Gokcumen’s research traces the source of salivary proteins

“Saliva is important for tasting, for digesting, for swallowing, for defending us from the pathogens that we are constantly inhaling and consuming,” says Omer Gokcumen, associate professor of biological sciences, College of Arts and Sciences. “The proteins in our mouth form an army, if you will, that’s working constantly to protect us. Before this, scientists had an idea of the proteins that are found in the mouth, but we didn’t have a complete picture of where they were coming from. We’re addressing this gap.” Read the news article by Charlotte Hsu.

Research News

UB researchers’ paper describes how saliva is made

An immunofluorescence microscopy image of cells in a human submandibular gland.

Artist's illustration by Marie Saitou. Immunofluorescence microscopy image by Eliza Gaylord​

By CHARLOTTE HSU

Published November 18, 2020

Print
“The proteins in our mouth form an army, if you will, that’s working constantly to protect us. ”
Omer Gokcumen, associate professor
Department of Biological Sciences

In the TV series, “How It’s Made,” viewers often discover that common objects like pencils or rubber bands are quite complicated to make. The show walks people through complex production processes that lie behind familiar items.

A new paper in the journal Cell Reports does the same for saliva.

The study, published on Nov. 17, breaks down, in detail, where the multitude of proteins floating in our saliva originate.

The research traces these vital proteins back to their source, showing which proteins are produced by each of the three major types of human salivary glands, and how individual cells within a single gland can secrete different proteins. The project also identifies proteins in the mouth that seem to be coming from outside of salivary glands, from places such as epithelial tissues or blood plasma.

“Saliva is important for tasting, for digesting, for swallowing, for defending us from the pathogens that we are constantly inhaling and consuming,” says Omer Gokcumen, associate professor of biological sciences, College of Arts and Sciences. “The proteins in our mouth form an army, if you will, that’s working constantly to protect us. Before this, scientists had an idea of the proteins that are found in the mouth, but we didn’t have a complete picture of where they were coming from. We’re addressing this gap.”

“From a biomedical perspective, our research opens the door for further studies into the functions of saliva and salivary glands, and the use of saliva as a diagnostic fluid,” says Stefan Ruhl, professor of oral biology in the School of Dental Medicine. “Our study takes a snapshot of how healthy salivary glands should function. Deviations from this healthy expectation can indicate disease.”

The study’s first author is Marie Saitou, a tenure-track researcher in biosciences at Norwegian University of Life Sciences, and a former postdoctoral researcher at the University of Chicago and UB. Saitou, Gokcumen and Ruhl led the study with Sarah Knox, associate professor of cell and tissue biology in the University of California, San Francisco (UCSF) School of Dentistry.

An immunofluorescence microscopy image of cells in a human submandibular gland.

An immunofluorescence microscopy image of cells in a human submandibular gland. The image reveals that secretory acinar cells, which were all thought to be the same, are actually much more diverse, as shown by the different cells in the same gland expressing different proteins. A green stain indicates the presence of mucin 7, and a red stain indicates the presence of amylase. Nuclei of cells are in grey, and the epithelial membrane in cyan. Image: Alison May

Biological factories that churn out saliva

To explain how our bodies make saliva, the scientists first sought to understand which proteins are produced by each major type of salivary gland — the parotid, submandibular and sublingual glands (humans have a pair of each).

To do this, the team used a method called transcriptomics to measure gene activity in each kind of gland. Gene activity provides insight into protein production because each gene provides instructions for making a specific protein.

This endeavor enabled the scientists to understand the proteins that each gland generates, and how the glands differ from one another in terms of what they produce.

For instance, the study finds that the parotid and submandibular glands create a lot of salivary amylase, an enzyme that helps to digest starch, while the sublingual gland makes almost none. Meanwhile, the sublingual gland produces relatively large quantities of certain GalNAc transferases, a family of enzymes that’s important in initiating a process called O-glycosylation that attaches a sugar to certain salivary mucin proteins. These are just a couple of examples.

“We show how the actions of different glands collectively help to produce a complex bodily fluid — our saliva,” Saitou says.

“Our work reveals that even a gland type itself is not homogenous. The saliva-producing acinar cells, which were once thought to produce the same proteins, and thus be the same cells, actually synthesize distinct saliva proteins, thus indicating a new level of cellular diversity,” Knox says.

Gokcumen says the research is one step toward understanding the immense complexity of saliva. Beyond parsing out the origins of proteins made by salivary glands, the team also concluded that some proteins drifting in saliva likely don’t originate from salivary glands, and that some important proteins that help to regulate gene expression are predominantly active in salivary glands, but not in a litany of other tissues.

“Salivary proteins are a gateway to our body,” Gokcumen says. “When they do not function properly, we suffer. Our work brings us one step closer to understanding their complex origins and the intricate interplay between them.”

