A study of mucins, a protein in mucus, gives insight into how novel gene functions evolve.
From slugs to saliva, mucus is responsible for making a lot of things slimy, but how did mucus evolve to be like that? A study by researchers at the University at Buffalo (NY, USA) and the University of California, San Francisco (CA, USA) has identified the mechanism through which a group of proteins found in mucus, called mucins, evolved.
In addition to being gooey and slimy, different mucins have different functions. They are functionally defined rather than evolutionarily meaning they are an ideal candidate to study convergent evolution – the evolutionary phenomenon through which different organisms independently evolve similar phenotypes or products to address the same selection pressure.
Using bioinformatics, phylogenetics, proteomics and immunohistochemical analysis, the researchers compared mucin genes from 49 different mammal species. In doing so, they identified 15 instances where new mucin genes emerged through an additive process where non-mucin genes are converted with the addition of amino acid chains that act as a binding site for protruding sugar molecules.
Over time, this added region is duplicated repeatedly, making the protein even longer and transforming it into a novel mucin protein. Sugar molecules that decorate the added amino acid chains on mucins are what give mucus its sliminess.
Stephen Ruhl (University at Buffalo), one of the senior authors of the study, explained: “The repeats we see in mucins are called ‘PTS repeats’ for their high content of the amino acids proline, threonine and serine, and they aid mucins in their important biological functions that range from lubricating and protecting tissue surfaces to helping make our food slippery so that we can swallow it.”
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“I don’t think it was previously known that protein function can evolve in this way, from a protein gaining repeated sequences,” explained Omer Gokcumen (University at Buffalo), another senior author of the paper.
Saliva in our mouths protects our teeth from decay and balances the microbiota residing there. Ruhl’s lab has been studying mucins from salivary glands for 30 years, which was one of the first mucins that was purified and characterized.
Whilst studying mucins from salivary glands, the research team noticed that a small mucin called MUC7 was present in humans but not in mice. Mice did, however, have a similarly sized salivary mucin called MUC10. The researchers wondered: are MUC7 and MUC10 evolutionarily related? Nope.
But, MUC10 in mice did have similarities with PROL1, a protein found in human tears. PROL1, which is not a mucin, had a similar structure to MUC10 but without the additional PTS repeat and accompanying sugar chain characteristic of mucins. “We think that somehow that tear gene ends up repurposed,” explained Gokcumen. “It gains the repeats that give it the mucin function, and it’s now abundantly expressed in mouse and rat saliva.”
The researchers started looking into other mucins and found more examples of similar ‘mucinzation’ processes, where non-mucin proteins are converted into mucins through the addition of a PTS repeat.
“How new gene functions evolve is still a question we are asking today,” said Petar Pajic (University at Buffalo), the first author of the study. “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.”
The researchers explain that this finding could mean there is an adaptive pressure making mucins beneficial, as they keep evolving in different species. It could also mean that if the mechanism goes awry, and happens too much or in the wrong tissue, it could lead to diseases including cancers and mucosal illnesses.
Gokcumen added: “It’s one of those times where we got lucky. We were studying saliva, and then found something that’s interesting and cool and decided to look into it.”
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