Study finds genes can combine to make unknown proteins

Researchers at Harvard Medical School have found that instructions from different genes — even those located on separate chromosomes — can combine to create chimeric mRNAs that produce previously unknown, functional proteins. The findings, published Wednesday in Nature Springer Nature Group, challenge the long-held understanding that each of the roughly 20,000 human genes encodes a single kind of protein.nature+1

A Library of 30,000 Hidden Molecules

Using a technique called direct RNA sequencing, the team compiled what senior author Ruaidhrí Jackson, an assistant professor of immunology at Harvard Medical School, calls a "dark genome" library — a catalog of more than 30,000 chimeric mRNAs observed at least once in mammalian cells. The researchers profiled nearly 400 of these that are regulated by inflammatory signals, including chimeric mRNAs conserved in both human and mouse immune cells.news-medical+1

"Nobody knows these exist. Medicine doesn't know they exist, the pharmaceutical industry doesn't know they exist," Jackson said in the Harvard Medical School announcement. "We've discovered an entirely new gene regulation system that could expand the known genome and proteome dramatically."hms.harvard+1

While chimeric mRNA had been seen in single-celled organisms and invertebrates, those systems do not appear to create proteins, and the phenomenon had not been documented in mammals. Previous RNA sequencing results occasionally hinted at chimeric mRNA in healthy tissue, but traditional techniques struggled to detect them reliably.news-medical+1

Proof of Function

To test whether chimeric mRNAs produce biologically relevant proteins, the team investigated one found in mice: a fusion of genes encoding GSDMD and TMEM106A. They confirmed the chimeric protein occurs naturally as part of the immune response across multiple mouse strains, then developed a genetic tool to block its production without disrupting the two parent proteins.news-medical+1

Mice lacking the chimeric protein mounted a slower immune response and were less able to fight off Salmonella infection, with nearly 50 percent of the immune process reduced. In a sepsis model, 70 percent of mice without the chimeric protein survived a normally lethal endotoxin dose because of their dampened immune response. Working with Moderna ↘ 20.82%, the researchers engineered mRNA to boost production of the chimeric protein, which confirmed its role in accelerating pyroptosis — though it cannot open cell membranes without the standard GSDMD protein.hms.harvard+1

Implications for Medicine

The Jackson Lab is now investigating chimeric mRNAs that could be involved in cancer, inflammatory disease, and neurodegenerative disease, sharing additional sequences with collaborators across multiple fields.news-medical+1

"We want to find out which ones are operative in currently incurable diseases," Jackson said. "We think we can find new players that have been completely overlooked by medicine, by pharma, by biomedical science in general."hms.harvard