“Long-wished-for diagnostic applications of saliva for monitoring systemic well-being and disease will need to measure quantitative differences of biomarkers in saliva,” Ruhl says. “One obstacle always hampering progress in this arena was that we did not know exactly which proteins were intrinsically produced by the salivary glands, and which proteins diffused into saliva from surrounding tissue leakage. Also, we were lacking a reliable baseline — a standard, if you will — that tells us what are normal and healthy values for the protein components in saliva. Our paper helps resolve these conflicts, providing information that I expect will propel salivary diagnostic applications forward.”

In addition to Saitou, Gokcumen, Knox and Ruhl, co-authors include Eliza A. Gaylord, Alison J. May, Sara Nathan, Anissa Grawe, Jolie Chang and William Ryan from UCSF; Erica Xu from UB and Weill Cornell Medical College; and Lubov Neznanova from UB.

Omer Gokcumen

PhD

Omer Gokcumen.

Omer Gokcumen

PhD

Omer Gokcumen

PhD

Associate Professor
Distinguished Postdoc Mentor Award, 2019

Research Interests

Human and primate evolution, ancient humans (including Neanderthals and Denisovans), anthropological genomics

Education

  • PhD, University of Pennsylvania
  • Postdoctoral Research, Harvard Medical School

Research Statement

Omer Gokcumen is an expert in evolutionary anthropology — the study of how humans evolved and how they differ from non-human primates such as gorillas and chimpanzees. His work is tied to human evolution, including evolutionary adaptation and the evolutionary processes that lead to genetic disease.

Gokcumen’s research examines the role that genomic variants, especially deletions and duplications, play in human disease and biology. His laboratory investigates the evolutionary history of genetic variations tied to interesting traits and diseases in modern and ancient human populations.

