Many slimy bodily fluids contain slime, from slimy slugs to the saliva in our mouths. So how did this marvel of biology evolve?
According to a new study of proteins called mucins, the answer in mammals is many times, and often in surprising ways. These molecules have different functions, but as a family they are known as components of mucus, where they contribute to the sticky consistency of the substance.
By comparing mucin genes in 49 mammalian species, the scientists identified 15 cases where new mucins appear to have evolved through an additional process that transformed a non-mucin protein into a mucin.
Scientists believe that each of these “mucinization” events started with a protein that was not mucin. At some point, evolution attached a new section to this non-mucin framework: one made up of a short chain of building blocks called amino acids that are decorated with sugar molecules. Over time, this new region was duplicated with the addition of several copies to further elongate the protein, making it a mucin.
The doubled regions, called “repeats,” are key to the mucin’s function, say University at Buffalo researchers Omer Gokkumen and Stefan Ruhl, senior authors of the study, and Petar Pazic, first author.
The sugars that coat these parts stick out like the bristles of a bottle brush and endow the mucins with mucilaginous properties vital to the many important tasks these proteins perform.
The study will be published on August 26 in Achievements of science.
“I don’t think it was known before that the function of a protein can evolve in this way when a protein gets repetitive sequences. A protein that is not a mucin becomes a mucin simply by gaining repeats. It’s an important way that evolution creates slime .. It’s an evolutionary trick, and now we’re documenting it happening over and over again,” says Gokkumen, Ph.D., associate professor of biological sciences in the UB College of Arts and Sciences.
“The repeats we see in mucins are called ‘PTS repeats’ because of their high content of the amino acids proline, threonine, and serine, and they help mucins perform their important biological functions, which range from lubricating and protecting tissue surfaces to to make our food slippery so we can swallow it,” says Stefan Ruhl, MD, interim dean of the UB School of Dental Medicine and professor of oral biology. “Beneficial microbes have evolved to live on mucus-covered surfaces, while mucus can in while also acting as a protective barrier and protecting against disease, protecting us from unwanted pathogenic invaders.’
“Not many people know that the first mucin to be purified and biochemically characterized came from the salivary gland,” Ruhl adds. “My lab has been studying mucins in saliva for the past 30 years, mainly because they protect teeth from tooth decay and because they help balance the microbiota in the mouth.”
The intriguing evolution of a ‘strange life trait’
“I think this work is really interesting,” says Gokkumen. “This is one of those cases where we got lucky. We were studying saliva, and then we found something interesting and cool and decided to study it.”
Examining the saliva, the team noticed that the mice lacked a small human salivary mucin called MUC7. However, rodents had a salivary mucin of the same size called MUC10. Scientists wanted to know: were these two proteins related from an evolutionary point of view?
The answer was negative. But further research was a surprise. While MUC10 did not appear to be related to MUC7, the PROL1 protein found in human tears did share part of the structure of MUC10. PROL1 was very similar to MUC10, minus the sugar-coated bottle brushes that make MUC10 a mucin.
“We think that somehow this tear gene ends up being reprogrammed,” says Gokkumen. “It gains repeats that give it mucin function, and it is now abundant in the saliva of mice and rats.”
Scientists wondered if other mucins could be formed in the same way. They began to investigate and found many examples of the same phenomena. Although many mucins share a common origin among different groups of mammals, the team documented 15 cases where evolution appears to have turned non-mucin proteins into mucins through the addition of PTS repeats.
And it was “pretty conservative looking,” Gokkumen says, noting that the study focused on one region of the genome of several dozen mammal species. He calls mucus “an amazing feature of life,” and he wonders if the same evolutionary mechanism could have led to the formation of some mucins in slugs, slimy eels, and other creatures. More research is needed to find the answer.
“The question we’re asking today is how do new gene functions evolve,” says Pajic, a UB biological sciences doctoral student. “Therefore, we add to this discourse by providing evidence for a new mechanism where the acquisition of repetitive sequences in a gene gives rise to a new function.”
“I think this could have even broader implications, both for understanding adaptive evolution and for possibly explaining certain disease-causing variants,” adds Pazic. “If these mucins continue to evolve from non-mucins over and over again in different species at different times, it suggests that there is some adaptive pressure that makes it beneficial. And then, at the other end of the spectrum, maybe if that mechanism goes ‘off the rails’ – happens too often or in the wrong tissue – then maybe it can lead to diseases like certain cancers or mucosal diseases.”
The study of mucins demonstrates how a long-term partnership between evolutionary biologists and dentists at University College is providing new insights into genes and proteins that are also important to human health.
“My team has been studying mucins for decades, and my collaboration with Dr. Gokkumen took this research to a new level, revealing all this exciting new knowledge about their evolutionary genetics,” Ruhl says. “At this advanced stage of my career, it is also great to see that the flame of scientific curiosity is being continued by a new generation of young researchers like Petar Paic.”
Additional study co-authors include Shichen Shen, Ph.D., Ph.D., and Jun Qu, Ph.D., Professor, both in the University’s Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, and Center of Excellence in Bioinformatics and Life Sciences; and Alison J. May, Ph.D., former postdoctoral fellow, and Sarah Knox, Ph.D., assistant professor, both in the Department of Cell and Tissue Biology at the University of California, San Francisco School of Dentistry. May is currently an assistant professor at the Icahn School of Medicine at Mount Sinai.
The scientists who conducted the study are supported by the US National Science Foundation, as well as the National Institute of Dental and Craniofacial Research and the National Cancer Institute, which are part of the US National Institutes of Health.
