Human Gene Map Upended as Different Genes Combine to Produce New Proteins

The human gene map has been upended. Different genes can combine to produce previously unknown functional proteins, a study has found for the first time.

Researchers at Harvard Medical School reported in the international journal Nature on the 2nd (local time) that the instructional information from different genes, including genes on different chromosomes, can merge to create “chimeric mRNA,” which then produces new proteins.

About 20,000 human genes have been thought to each contain information for one type of protein. Using direct RNA sequencing, the researchers identified more than 30,000 chimeric mRNAs observed at least once in mammalian cells and built a “dark genome” library.

Senior author Ruairidh Jackson, an assistant professor of immunology at Harvard Medical School, said, “No one knows they exist. Neither the medical community nor the pharmaceutical industry knows about them,” adding, “We discovered a completely new gene-regulatory system that could dramatically expand the known genome and proteome.”

To determine whether chimeric mRNAs have actual biological functions, the researchers investigated a fusion protein produced by the GSDMD and TMEM106A genes identified in mice. The GSDMD protein alone opens the cell membrane during pyroptosis, a process in which immune cells rupture and trigger an inflammatory response.

Mice in which only chimeric protein production was blocked had slower immune responses than normal mice and failed to respond properly to Salmonella infection. Assistant Professor Jackson explained, “Even though normal GSDMD remained intact, the absence of the chimeric protein reduced about 50% of the immune process.”

In an endotoxin experiment that induces sepsis, 70% of mice without the chimeric protein survived even a lethal dose. In contrast, mice in which chimeric protein production was increased in collaboration with pharmaceutical company Moderna did not survive even a low dose of endotoxin.

However, the chimeric protein did not open the cell membrane without GSDMD. The researchers analyzed that the protein greatly accelerates pyroptosis but does not function independently.

Co-first author Harry Kane, a researcher, said, “It was very interesting that GSDMD-TMEM106A is not only an actual protein but also functional.”

The researchers are investigating cases in which chimeric mRNAs are involved in cancer, inflammatory diseases and neurodegenerative diseases. Assistant Professor Jackson said, “We want to find chimeric mRNAs that function in diseases that currently have no treatment,” adding, “We may discover new elements that medicine, pharmaceuticals and biomedicine have completely overlooked.”