ARTICLE: Dual Discoveries In Genetic Processing Improve Accuracy Of Genome Information

[Murray Charters <mcharters@xxxxxxxxxxxxxx>]

Science Daily

Source:
National Science Foundation


Date:
2003-08-11

Dual Discoveries In Genetic Processing Improve Accuracy Of Genome Information

ARLINGTON, Va. -- 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
"coding" 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 system-specific 
genes, including those responsible for
epilepsy and Parkinson Disease.

Editor's Note: The original news release can be found here.


SOURCE: Science Daily


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