Humans are protected from mast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations Neil N. Trivedi, M.D. 1,2,6 , Bani Tamraz, Pharm. D. 1,4 , Catherine Chu, B.S. 3,4 , Pui-Yan Kwok, M.D., Ph.D. 1,3,4 , and George H. Caughey, M.D. 1,2,5,6 1 Cardiovascular Research Institute of the University of California at San Francisco, California 2 Department of Medicine of the University of California at San Francisco, California 3 Department of Dermatology of the University of California at San Francisco, California 4 Institute for Human Genetics of the University of California at San Francisco, California 5 Veterans Health Research Institute, San Francisco, California 6 Veterans Affairs Medical Center, San Francisco, California Abstract Background—Mast cell tryptases have proposed roles in allergic inflammation and host defense against infection. Tryptase gene loci TPSAB1 and TPSB2 are known to be polymorphic but the nature and extent of diversity at these loci have not been fully explored. Objective—To compare functional and nonfunctional tryptase allele frequencies and establish haplotypes in human populations. Methods—Tryptase allele frequencies were determined by direct sequencing in 270 individuals from HapMap populations of European, African, Chinese and Japanese ancestry. Haplotypes were predicted, validated in parent-child trios, and compared between populations. Results—We identify a new frame-shifted tryptase allele (ȕIII FS ) carried by 23% and 19% of individuals of European and African ancestry, but 0% of Asians. Homology models predict that ȕIII FS is functionless. Our genotyping assay shows that allele and haplotype distributions in each population are unique. Strong linkage disequilibrium between TPSAB1 and TPSB2 (r 2 = 0.83, D’ = 0.85) yields two major and five minor tryptase haplotypes. Conclusions—Tryptase deficiency alleles (α and newly discovered ȕIII FS ) are common, causing the number of inherited active genes to range from a minimum of two to a maximum of four, with major differences between populations in proportion of individuals inheriting two versus four active alleles. African and Asian populations are especially enriched in genes encoding functional and non- functional tryptases, respectively. Strong linkage of TPSAB1 and TPSB2, and pairing of deficiency alleles with functional alleles in observed haplotypes, protect humans from “knockout” genomes, and indeed from inheritance of fewer than two active alleles. Address correspondence to: Dr. George H. Caughey, Veterans Affairs Medical Center 111D, 4150 Clement Street, San Francisco, CA 94121, George.Caughey@ucsf.edu, Tel: 415-221-4810 x2385, Fax: 415-387-3568. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript J Allergy Clin Immunol. Author manuscript; available in PMC 2010 November 1. Published in final edited form as: J Allergy Clin Immunol. 2009 November ; 124(5): 1099–105.e1-4. doi:10.1016/j.jaci.2009.07.026. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript