Where did our mucus evolve from? The answer could help explain cancers

Mucus is a gelatinous or slippery fluid produced by mucous membranes in the body and is found in various bodily fluids, such as the saliva in our mouths.

The production of mucus has many purposes for our health. Mucus contains antibodies and enzymes that function to eliminate or neutralize harmful bacteria in the air. It protects and prevents drying out of the tissue that coats your lungs, throat, and nasal and sinus passageways. But how did this marvel of biology evolve?

According to a press release published on August 26th, a new study about proteins called mucins suggests that mucins in mammals have evolved repeatedly by surprisingly co-opting non-mucin proteins.

The research team used a gel electrophoresis technique to separate mucins from other proteins in the saliva of various animals. The study revealed that from the mucin genes in 49 animal species, 15 instances were identified where new mucins appeared to have evolved through an additive process that changed a non-mucin protein into mucin.

The study indicates that this 'mucinization' process begins with a protein that wasn't originally a mucin. Evolution added a short chain of building blocks known as amino acids embellished with sugar molecules at some point to this non-mucin basis. Over time, this new area was duplicated, with further copies added to lengthen the protein, turning it into mucin.

These doubled regions called "repeats" are key to a mucin's function, explains University at Buffalo researchers Omer Gokcumen and Stefan Ruhl, the study's senior authors, and Petar Pajic, the first author.

The sugars covering these regions extend outward like bottle brush bristles, giving mucins the slimy quality essential to the many crucial functions these proteins perform.

"I don't think it was previously known that protein function can evolve this way, from a protein gaining repeated sequences. A protein that isn't a mucin becomes a mucin just by gaining repeats. This is an important way that evolution makes slime. It's an evolutionary trick, and we now document this happening over and over again," says Gokcumen, Ph.D., associate professor of biological sciences at the UB College of Arts and Sciences.

A mesmerizing journey of evolution

The researchers found that mice lacked MUC7, a tiny salivary mucin seen in humans. However, MUC10, a salivary mucin of comparable size, was present in the rodents. So the researchers wondered if these two proteins were related from an evolutionary perspective.

Even though the answer to this was no, the research revealed that while MUC10 did not appear to be connected to MUC7, PROL1, a protein identified in human tears, did have some structural similarities to MUC10. Without the sugar-coated bottlebrush repetitions that define MUC10 as a mucin, PROL1 resembled MUC10 in appearance.

"We think that somehow that tear gene ends up repurposed," states Gokcumen. "It gains the repeats that give it the mucin function, and it's now abundantly expressed in mouse and rat saliva."

The researchers also wondered if other mucins could have formed the same way and decided to look into it. They came across numerous instances of the same phenomenon. The scientists identified 15 instances in which evolution appears to have transformed non-mucin proteins into mucins by adding PTS repeats, even though many mucins had a common ancestor among different groups of mammals.

"How new gene functions evolve is still a question we are asking today," says Pajic, a UB Ph.D. student in biological sciences. "Thus, we are adding to this discourse by providing evidence of a new mechanism, where gaining repeated sequences within a gene births a novel function."

A potentially disease-causing mechanism if 'off the rails'

"I think this could have even broader implications, both in understanding adaptive evolution and in possibly explaining certain disease-causing variants,” Pajic adds.

Whilst the evolution of non-mucins over and over again in different species at different times suggests this mechanism is a beneficial one, equally a darker side to these repeats comes to mind. Pajic questions whether, 'if off the rails' or occurs in the wrong tissue, the mechanism could lead to certain mucosal diseases or cancers.

The research on mucins shows how an ongoing collaboration between evolutionary biologists and dental scientists at UB produces a fresh understanding of genes and proteins that are also crucial to human health.

The research was published in the journal Science Advances.

Abstract:

How novel gene functions evolve is a fundamental question in biology. Mucin proteins, a functionally but not evolutionarily defined group of proteins, allow the study of convergent evolution of gene function. By analyzing the genomic variation of mucins across a wide range of mammalian genomes, we propose that exonic repeats and their copy number variation contribute substantially to the de novo evolution of new gene functions. By integrating bioinformatic, phylogenetic, proteomic, and immunohistochemical approaches, we identified 15 undescribed instances of evolutionary convergence, where novel mucins originated by gaining densely O-glycosylated exonic repeat domains. Our results suggest that secreted proteins rich in proline are natural precursors for acquiring mucin function. Our findings have broad implications for understanding the role of exonic repeats in the parallel evolution of new gene functions, especially those involving protein glycosylation.