Rapid evolution and diversification of mammalian α-defensins as revealed by comparative analysis of rodent and primate genes

Abstract

Mammalian α-defensins constitute a family of cysteine-rich, cationic antimicrobial peptides produced by phagocytes and intestinal Paneth cells, playing an important role in innate host defense. Following comprehensive computational searches, here we report the discovery of complete repertoires of the α-defensin gene family in the human, chimpanzee, rat, and mouse with new genes identified in each species. The human genome was found to encode a cluster of 10 distinct α-defensin genes and pseudogenes expanding 132 kb continuously on chromosome 8p23. Such α-defensin loci are also conserved in the syntenic chromosomal regions of chimpanzee, rat, and mouse. Phylogenetic analyses showed formation of two distinct clusters with primate α-defensins forming one cluster and rodent enteric α-defensins forming the other cluster. Species-specific clustering of genes is evident in nonprimate species but not in the primates. Phylogenetically distinct subsets of α-defensins also exist in each species, with most subsets containing multiple members. In addition, natural selection appears to have acted to diversify the functionally active mature defensin region but not signal or prosegment sequences. We concluded that mammalian α-defensin genes may have evolved from two separate ancestors originated from β-defensins. The current repertoires of the α-defensin gene family in each species are primarily a result of repeated gene duplication and positive diversifying selection after divergence of mammalian species from each other, except for the primate genes, which were evolved prior to the separation of the primate species. We argue that the presence of multiple, divergent subsets of α-defensins in each species may help animals to better cope with different microbial challenges in the ecological niches which they inhabit.