Dual Discoveries in Genetic Processing Improve Accuracy of Genome Information

University of Connecticut Health Center geneticists have made a two-fold discovery in gene recoding that will significantly increase understanding of the information in genome sequences and could prove to be a knowledge expressway scientists need for unraveling nervous system disorders such as Parkinson Disease and epilepsy.

The research, published in the Aug. 8 issue of the journal Science, was supported by the National Science Foundation (NSF), the independent federal agency that supports fundamental research and education across all fields of science and engineering.

Geneticist Robert Reenan and fellow researchers used comparative genomics to discover a telltale signature of genes that are recoded as DNA is converted to RNA during the protein-making process. There, an enzyme converts adenosine to the nucleoside inosine by a process called “A-to-I” RNA editing. The scientists subsequently found that such recoding is largely confined to the nervous system across species and pinpointed a target of the process in humans.

“The proteins targeted by editing are basically the machinery that allow nervous systems to function on a timescale of milliseconds, which is not a demand placed on every organ,” said Reenan.

The phylogenetic signatures are identical sequences of genetic coding found in each species studied, serving as markers corresponding to specific genes targeted for A-to-I RNA editing. The identical presence in both species suggests that the editing site arose some time ago evolutionarily and has been retained in these species — and likely others — because it provides a broadly useful selective advantage for survival.

Recoding, or “RNA editing,” and the entire process are much like photocopying a recipe from a cookbook and writing changes on the photocopy rather than on the book’s pages. The revisions on the copy would then be used to prepare the food, but the original recipe in the book would remain unchanged.

For cells to manufacture protein, they must first copy the segment of the gene’s DNA that holds the blueprint or Scoding” for the protein. This copy, which consists of a single strand of RNA, is called messenger RNA, or “mRNA.” Converting the DNA into the mRNA instructions that code for the manufacture of protein from amino acids is called “transcription.” The working mRNA copy is sometimes modified, or “recoded,” as it is formed. It is unknown how many RNA transcripts for genes are recoded in the human genome because this process occurs on the copies rather than the original.

For more than a decade, sites where A-to-I RNA editing had occurred were discovered largely by chance. “The one thing that becomes clear about the RNA editing sites is that they’re all different; there (was) no way to predict where an RNA editing site would occur from genome sequence,” said Reenan. “We hoped to get clues about RNA editing by comparing genomes of different species.”

Clues came as the researchers compared more than 900 genes between two species of the fruit fly Drosophila. They found a signature in genomic DNA in genes shared between species where RNA transcription products are destined to be edited by the enzyme adenosine deaminase. “The signature we found was an unexpectedly high level of DNA sequence identity between species,” said Reenan. The signature reliably identifies genes that are recoded during transcription, providing scientists with a means to predict the occurrence of editing.

“Being able to predict editing sites is a revolutionary discovery that will greatly increase the value of existing genome sequences,” said Molecular Biologist Joanne Tornow, a program director with the NSF’s Division of Molecular and Cellular Biosciences. “Dr. Reenan’s use of comparative genomics to make this very significant finding underscores the importance of investing in the sequencing of a wide variety of organisms.” Reenan and his colleagues then applied their newfound knowledge to a wide range of human, mouse and rat genes. They found the process also targets a gene in the human brain already known to foster an inherited form of epilepsy.

So far, the researchers have noticed A-to-I RNA editing in only nervous systems and specifically in genes encoding proteins necessary for sending fast electrical and chemical signals. They examined many genes not directly involved in nervous system function.

“The literal genome is not the final word and, for whatever reason, this mechanism (A-to-I editing) is almost exclusive to the nervous system,” Reenan said.

With the knowledge of the signature and that A-to-I RNA editing occurs primarily in nervous systems, scientists can now more closely examine how recoding affects expression by nervous systemspecific genes, including those responsible for epilepsy and Parkinson Disease.

Principal Investigator: Robert Reenan, (+1-860) 679-3691, rreenan@neuron.uchc.edu