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High degree of conservation of the multigene tryptase locus over the past 150-200 million years of mammalian evolution
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2010 (English)In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 62, no 6, 369-382 p.Article in journal (Refereed) Published
Abstract [en]

Activated mast cells release a number of potent inflammatory mediators including histamine, proteoglycans, cytokines, and serine proteases. The proteases constitute the majority of the mast cell granule proteins, and they belong to either the chymase or the tryptase family. In mammals, these enzymes are encoded by two different loci, the mast cell chymase and the multigene tryptase loci. In mice and humans, a relatively large number of tryptic enzymes are encoded from the latter locus. These enzymes can be grouped into two subfamilies, the group 1 tryptases, with primarily membrane-anchored enzymes, and the group 2 tryptases, consisting of the soluble mast cell tryptases. In order to study the appearance of these enzymes during vertebrate evolution, we have analyzed the dog, cattle, opossum, and platypus genomes and sought orthologues in the genomes of several bird, frog, and fish species as well. Our results show that the overall structure and the number of genes within this locus have been well conserved from marsupial to placental mammals. In addition, two relatively distantly related group 2 tryptase genes and several direct homologues of some of the group 1 genes are present in the genome of the platypus, a monotreme. However, no direct homologues of the individual genes of either group 1 or 2 enzymes were identified in bird, amphibian, or fish genomes. Our results indicate that the individual genes within the multigene tryptase locus, in their present form, are essentially mammal-specific.

Place, publisher, year, edition, pages
2010. Vol. 62, no 6, 369-382 p.
Keyword [en]
Evolution, Granule protease, Locus, Mast cell, Serine protease, Tryptase
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97132DOI: 10.1007/s00251-010-0443-2ISI: 000278026700003PubMedID: 20383634OAI: oai:DiVA.org:uu-97132DiVA: diva2:171935
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Hematopoietic Serine Proteases from the Mast Cell Chymase and Tryptase Loci - a Functional and Evolutionary Analysis
Open this publication in new window or tab >>Hematopoietic Serine Proteases from the Mast Cell Chymase and Tryptase Loci - a Functional and Evolutionary Analysis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells are key effector cells in allergic and inflammatory diseases. However, their primary role is most likely in host defence against parasitic and bacterial infections. Mast cells are a particularly rich source of serine proteases. These proteases belong to the chymase or the tryptase family, which are encoded from the mast cell chymase and the multigene tryptase loci, respectively. To better understand the biological functions and the molecular evolution of these enzymes we have studied the organisation of these two loci in species ranging from fish to human. We show that the mast cell chymase locus has evolved from a single founder gene to a complex locus during the past 200 Myr of mammalian evolution. Forty-five fish candidate genes for hematopoietic serine proteases were also identified. However, in phylogenetic analyses none of them grouped with individual branches holding mammalian mast cell chymase locus genes, indicating an independent parallel evolution in fish.

Studies of the evolution of the multigene tryptase locus showed that this locus has been highly conserved between marsupials and eutherians. However, no genes belonging to the individual subfamilies identified in eutherians could be identified in fish, amphibians or in birds, which also here indicates parallel evolution.

To study the evolution of specific cleavage specificities associated with these proteases, the extended cleavage specificity of opossum α-chymase was determined and found to be nearly identical to human mast cell chymase and the major mouse mast cell chymase mMCP-4. This indicates a strong pressure to maintain this specificity during mammalian evolution.

Basophils are rare blood cells with functions similar to mast cells that when mature almost completely lack mRNA. To study the proteome and to primarily characterize the granule protein content of basophils, an in vitro purification protocol was developed to obtain transcriptionally active umbilical cord blood-derived basophil precursors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 427
Keyword
Cell and molecular biology, immune system, mast cell, basophil, mast cell chymase locus, multigene tryptase locus, serine protease, evolution, Cell- och molekylärbiologi
Identifiers
urn:nbn:se:uu:diva-8676 (URN)978-91-554-7179-8 (ISBN)
Public defence
2008-05-16, C10:305, BMC, Husargatan 3, Box 596, 75124 Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2011-07-08Bibliographically approved

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