The complexity of selection at the major primate beta-defensin locus.
BACKGROUND
We have examined the evolution of the genes at the major human beta-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.


RESULTS
We 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 beta-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 beta-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 beta-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.


CONCLUSIONS
Identification of these putatively functional sites has important implications for our understanding of beta-defensin function and for novel antibiotic design.
Semple
Colin A M
CA
MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK. colins@hgu.mrc.ac.uk
Maxwell
Alison
A
Gautier
Philippe
P
Kilanowski
Fiona M
FM
Eastwood
Hayden
H
Barran
Perdita E
PE
Dorin
Julia R
JR
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D005075:Biological Evolution; D016000:Cluster Analysis; D019143:Evolution, Molecular; D005091:Exons; D014644:Genetic Variation; D016678:Genome; D007438:Introns; D016013:Likelihood Functions; D051379:Mice; D008957:Models, Genetic; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011323:Primates; D012641:Selection, Genetic; D013997:Time Factors; D023083:beta-Defensins / Q000235:genetics*
D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; D023083:beta-Defensins