Newly Discovered Genetic Code Enables Directed Evolution Of Nervous Systems

DNA sequences spell out the instructions for making protein but they aren’t always followed to the letter. Sometimes, the genetic recipe gets edited after cells copy DNA to RNA–a close chemical relative–during transcription. Think of DNA as an unalterable “read only” copy of the genetic code and the RNA as a “writable” working copy that cells can edit extensively–adding, deleting, and modifying the molecular letters and words that guide protein assembly. Often, even simple editing such as changing one letter in an RNA molecule affects the resulting protein’s function. There are many different types of RNA editing.

Reenan’s group studies one particular method called A-to-I RNA recoding. It occurs when an enzyme chemically “retypes” RNA letters at specific locations, changing adenosine (A) to inosine (I). Proteins responsible for fast chemical and electrical signaling in animal nervous systems are the main targets of this process. In a prior study, Reenan’s group identified species-specific patterns of RNA recoding on such targets, but didn’t explain how they were determined or how they may have evolved. His new study does both.

By comparing the same highly edited RNA from over 30 insects, Reenan uncovered some general rules of A-to-I recoding. He observed that the RNA of different insects folds into unique structures. These shapes single-handedly determine the species-specific RNA editing patterns that Reenan previously observed. For example, part of the RNA molecule he focused on–the code for the protein synaptotagmin, a key player in neuronal chemical signaling–looks like a knot in fruit flies, but a loop in butterflies. These molecular knots and loops bring regulatory regions of the RNA together with sites destined for recoding, guiding editing enzymes to act there. As proof, Reenan coaxed fruit fly RNA to adopt a “mosquito-like” structure by making small changes in the molecule–a procedure he dubbed “guided evolution.” Predictably, cells edited the reconfigured fly RNA in the mosquito-like pattern.

Researchers still don’t know why editing occurs, but posit that organisms use it to increase protein variety. RNA recoding lets cells generate an array of proteins from a single DNA sequence, each with a slightly different function. Producing different proteins in a cell at once could let organisms fine tune biological processes with extreme precision–a level of flexibility the DNA code doesn’t afford. “Genetics is digital,” says Reenan, adding “Editing changes digital to analog,” letting cells “dial up” the exact amounts of altered proteins required at any given time or place.

From a NSF press release.