Abstract
BackgroundWe have examined the evolution of the genes at the major human β-defensin locus and the orthologous loci in a range of other primates and mouse. For the first time these data allow us to examine selective episodes in the more recent evolutionary history of this locus as well as the ancient past. We have used a combination of maximum likelihood based tests and a maximum parsimony based sliding window approach to give a detailed view of the varying modes of selection operating at this locus.ResultsWe provide evidence for strong positive selection soon after the duplication of these genes within an ancestral mammalian genome. Consequently variable selective pressures have acted on β-defensin genes in different evolutionary lineages, with episodes both of negative, and more rarely positive selection, during the divergence of primates. Positive selection appears to have been more common in the rodent lineage, accompanying the birth of novel, rodent-specific β-defensin genes. These observations allow a fuller understanding of the evolution of mammalian innate immunity.In both the rodent and primate lineages, sites in the second exon have been subject to positive selection and by implication are important in functional diversity. A small number of sites in the mature human peptides were found to have undergone repeated episodes of selection in different primate lineages. Particular sites were consistently implicated by multiple methods at positions throughout the mature peptides. These sites are clustered at positions predicted to be important for the specificity of the antimicrobial or chemoattractant properties of β-defensins. Surprisingly, sites within the prepropeptide region were also implicated as being subject to significant positive selection, suggesting previously unappreciated functional significance for this region.ConclusionsIdentification of these putatively functional sites has important implications for our understanding of β-defensin function and for novel antibiotic design.
Highlights
We have examined the evolution of the genes at the major human β-defensin locus and the orthologous loci in a range of other primates and mouse
Defensins are peptides, which are generally cationic, are produced as prepropeptides and can be divided into subclasses based on the distribution of the six canonical cysteines that are located in the mature peptide
We provide statistically significant evidence for the action of both positive and negative selection in both rodent and primate lineages, and reveal the putatively functional sites within the peptide structures that have been subject to these forces at different times
Summary
We have examined the evolution of the genes at the major human β-defensin locus and the orthologous loci in a range of other primates and mouse. Antimicrobial peptides have a critical role in the vertebrate innate immune defence against microbes These peptides have potential as therapeutics and intelligent drug design relies on understanding how these molecules function. More recently βdefensins have been shown to act as a link between adaptive and innate immunity [3] and play important roles in cancer progression [4]. This has stimulated great interest in the function and evolution of β-defensins in primate lineages [5]
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