Strain-specific polymorphisms in Paneth cell alpha-defensins of C57BL/6 mice and evidence of vestigial myeloid alpha-defensin pseudogenes

Paneth cells at the base of small intestinal crypts secrete microbicidal -defensins, termed cryptdins (Crps) in mice, as mediators of innate immunity. Proteomic studies show that five abundant Paneth cell -defensins in C57BL/6 mice are strain specific in that they have not been identified in other inbred strains of mice. Two C57BL/6-specific peptides are coded for by the Defcr20 and-21 genes evident in the NIH C57BL/6 genome but absent from the Celera mixed-strain assembly, which excludes C57BL/6 data and differs from the NIH build with respect to the organization of the -defensin gene locus. Conversely, C57BL/6 mice lack the Crp1,-2,-4, and-6 peptides and their corresponding Defcr1,-2,-4, and-6 genes, which are common to several mouse strains, including those of the Celera assembly. In C57BL/6 mice, -defensin gene diversification appears to have occurred by tandem duplication of a multigene cassette that was not found in the mixed-strain assembly. Both mouse genome assemblies contain conserved -defensin pseudogenes that are closely related to func-tional myeloid -defensin genes in the rat, suggesting that the neutrophil -defensin defect in mice resulted from progressive gene loss. Given the role of -defensins in shaping the composition of the enteric microflora, such polymorphisms may influence outcomes in mouse models of disease or infection. Mammalian -defensins are cationic antimicrobial peptides (AMPs) with microbicidal activities against many species o