Gene Redundancy Evolved to Prevent Intracellular mRNA Aggregation

Gene sequence redundancy evolved in a way that prevents messenger RNA (mRNA) molecules from sticking together and aggregating inside cells, according to a new study.

On the 14th (local time), the Whitehead Institute for Biomedical Research in the United States announced that the study, led by researcher Ankur Jain and postdoctoral researcher Marco Todisco, was published in the Proceedings of the National Academy of Sciences (PNAS). The science news outlet Azure Life Science reported on the findings.

mRNA is best known for carrying genetic information from DNA to the cellular machinery that makes proteins. But all RNA molecules have a tendency to bind to one another and clump together.

Thousands of mRNA molecules are packed into a small space inside cells, yet the large-scale aggregation that might be expected based on their physical properties is not normally observed. When RNA clumps together, it cannot be used to make proteins, and large aggregates can be toxic to cells.

The researchers used computer simulations to track the movement of mRNA molecules in E. coli under conditions similar to intracellular concentrations. The results showed that RNA’s physicochemical properties alone should cause the molecules to aggregate, with longer mRNAs especially prone to clumping.

Experiments with purified mRNA from E. coli confirmed that aggregation occurs in the absence of surrounding components such as proteins. RNA sequence analysis also showed that the characteristics of mRNAs in the aggregates matched the simulation predictions.

The researchers concluded that part of the answer lies in the gene sequences themselves. DNA specifies amino acids using codons made up of three bases, and most amino acids can be encoded by multiple codons. This means there are countless different mRNA sequences that can produce the same protein.

The researchers used computers to create alternative versions that changed only the RNA sequence while keeping the protein unchanged, then compared them with natural E. coli mRNA. The results showed that natural sequences were less likely to interact with one another. Natural mRNAs tended to fold in ways that did not expose regions prone to sticking together.

The researchers found similar characteristics in abundant human mRNAs. Naturally occurring human RNA sequences were also less likely to aggregate than alternative sequences.

Researcher Jain said, “Sequences do not evolve only to encode functional proteins; there is an additional constraint to produce mRNAs that are less likely to stick to one another. This finding could provide guidance for designing sequences for mRNA vaccines and other RNA therapeutics.”

However, because natural mRNA sequences still readily clump together when purified, the researchers concluded that other cellular components, such as proteins, provide additional protection that prevents aggregation in healthy cells.