Balancing selection at the human salivary agglutinin gene (DMBT1) driven by host-microbe interactions

Alharbi, Adel F.; Sheng, Nongfei; Nicol, Katie; Strömberg, Nicklas; Hollox, Edward J.

doi:10.1016/j.isci.2022.104189

Cited by 8 publications

(6 citation statements)

References 60 publications

(81 reference statements)

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“…In fact, the higher fitness of heterozygotes for thalassemia alleles in malaria-struck regions was presciently predicted by Haldane in 1949 ( Lederberg, 1999 ). In the realm of structural variants, complex copy number variation in the human salivary agglutinin genes ( Alharbi et al, 2022 ), a regulatory deletion upstream of APOBEC3 gene family ( Gokcumen et al, 2013 ), and a deletion spanning LCE3B and LCE3C ( Pajic et al, 2016 ), which is associated with psoriasis, have been explicitly argued to be evolving in the human lineage under balancing selection.…”

Section: Introductionmentioning

confidence: 99%

Balancing selection on genomic deletion polymorphisms in humans

Aqil¹,

Speidel

Pavlidis

et al. 2023

eLife

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A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigation of ancient and possibly adaptive deletions remains imperative. Here, we demonstrate an excess of polymorphisms in present-day humans that predate the modern human-Neanderthal split (ancient polymorphisms), which cannot be explained solely by selectively neutral scenarios. We analyze the adaptive mechanisms that underlie this excess in deletion polymorphisms. Using a previously published measure of balancing selection, we show that this excess of ancient deletions is largely owing to balancing selection. Based on the absence of signatures of overdominance, we conclude that it is a rare mode of balancing selection among ancient deletions. Instead, more complex scenarios involving spatially and temporally variable selective pressures are likely more common mechanisms. Our results suggest that balancing selection resulted in ancient deletions harboring disproportionately more exonic variants with GWAS associations. We further found that ancient deletions are significantly enriched for traits related to metabolism and immunity. As a by-product of our analysis, we show that deletions are, on average, more deleterious than single-nucleotide variants. We can now argue that not only is a vast majority of common variants shared among human populations, but a considerable portion of biologically relevant variants has been segregating among our ancestors for hundreds of thousands, if not millions, of years.

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Section: Introductionmentioning

confidence: 99%

Balancing selection on genomic deletion polymorphisms in humans

Aqil¹,

Speidel

Pavlidis

et al. 2023

eLife

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“…Of note, the small DMBT1 caries susceptibility allele I is associated with the loss of binding of a Cnm strain and FUT2 fucose glycosylation. 47 We hypothesise that the Cnm phenotype may change SpaP and Cnm expression and glycotype depending on local and systemic niches and conditions during infection.…”

Section: Discussionmentioning

confidence: 99%

Human PRH1, PRH2 susceptibility and resistance and Streptococcus mutans virulence phenotypes specify different microbial profiles in caries

Sheng,

Mårell,

Sitaram

et al. 2024

eBioMedicine

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“…This seems to be in line with other authors (Yang et al, 2019). The variability of SpaP, although low, is to be compared with that of its ligand: salivary agglutinin (SAG)/DMBT-1 (Alharbi et al, 2022). Salivary agglutinin is a pattern recognition receptor for many bacteria, including S. mutans (Ligtenberg et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Serotype and distribution of adhesion genes inStreptococcus mutansclinical isolates

Donnet,

Claisse,

Samot

2024

Preprint

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The delicate balance of the oral cavity is disrupted by hygiene and diet changes, leading to caries. The virulence ofStreptococcus mutans, a key caries pathogen, is partly explained by its rhamnose-glucose polysaccharide (RGP) and its sucrose-dependent and -independent adhesion mechanisms. This study investigates the diversity ofS. mutansthrough analysis of its RGP and the distribution of sucrose-independent adhesion proteins (SpaP, WapA, Cnm, Cbm) in Parkinson’s disease patients.In the PARKIDENT clinical trial, strains were isolated from saliva samples of Parkinson’s patients before and after oral hygiene procedures. Strains were preanalyzed by multiplex PCR for serotype and collagen-binding proteins, followed by high-throughput sequencing and bioinformatics analysis using RAST® and BLAST®. Phylogenetic analyses and protein modeling were also conducted.Of 40 patients in the Parkident clinical trial, only 24 hadStreptococcus mutansstrains isolable from salivary swabs. Serotyping revealed that over 80% of the 44 strains isolated were serotype c, in line with prevalence data in the literature. Furthermore, only SpaP types A and B were identified in the strains. The low variability observed for the WapA protein underlines its functional importance. Finally, thecbmgene was not found in any strain, and only 5 strains possessed thecnmgene, all of them serotype c.The study of these 44Streptococcus mutansstrains showed characteristics similar to other populations. Serotype c predominates, with minimal peptide variability in adhesion proteins (SpaP, WapA). Collagen-binding proteins Cnm and Cbm are rare or absent. Further research is essential for detailed strain distribution in Parkinson’s-affected and general French populations due toS. mutans’growing role in extra-oral pathologies.

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Balancing selection at the human salivary agglutinin gene (DMBT1) driven by host-microbe interactions

Cited by 8 publications

References 60 publications

Balancing selection on genomic deletion polymorphisms in humans

Balancing selection on genomic deletion polymorphisms in humans

Human PRH1, PRH2 susceptibility and resistance and Streptococcus mutans virulence phenotypes specify different microbial profiles in caries

Serotype and distribution of adhesion genes inStreptococcus mutansclinical isolates

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