & Eijsink V.G. 2001. Structural insights into the catalytic mechanism of a family 18 exo-chitinase. Proc. Natl. Acad. Sci. USA 98: 8979–8984. http://dx.doi.org/10.1073/pnas.151103798CrossrefGoogle Scholar

  • [46] Volck B., Johansen J.S., Stoltenberg M., Garbarsch C., Price P.A., Ostergaard M., Ostergaard K., Lovgreen-Nielsen P., Sonne-Holm S. & Lorenzen I. 2001. Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology. Osteoarthritis Cartilage 9: 203–214. http://dx.doi.org/10.1053/joca.2000.0377CrossrefGoogle Scholar

  • [47] Volck B., Ostergaard K., Johansen J.S., Garbarsch C. & Price P.A. 1999. The distribution of YKL-40 in osteoarthritic and normal human articular cartilage. Scand. J. Rheumatol. 28: 171–179. http://dx.doi.org/10.1080/03009749950154257CrossrefGoogle Scholar

  • [48] Volck B., Price P.A., Johansen J.S., Sorensen O., Benfield T.L., Nielsen H.J., Calafat J. & Borregaard N. 1998. YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils. Proc. Assoc. Am. Physicians 110: 351–360. Google Scholar

  • [49] Yang M.S., Morris D.W., Donohoe G., Kenny E., O’Dushalaine C.T., Schwaiger S., Nangle J.M., Clarke S., Scully P., Quinn J., Meagher D., Baldwin P., Crumlish N., O’Callaghan E., Waddington J.L., Gill M. & Corvin A. 2008. Chitinase-3-Like 1 (CHI3L1) gene and schizophrenia: genetic association and a potential functional mechanism. Biol. Psychiatry 64: 98–103. http://dx.doi.org/10.1016/j.biopsych.2007.12.012Google Scholar

  • [50] Yang Z. 1997. PAML: a program package for phylogenetic analysis by maximum likelihood. Comput. Appl. Biosci. 13: 555–556. Google Scholar

  • [51] Yang Z., Wong W.S. & Nielsen R. 2005. Bayes empirical bayes inference of amino acid sites under positive selection. Mol. Biol. Evol. 22: 1107–1118. http://dx.doi.org/10.1093/molbev/msi097CrossrefGoogle Scholar

  • [52] Zhao X., Tang R., Gao B., Shi Y., Zhou J., Guo S., Zhang J., Wang Y., Tang W., Meng J., Li S., Wang H., Ma G., Lin C., Xiao Y., Feng G., Lin Z., Zhu S., Xing Y., Sang H., St Clair D. & He L. 2007. Functional variants in the promoter region of chitinase 3-like 1 (CHI3L1) and susceptibility to schizophrenia. Am. J. Hum. Genet. 80: 12–18. http://dx.doi.org/10.1086/510438CrossrefGoogle Scholar

  • [53] Zheng T., Rabach M., Chen N.Y., Rabach L., Hu X., Elias J.A. & Zhu Z. 2005. Molecular cloning and functional characterization of mouse chitotriosidase. Gene 357: 37–46. http://dx.doi.org/10.1016/j.gene.2005.05.006CrossrefGoogle Scholar

  • [54] Zhu Z., Zheng T., Homer R.J., Kim Y.K., Chen N.Y., Cohn L., Hamid Q. & Elias J.A. 2004. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304: 1678–1682. http://dx.doi.org/10.1126/science.1095336CrossrefGoogle Scholar

About the article

Published Online: 2009-07-17

Published in Print: 2009-08-01

Citation Information: Biologia, Volume 64, Issue 4, Pages 819–825, ISSN (Online) 1336-9563, ISSN (Print) 0006-3088, DOI: https://doi.org/10.2478/s11756-009-0117-4.

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© 2009 Slovak Academy of Sciences. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

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