Biology subjects

Ruhl, S.

Publications and source records attributed to Ruhl, S..

7 recordsLinked to original sources

bioRxiv2026

Gene Expansion and Regulatory Rewiring Shape Sex-Biased Evolution of the Mouse Submandibular Gland Secretome

Background Mammalian saliva plays essential roles in digestion, immunity, and host-microbiome interactions, yet its protein composition varies widely across species and sexes. This diversity makes saliva a powerful model to study evolution of gene expression. Here, we compared mouse and human salivary glands at the genomic, transcriptomic, and proteomic levels to understand how saliva composition evolves. Results We found that evolution of gene expression in mouse salivary glands is driven by rapid gene turnover and sexual dimorphism. In the submandibular and sublingual glands, 68% and 73% of expression from genes encoding secreted proteins derives from lineage-specific genes that lack one-to-one human orthologs. This contrasts the prevailing view that gene expression is largely conserved across tissues and highlights saliva as an unusually dynamic system of molecular evolution. Mouse submandibular gland shows striking sexual dimorphism, with 1537 tissue specific sex-biased genes, 3.8 times higher than in the liver (p<0.001), a classic model of sex-biased expression. We also identified sex-specific expression of glycosylation genes associated with differential Muc19 sialylation. These results suggest that sexual dimorphism in mouse saliva arises from both transcriptional differences in secreted proteins and sex-specific post-translational modifications. Further, differentially expressed genes in submandibular gland cluster in genomic regions shaped by recent gene duplication, such as the kallikrein gene cluster, a mouse-specific expansion that accounts for ~16.4% of male-biased submandibular gland expression. Our analyses suggest that this bias arises through regulatory changes that are expanded by gene duplication, including the spread of a testosterone-associated regulatory motif and the expansion of a shared chromatin domain that promotes coordinated gene regulation. Conclusions Together, our results reveal that lineage-specific genes disproportionately shape the mouse salivary transcriptome and that gene duplication and regulatory rewiring contribute to the rapid evolution of sex-biased expression in the submandibular gland. We describe a novel mechanism through which lineage-specific gene duplication and regulatory rewiring drive rapid, sex-specific evolution of the mammalian saliva. Our findings support saliva as an evolutionarily dynamic system and are consistent with developmental systems drift, whereby similar phenotypes across species may be maintained despite substantial divergence in their underlying gene-regulatory programs.

evolutionary biology↗

bioRxiv2025

Convergent evolution through independent rearrangements in the primate amylase locus

Structurally complex genomic regions can foster evolutionary convergence by repeatedly generating gene duplications that yield similar expression patterns and traits across lineages. Focusing on the primate amylase locus, we leveraged high-quality genome assemblies from 53 primate species and multi-tissue transcriptomes from Old World monkeys to reconstruct the evolutionary history of recurrent duplications. We show that lineage-specific long terminal repeat retrotransposon insertions may be associated with initial structural instability, while subsequent duplications are primarily driven by non-allelic homologous recombination. Independent duplications in rhesus macaques, olive baboons, and great apes produced distinct amylase copies with convergent expression in pancreas and salivary glands and signals of episodic diversifying selection, consistent with emerging functional divergence. Our analyses indicate that a ancestral gene with dual pancreas and salivary expression in Catarrhini duplicated in great apes, facilitating subfunctionalization and regulatory rewiring. These findings illuminate how modular structural and regulatory variation drives evolutionary innovation and molecular convergence.

evolutionary biology↗

bioRxiv2025

Sialic Acid Identity Modulates Host Tropism of Sialoglycan-binding Viridans Group Streptococci

Microbial interactions with multiple species may expand the range of potential hosts, supporting both pathogen reservoirs and zoonotic spillover. Viridans group streptococci interact with host cells by engaging protein-attached glycosylations capped with terminal sialic acids (sialoglycans). One potential origin for host tropism of these streptococci arises because humans exclusively synthesize the N-acetylneuraminic acid (Neu5Ac) form of sialic acid, while non-human mammals synthesize both Neu5Ac and a hydroxylated N-glycolylneuraminic acid (Neu5Gc). However, the link between binding preference for these sialic acids and preference for host has not been tested experimentally. Here, we investigate sialoglycan-binding by Neu5Ac/Neu5Gc cross-reactive Siglec-like binding regions (SLBRs) from two strains of streptococci, Streptococcus gordonii strain Challis (SLBRHsa) and Streptococcus sanguinis strain SK36 (SLBRSrpA). Structural and computational analyses of SLBRHsa identified molecular details for the binding of disaccharides capped in Neu5Ac or Neu5Gc. Engineering SLBRHsa and SLBRSrpA for narrow selectivity to synthetic Neu5Gc-terminated glycans shifted the binding preference from authentic human plasma receptors to plasma receptors from rat sources. However, host receptor preference did not fully recapitulate purified Neu5Ac/Neu5Gc-capped sialoglycan preference. These findings suggest that sialic acid identity modulates, but does not uniquely determine, host preference by these streptococci. This work refines our understanding of host specificity and challenges prevailing assumptions about the relative role of sialic acids in host tropism.

