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 cysteinerich (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-pathogenculture coevolution in humans.copy number variation | agriculture | DMBT1 | mutation | structural variation

Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences

“…To validate the computational callsets, we used: aCGH; alkaline lysis fibre-FISH, following the protocol of Perry, et al 42 ; and molecular combing fibre-FISH, following Polley et al 43 , Carpenter et al 44 , and instructions from the manufacturer, Genomic Vision.…”

Glycan recognition at the saliva – oral microbiome interface

“…Microbial-host coevolution may not only affect the structure of glycans, but also their numbers, densities, and sterical presentations on their protein or lipid backbone, and perhaps in a larger sense on any cell or biological surface [102]. An example for that effect may be the observed variations in the number of densly O-glycosylated PTS repeat domains in salivary agglutinins [103] and mucins [104, 105] which are known to interact with microbes through glycan-mediated binding (sections 3.1 and 3.2 ). For example, variations in subexonic PTS copy number repeats in salivary mucin MUC7 underwent rapid evolution in the primate lineage and among other mammalian species [59], and similar mechanisms involving possible pathogenic pressure may explain the observable variations in MUC7 among geographically distinct human populations [58].…”

Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots

“…Given their larger size, an individual SV potentially has a higher phenotypic impact than single nucleotide variants, especially when affecting functional sequences (Conrad et al 2009;Iskow et al 2012aIskow et al , 2012b. In fact, SVs have been associated with many human diseases (Weischenfeldt et al 2013), especially autoimmune, metabolic and cognitive disorders (Polley et al 2015;Hollox et al 2008;Stefansson et al 2008;Traherne et al 2010). However, the haplotype architectures around SVs are generally complex due to repeat content, gene conversion and recurrent formation of SVs, making it difficult to accurately impute them in genome-wide association studies (Sudmant et al 2015).…”

“…Indeed, previous studies have shown a drastic depletion of deletion polymorphisms from exonic regions (Conrad et al 2009). Despite the overall depletion of SVs in functional sequences, there are still some SVs that are passively tolerated under relaxed negative selection (Nguyen et al 2008;Eaaswarkhanth et al 2016), and some others that are actively maintained by non-neutral evolutionary forces (Gokcumen et al 2013b;Pajic et al 2016;Perry et al 2007;Polley et al 2015).…”