title: 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 bacterium Streptococcus 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 of S. mutans to hydroxyapatite on the surface of the tooth. In this study we show that multiallelic copy number variation (CNV) within DMBT1 is 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 bind S. mutans and hydroxyapatite in the tooth, we investigated the association of sequence diversity at the SAG-binding gene of S. mutans, and DMBT1 CNV. Furthermore, we show that DMBT1 CNV 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 at DMBT1, and that the DMBT1-S. mutans interaction is a promising model of host-pathogen-culture coevolution in humans.
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
authors.forename: Shamik
authors.initials: S
authors.lastname: Polley
authors.affiliation: Molecular Cytogenetics Facility, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Sandra
authors.initials: S
authors.lastname: Louzada
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, Italy; and.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.affiliation: Bioinformatics, Scientific Institute IRCCS E. Medea, 23842 Bosisio Parini, Italy; and.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom;
authors.forename: Theodosius
authors.initials: T
authors.lastname: Balaskas
authors.affiliation: Division of Pediatric Nephrology, University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis, TN 38103.
authors.forename: David S
authors.initials: DS
authors.lastname: Hains
authors.affiliation: Molecular Cytogenetics Facility, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Fengtang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, United Kingdom; ejh33@le.ac.uk.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hollox
mesh_terms: D000383:Agriculture; D000595:Amino Acid Sequence; D005075:Biological Evolution; D002135:Calcium-Binding Proteins; D056915:DNA Copy Number Variations / Q000235:genetics; D004268:DNA-Binding Proteins; D005828:Genetics, Population; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*; D013295:Streptococcus mutans / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D008024:Ligands; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins
keywords: DMBT1; agriculture; copy number variation; mutation; structural variation
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