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.

Glycan recognition at the saliva – oral microbiome interface

“…The predominant mucins in human saliva are the high-molecular-weight mucin MUC5B and the lower molecular-weight mucin MUC7 [54]. MUC5B is a gel-forming mucin [56, 57] and much larger than the soluble and evolutionary younger mucin MUC7 [58, 59]. Recently, the presence of MUC19, another largemolecular-weight mucin in human saliva has been described [60].…”

“…A number of such agglutinins have been identified by in vitro studies. Among them are the salivary mucins MUC5B [50] and MUC7 [49, 59, 78] (Fig. 2A), salivary agglutinin gp340/DMBT1 [72, 79, 80] (Fig.…”

“…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]. …”

Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva

“…In future studies, it will be important to investigate how functional salivary gland tissue differentiation, transcriptional and posttranslational regulation, and intra-glandular heterogeneity play their roles in human health. We are particularly excited about opening up the possibility of asking specific questions about human evolutionary adaptations to different environmental conditions, food resources, and pathogen challenges among geographically and culturally distinct human populations with respect to their composition of saliva (Pajic et al, 2019;Perry et al, 2007;Thamadilok et al, 2019;Xu et al, 2016Xu et al, , 2017 .…”

New genes and functional innovation in mammals

“…Another example was the abundant antimicrobial salivary peptide mucin-7 (Bobek and Situ 2003). This gene likley originated in a placental mammal ancestor and evolved under positive selection in 25 response to pathogens (Xu et al 2016). Another example was dermcidin, a primate-specific antimicrobial peptide secreted in the skin (Toll-Riera et al 2009).…”