title: Human subjects are protected from mast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations.
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
  We sought to compare functional and nonfunctional tryptase allele frequencies and establish haplotypes in human populations.
  
  
  METHODS
  Tryptase allele frequencies were determined by means of 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 (betaIII(FS)) carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. Homology models predict that betaIII(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 2 major and 5 minor tryptase haplotypes.
  
  
  CONCLUSIONS
  Tryptase deficiency alleles (alpha and the newly discovered betaIII(FS)) are common, causing the number of inherited active genes to range from a minimum of 2 to a maximum of 4, with major differences between populations in the proportion of individuals inheriting 2 versus 4 active alleles. African and Asian populations are especially enriched in genes encoding functional and nonfunctional tryptases, respectively. Strong linkage of TPSAB1 and TPSB2 and pairing of deficiency alleles with functional alleles in observed haplotypes protect human subjects from "knockout" genomes and indeed from inheritance of fewer than 2 active alleles.
authors.affiliation: Cardiovascular Research Institute, University of California at San Francisco, San Francisco, Calif, USA.
authors.forename: Neil N
authors.initials: NN
authors.lastname: Trivedi
authors.forename: Bani
authors.initials: B
authors.lastname: Tamraz
authors.forename: Catherine
authors.initials: C
authors.lastname: Chu
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: George H
authors.initials: GH
authors.lastname: Caughey
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002460:Cell Line; D018628:Gene Dosage; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology / Q000235:genetics; D015810:Linkage Disequilibrium; D008407:Mast Cells / Q000201:enzymology*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D016415:Sequence Alignment; D053802:Tryptases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*
chemical_list: D053802:Tryptases