Evolution of the rapidly mutating human salivary agglutinin gene (DMBT1) and population subsistence strategy

Abstract

The dietary change resulting from the domestication of plant and animal species and development of agriculture at different locations across the world was one of the most significant changes in human evolution. An increase in dietary carbohydrates caused an increase in dental caries following the development of agriculture, mediated by the cariogenic oral bacteriumStreptococcus mutans. Salivary agglutinin [SAG, encoded by the deleted in malignant brain tumors 1 (DMBT1) gene] is an innate immune receptor glycoprotein that binds a variety of bacteria and viruses, and mediates attachment ofS. mutansto hydroxyapatite on the surface of the tooth. In this study we show that multiallelic copy number variation (CNV) withinDMBT1is extensive across all populations and is predicted to result in between 7–20 scavenger–receptor cysteine-rich (SRCR) domains within each SAG molecule. Direct observation of de novo mutation in multigeneration families suggests these CNVs have a very high mutation rate for a protein-coding locus, with a mutation rate of up to 5% per gamete. Given that the SRCR domains bindS. mutansand hydroxyapatite in the tooth, we investigated the association of sequence diversity at the SAG-binding gene ofS. mutans, andDMBT1CNV. Furthermore, we show thatDMBT1CNV is also associated with a history of agriculture across global populations, suggesting that dietary change as a result of agriculture has shaped the pattern of CNV atDMBT1, and that theDMBT1-S. mutansinteraction is a promising model of host-pathogen-culture coevolution in humans.