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Mast Cell and Tryptases Changed Rapidly during Primate Speciation and Evolved from -Like Transmembrane Peptidases in Ancestral Vertebrates¹

Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, CA 94143; Northern California Institute for Research and Education, San Francisco, CA 94121; and Veterans Affairs Medical Center, San Francisco, CA 94121

Human mast cell tryptases vary strikingly in secretion, catalytic competence, and inheritance. To explore the basis of variation, we compared genes from a range of primates, including humans, great apes (chimpanzee, gorilla, orangutan), Old- and New-World monkeys (macaque and marmoset), and a prosimian (galago), tracking key changes. Our analysis reveals that extant soluble tryptase-like proteins, including - and -like tryptases, mastins, and implantation serine proteases, likely evolved from membrane-anchored ancestors because their more deeply rooted relatives ( tryptases, pancreasins, prostasins) are type I transmembrane peptidases. Function-altering mutations appeared at widely separated times during primate speciation, with tryptases evolving by duplication, gene conversion, and point mutation. The -tryptase Gly²¹⁶Asp catalytic domain mutation, which diminishes activity, is present in macaque tryptases, and thus arose before great apes and Old World monkeys shared an ancestor, and before the split. However, the Arg^–3Gln processing mutation appeared recently, affecting only human . By comparison, the transmembrane -tryptase gene, which anchors the telomeric end of the multigene tryptase locus, changed little during primate evolution. Related transmembrane peptidase genes were found in reptiles, amphibians, and fish. We identified soluble tryptase-like genes in the full spectrum of mammals, including marsupial (opossum) and monotreme (platypus), but not in nonmammalian vertebrates. Overall, our analysis suggests that soluble tryptases evolved rapidly from membrane-anchored, two-chain peptidases in ancestral vertebrates into soluble, single-chain, self-compartmentalizing, inhibitor-resistant oligomers expressed primarily by mast cells, and that much of present numerical, behavioral, and genetic diversity of - and -like tryptases was acquired during primate evolution.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant HL024136 and the Northern California Institute for Research and Education.

² Address correspondence and reprint requests to Dr. George H. Caughey, Veterans Affairs Medical Center, Mailstop 111D, 4150 Clement Street, San Francisco, CA 94121. E-mail address: George.Caughey{at}ucsf.edu

³ Abbreviations used in this paper: BLAST, basic local alignment search tool; ISP, implantation serine protease; BAC, bacterial artificial chromosome; UPGMA, unweighted pair group method with arithmetic mean.