pathology↗

bioRxiv2024

Emergence of saliva protein genes in the secretory calcium-binding phosphoprotein (SCPP) locus and accelerated evolution in primates

Genes within the secretory calcium-binding phosphoprotein (SCPP) family evolved in conjunction with major evolutionary milestones: the formation of a calcified skeleton in vertebrates, the emergence of tooth enamel in fish, and the introduction of lactation in mammals. The SCPP gene family also contains genes expressed primarily and abundantly in human saliva. Here, we explored the evolution of the saliva-related SCPP genes by harnessing currently available genomic and transcriptomic resources. Our findings provide insights into the expansion and diversification of SCPP genes, notably identifying previously undocumented convergent gene duplications. In primate genomes, we found additional duplication and diversification events that affected genes coding for proteins secreted in saliva. These saliva-related SCPP genes exhibit signatures of positive selection in the primate lineage while the other genes in the same locus remain conserved. We found that regulatory shifts and gene turnover events facilitated the accelerated gain of salivary expression. Collectively, our results position the SCPP gene family as a hotbed of evolutionary innovation, suggesting the potential role of dietary and pathogenic pressures in the adaptive diversification of the saliva composition in primates, including humans.

evolutionary biology↗

bioRxiv2020

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

Salivary proteins are essential for maintaining health in the oral cavity and proximal digestive tract and serve as a diagnostic window into human disease. However, their precise organ origins remain unclear. Through transcriptomic analysis of major adult and fetal salivary glands, and integration with the saliva proteome and transcriptomes of 28+ organs, we linked human saliva proteins to their source, identified salivary gland-specific genes, and uncovered fetal- and adult-specific gene repertoires. Our results also provide new insights into the degree of gene retention during maturation and suggest that functional diversity between adult gland-types is driven by specific dosage combinations of hundreds of transcriptional regulators rather than a few gland-specific factors. Finally, we demonstrate the hitherto unrecognized heterogeneity of the human acinar cell lineage. Our results pave the way for future investigations into glandular biology and pathology, as well as salivas use as a diagnostic fluid.

developmental biology↗

bioRxiv2019

The effects of modified sialic acids on mucus and erythrocytes on influenza A virus HA and NA functions

Sialic acids (Sia) are the primary receptors for influenza viruses, and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include O-acetyl modifications at C4, C7, C8, and C9 positions, and N-acetyl or N-glycolyl at C5. They can also vary in their linkages, including 2-3 or 2-6-linkages. Here, we analyzed the distribution of modified Sia in cells and tissues of wild-type mice, or in mice lacking cytidine 5-monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) enzyme that synthesizes N-glycolyl modifications (Neu5Gc). We also examined the variation of Sia forms on erythrocytes and saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9-O-acetyl, 7,9-O-acetyl, 4-O-acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a great degree of variability in display of modified Sia between different species. IAV HA from different virus strains showed consistently reduced binding to both Neu5Gc and O-acetyl modified Sia; however, while IAV NA were inhibited by Neu5Gc and O-acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV, and may affect both pathogens and the normal flora of different mucosal sites.\n\nIMPORTANCESialic acids (Sia) are involved in many different cellular functions and are receptors for many pathogens. Sia come in many chemically modified forms but we lack a clear understanding of how they alter the interactions with microbes. Here we examine the expression of modified Sia in mouse tissues, on secreted mucus in saliva, and on erythrocytes, including those from IAV host species and animals used in IAV research. These Sia forms varied considerably between different animals, and their inhibitory effects on IAV NA and HA activities and on bacterial sialidases (neuraminidases) suggest a host-variable protective role in secreted mucus.

microbiology↗

bioRxiv2018

Amylase copy number analysis in several mammalian lineages reveals convergent adaptive bursts shaped by diet

The amylase gene (AMY), which codes for a starch-digesting enzyme in animals, underwent several gene copy number gains in humans1, dogs2, and mice3, presumably along with increased starch consumption during the evolution of these species. Here we present evidence for additional AMY copy number expansions in several mammalian species, most of which also consume starch-rich diets. We also show that these independent AMY copy number gains are often accompanied by a gain in enzymatic activity of amylase in saliva. We used multi-species coalescent modeling to provide further evidence that these recurrent AMY gene copy number expansions were adaptive. Our findings underscore the overall importance of gene copy number amplification as a flexible and fast adaptive mechanism in evolution that can independently occur in different branches of the phylogeny.

evolutionary biology↗