Molecular evolution of transferrin: evidence for positive selection in salmonids.

Transferrins are iron-binding proteins that are involved in iron storage and resistance to bacterial disease. Previous work has shown that nonsynonymous-to-synonymous-site substitution ratios (d(n)/d(s) ratios) between transferrin genes from some salmonid species were significantly greater than 1.0, providing evidence for positive selection at the transferrin gene. The purpose of the current study was to put these earlier results in a broader evolutionary context by examining variation among 25 previously published transferrin sequences from fish, amphibians, and mammals. The results of the study show that evidence for positive selection at transferrin is limited to salmonids-d(n)/d(s) ratios estimated for nonsalmonid lineages were generally less than 1.0. Within the salmonids, approximately 13% of the transferrin codon sites are estimated to be subject to positive selection, with an estimated d(n)/d(s) ratio of approximately 7. The three- dimensional locations of some of the selected sites were inferred by comparing these sites to homologous sites in the bovine lactoferrin crystallographic structure. The selected sites generally fall on the outside of the molecule, within and near areas that are bound by transferrin-binding proteins from human pathogenic bacteria. The physical locations of sites estimated to be subject to positive selection support previous speculation that competition for iron from pathogenic bacteria could be the source of positive selection.