Dataset Information

Recent evolution of the salivary mucin MUC7.

ABSTRACT: Genomic structural variants constitute the majority of variable base pairs in primate genomes and affect gene function in multiple ways. While whole gene duplications and deletions are relatively well-studied, the biology of subexonic (i.e., within coding exon sequences), copy number variation remains elusive. The salivary MUC7 gene provides an opportunity for studying such variation, as it harbors copy number variable subexonic repeat sequences that encode for densely O-glycosylated domains (PTS-repeats) with microbe-binding properties. To understand the evolution of this gene, we analyzed mammalian and primate genomes within a comparative framework. Our analyses revealed that (i) MUC7 has emerged in the placental mammal ancestor and rapidly gained multiple sites for O-glycosylation; (ii) MUC7 has retained its extracellular activity in saliva in placental mammals; (iii) the anti-fungal domain of the protein was remodified under positive selection in the primate lineage; and (iv) MUC7 PTS-repeats have evolved recurrently and under adaptive constraints. Our results establish MUC7 as a major player in salivary adaptation, likely as a response to diverse pathogenic exposure in primates. On a broader scale, our study highlights variable subexonic repeats as a primary source for modular evolutionary innovation that lead to rapid functional adaptation.

SUBMITTER: Xu D

PROVIDER: S-EPMC4997351 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Recent evolution of the salivary mucin MUC7.

Xu Duo D Pavlidis Pavlos P Thamadilok Supaporn S Redwood Emilie E Fox Sara S Blekhman Ran R Ruhl Stefan S Gokcumen Omer O

Scientific reports 20160825

Genomic structural variants constitute the majority of variable base pairs in primate genomes and affect gene function in multiple ways. While whole gene duplications and deletions are relatively well-studied, the biology of subexonic (i.e., within coding exon sequences), copy number variation remains elusive. The salivary MUC7 gene provides an opportunity for studying such variation, as it harbors copy number variable subexonic repeat sequences that encode for densely O-glycosylated domains (PT ...[more]

PMID: 27558399

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Project description:Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and hypofunction of salivary and lacrimal glands. This loss of salivary function leads to oral dryness, impaired swallowing and speech, and increased infection and is associated with other autoimmune diseases and an increased risk of certain cancers. Despite the implications of this prevalent disease, diagnosis currently takes years, partly due to the diversity in patient presentation. Saliva is a complicated biological fluid with major constituents, including heavily glycosylated mucins MUC5B and MUC7, important for its viscoelastic and hydrating and lubricating properties. This study investigated Sjögren's patient's perception of dryness (bother index questionnaires) along with the rheological, protein composition, and glycan analysis of whole mouth saliva and the saliva on the mucosal surface (residual mucosal saliva) to understand the properties that most affect patient wellbeing. Sjögren's patients exhibited a statistically significant reduction in residual mucosal saliva, salivary flow rate, and extensional rheology, spinnbarkeit (stringiness). Although the concentration of mucins MUC5B and MUC7 were similar between patients and controls, a comparison of protein Western blotting and glycan staining identified a reduction in mucin glycosylation in Sjögren's, particularly on MUC7. LC-MS/MS analysis of O-glycans released from MUC7 by β-elimination revealed that although patients had an increase in core 1 sulfation, the even larger reduction in sialylation resulted in a global decline of charged glycans. This was primarily due to the loss of the extended core 2 disialylated structure, with and without fucosylation. A decrease in the extended, fucosylated core 2 disialylated structure on MUC7, residual mucosal wetness, and whole mouth saliva flow rate appeared to have a negative and cumulative effect on the perception of oral dryness. The observed changes in MUC7 glycosylation could be a potential diagnostic tool for saliva quality and taken into consideration for future therapies for this multifactorial syndrome.

Project description:Saliva contains two major families of mucins (MG1 and MG2); the polypeptide of the smaller of these glycoproteins (MG2) has been assigned as the product of the MUC7 gene. In this study we have devised a rapid two-step procedure that recovers this glycoprotein essentially free of other components and in sufficient quantity to enable physical and self-interaction studies. Raw saliva was solubilized in 4 M guanidinium chloride and thereafter subjected to Sepharose CL-4B chromatography. The MG2-rich fraction was recovered free from the larger MG1 glycoproteins and also smaller proteins/glycoproteins (molecular mass less than 100 kDa). MG2 glycoproteins were finally purified by anion-exchange chromatography on Mono Q. The purity of the preparation was assessed by SDS/PAGE after radiolabelling of the molecules with [14C]acetic anhydride. Peptide mapping, N-terminal sequencing and amino acid analysis verified the polypeptide of the mucins as the MUC7 gene product. The isolated molecules were examined by electron microscopy and appeared as short flexible worm-like structures 30-120 nm in length. The distribution was heterogeneous, containing a major component with number-average and weight-average lengths of 52 and 55 nm respectively and a minor component with number-average and weight-average lengths of 94 and 98 nm respectively. We propose that the two differently sized populations represent monomeric and dimeric species of the mucins. Gel chromatography performed in 0.2 M NaCl indicated the presence of monomers, dimers and tetramers; an average molecular mass for the preparation was 192 kDa. However, in 4 M guanidinium chloride the molecular mass was 158 kDa and a similar molecular mass (155 kDa) was determined for the mucin preparation after reduction. These results suggest that the mucins might self-associate via a protein-mediated interaction. On the basis of the results a model is proposed for the self-association of the MUC7 mucin, which might be important for its biological function.

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Recent evolution of the salivary mucin MUC7.

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Recent evolution of the salivary mucin MUC7.

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