Selected Links

Selected Publications

  • Pradhani et al. (2021). Protein acylation by saturated very long chain fatty acids and endocytosis are involved in necroptosis. Cell Chemical Biology. (In Press)
  • Xu, D., Gokcumen, O*., Khurana, E. (2020). Loss-of-function tolerance of enhancers in the human genome. PLoS Genetics. 6:e1008663.
  • Eaaswarkhanth, E., dos Santos, A.L.*, Gokcumen, O.*, Al-Mulla, F., Thanaraj, T.A. (2020). Genome-Wide Selection Scan in an Arabian Peninsula Population Identifies a TNKS Haplotype Linked to Metabolic Traits and Hypertension. Genome Biology and Evolution, 12:  77–87 [Highlighted in Human Genetics].
  • Gokcumen, O. (2020) Archaic hominin introgression into modern human genomes. Yearbook of Physical Anthropology. 171: 60.
  • Saitou, M.* & Gokcumen, O. (2020). An Evolutionary Perspective on the Impact of Genomic Copy Number Variation on Human Health. Journal of Molecular Evolution. 88: 104.
  • Thamadilok, S., Choi, K.-S., Ruhl, L., Schulte, F., Kazim, A. L., Hardt, M., Gokcumen, O*., Ruhl, S. (2020).Human and Non-Human Primate Lineage-Specific Footprints in the Salivary Proteome. Molecular Biology and Evolution. 37:39-405.
  • O Gokcumen, M Frachetti. The Impact of Ancient Genome Studies in Archaeology.  Annual Review of Anthropology. (2020) 49:277–98
  • Saitou, M*., Gaylord, E., Xu, D.,Neznanova, L., Nathan, S., Grawe, A., Chang, J., Ryan, William., Ruhl, S., Knox, S.M., and Gokcumen, O*.  (2020). Functional Specialization of Human Salivary Glands and Origins of Proteins Intrinsic to Human Saliva. Cell Reports. 33, 108402. [Corresponding Author].
  • Ozgur Taskent, Yen Lung Lin, Ioannis Patramanis, Pavlos Pavlidis and Omer Gokcumen, 2020. Analysis of Haplotypic Variation and Deletion Polymorphisms Point to Multiple Archaic Introgression Events, Including from Altai Neanderthal Lineage. https://doi.org/10.1534/genetics.120.303167
  • Saito, M., Gokcumen, O. (2019). Resolving the insertion sites of polymorphic duplications reveals a HERC2 haplotype under selection. Genome Biology and Evolution. evz107  [Corresponding Author].
  • Pajic, P., Pavlidis, P., Dean, K., Neznanova, L., Daugherity, E., Romano R-A., Garneau, D., Globig, A., Ruhl, S., Gokcumen, O. (2019). Independent amylase gene copy number bursts correlate with dietary preferences in mammals. eLife. 8:e44628 [Corresponding Author].
  • Chow J, Starr I*, Jamalzadeh S, Muniz O, Kumar A, Gokcumen, O.*, Ferkey DM, Cullen PJ. 2019. Filamentation Regulatory Pathways Control Adhesion-Dependent Surface Responses in Yeast. Genetics [Internet]:genetics.302004.2019. Available from: http://dx.doi.org/10.1534/genetics.119.302004
  • Lin, Y.-L.*, & Gokcumen, O.* (2019). Fine-Scale Characterization of Genomic Structural Variation in the Human Genome Reveals Adaptive and Biomedically Relevant Hotspots. Genome Biology and Evolution, 11(4), 1136–1151.  [Corresponding Author].Lin, Y-L., Gokcumen, O. (2018). Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots. BioRxiv [preprint]. April 4, 2018. Available here.
  • Pajic, P., Pavlidis, P., Dean, K., Neznanova, L., Daugherity, E., Romano R-A., Garneau, D., Globig, A., Ruhl, S., Gokcumen, O. (2018). Amylase copy number analysis in several mammalian lineages reveals convergent adaptive bursts shaped by diet. BioRxiv [preprint]. June 5, 2018. Available here.
  • Saito, M.*, Satta, Y., Gokcumen, O.* (2018). Complex haplotypes of GSTM1 gene deletions harbor signatures of a selective sweep in East Asian populations. G3. 8:2953.
  • Saito, M*. Lizardo, D., Taskent, R. O.*, Millner, A., Gokcumen, O., Atilla-Gokcumen, G. (2018). An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence. Mol Omics 14, 237 (a journal of Royal Society of Chemistry). [Cover article, co-Corresponding Author]. 
  • Saito, M.*, Satta, Y., Gokcumen, O.*, Ishida, T. (2018). Complex evolution of the GSTM gene family involves sharing of GSTM1 deletion polymorphism in humans and chimpanzees. BMC Genomics. 19:293. [co-Corresponding Author, IF:4.3]. 
  • Quillen, E., Norton, H., Parra, E., Lona-Durazo, F., Ang, K., I, Florin M., Pearson, L., Shriver, M., Lasisi, T., Gokcumen, O., Starr, I*., Lin, YL*., Martin, A., Jablonski, N. (2018). Shades of complexity: New perspectives on the evolution and genetic architecture of human skin. Yearbook of Physical Anthropology. (Early View).
  • Gokcumen, O. (2018). The Year in Genetics Anthropology: New Lands, New Technologies, New Questions. American Anthropologist. 120:266. [Also highlighted in the special virtual issue: “Genetics, Biology, and Race: Understanding Human Difference”].
  • Resendez, S.D.*, Bradley, J.*, Xu, D.*, Gokcumen, O.* (2018). Structural variants in ancient genomes. In: Rajora and Lindqvist, eds. Paleogenomics. Springer Population Genomics Series.
  • Schmidt, C. and Gokcumen, O.* (In press). Primate Genomics and Phylogenetics. In: O’Rourke, eds. A Companion to Anthropological Genetics. Wiley Press
  • Taskent et al. (2017). Variation and functional impact of Neanderthal ancestry in Western Asia.  Genome Biology and Evolution.  evx216. For press release.
  • Xu et al. (2017). VCFtoTree: a user-friendly tool to construct locus-specific alignments and phylogenies from thousands of anthropologically relevant genome sequences. BMC Bioinformatics. 18:426.
  • Xu et al. (2017). Archaic hominin introgression in Africa contributes to functional salivary MUC7 genetic variation. Mol Biol Evol. Press release from UB Press Office. A write-up in the Guardian is here. For further media coverage, please see its Altmetric page.
  • Taskent and Gokcumen (2017). The multiple histories of Western Asia: Perspectives from ancient, and modern genomes. PrePrint (before proofs). Hum. Bio.
  • Lizardo et al. (2017). Regulation of lipids is central to replicative senescence.  Molecular BioSystems. 13, 498-509 – This study was also recognized by the Royal Society of Chemistry as an article of particular interest.
  • Pajic et al. (2016). The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since Human Denisovan divergence. BMC Evolutionary Biology. 16,265.
  • Muthukrishnan et al. (2016). Atopic Dermatitis Susceptibility Variants In Filaggrin Hitchhike Hornerin Selective Sweep. Genome Biology and Evolution. 8, 3240 – For media coverage, please see its Altmetric page.
  • Xu et al. Recent Evolution of the salivary mucin MUC7. (2016). Scientific Reports. 6, 31791. Press release from UB Press Office. For further media coverage, please see its Altmetric page.
  • Lin et al. (2015). The evolution and functional impact of human deletion variants shared with archaic hominin genomes. Mol Biol Evol. Early Access. [Corresponding Author]. – Press release from UB Press Office. For further media coverage, please see its Altmetric page.  Here is also Omer’s Talk on this paper at EMPH @Tempe 2015.
  • Muthukrishan et al. (2014). Geographic Distribution And Adaptive Significance Of Genomic Structural Variants: An Anthropological Genetics Perspective. Hum Bio. 86(4):260-275. 2014. [Cover Article].