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Rapid lineage-specific diversification of the mast cell chymase locus during mammalian evolution

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Abstract

Serine proteases constitute the major protein granule content of cells of several hematopoietic cell lineages. A subgroup of these proteases, including the mast cell chymases, neutrophil cathepsin G, and T cell granzymes B to F and N, are in all investigated mammals encoded in one locus, the chymase locus. It is interesting to note that this locus has diversified greatly during the last 95 Myr of mammalian evolution. This divergence is exemplified by the presence of Mcpt8-related genes and multiple β-chymases in the mouse and rat, which lack direct counterparts in primates and in seven functional granzyme genes in the mouse where the human locus has only two. To study the expansion of the locus during rodent evolution and to better understand the evolutionary origin of β-chymases and the Mcpt8-family, we have performed a detailed analysis of the chymase locus of four mammalian species, i.e., human, dog, mouse, and rat. As a result, we report here a second chymase-like gene in dog, Cma2, which clusters with β-chymases in phylogenetic analyses. This finding supports a duplication of the common ancestor for α- and β-chymases before the major radiation of placental mammals, and a loss of the ancestral β-chymase gene sometime during primate evolution. Moreover, we show that in the rat, the Mcpt8-family diversified relatively recently together with sequences related to the β-chymase Mcpt2. Eight novel genes were identified in the duplication region, four of which are predicted to be functional. Duplications of rat granzyme B- and C-like sequences occurred seemingly independently within a similar time frame, but did not give rise to functional genes. Due to the duplications in rat and deletions in the carnivore/primate lineage, the rat chymase locus is approximately 15 and 9 times larger than its counterparts in dog and human, respectively. These findings illustrate the importance of gene duplications in conferring rapid changes in mammalian genomes.

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Abbreviations

aa:

amino acid

indels:

insertions and/or deletions

Myr:

million years

MC:

mast cell

MMC:

mucosal mast cells

CTMC:

connective tissue mast cells

mMCP:

mouse mast cell protease (protein)

rMCP:

rat mast cell protease (protein)

Mcpt:

mast cell protease (protein)

Mcpt :

mast cell protease (gene)

M/R8-family:

mouse/rat Mcpt8-family

R8-family:

rat Mcpt8-family

M1/R2-family:

mouse Mcpt1-/rat Mcpt2-family

R2-family:

rat Mcpt2-family

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Acknowledgements

We thank Dr. Robert Fredriksson for excellent advice on bioinformatic tools. We thank professor Lars Pilström and Jenny Reimer for critical reading of the manuscript. This work was funded by the Swedish Research Council.

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Correspondence to Lars Hellman.

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Gallwitz, M., Hellman, L. Rapid lineage-specific diversification of the mast cell chymase locus during mammalian evolution. Immunogenetics 58, 641–654 (2006). https://doi.org/10.1007/s00251-006-0123-4

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