Category Archives: Transhuman News

Feb 06, 2014 Messenger were RNAs charted, with A's and I's representing specific nucleotides. ADR-1 does not alter editing activity of ADR-2 at all of the hundreds of newly found editing sites, but the ability of ADR-1 to bind to these mRNAs is required for its regulatory activity at the majority of ADR-1 affected editing sites. Credit: Heather A. Hundley

Molecular biologists from Indiana University are part of a team that has identified a protein that regulates the information present in a large number of messenger ribonucleic acid molecules that are important for carrying genetic information from DNA to protein synthesis.

The new work, published today in Cell Reports, finds that the protein ADR-1 binds to messenger ribonucleic acid, or mRNA, and then enhances RNA editing, a process that allows a gene to be present as multiple mRNAs that can then each affect gene expression differently.

Organisms ranging from sea anemone to humans utilize RNA editing to express different mRNAs at various times in development. Decreased mRNA editing has been reported in patients with neuropathological diseases like epilepsy, schizophrenia, amyotrophic lateral sclerosis and several types of cancer, including glioblastomas (brain tumors).

Using the model organism, Caenorhabditis elegans, the researchers identified over 400 new mRNA editing sitesthe majority regulated by ADR-1and declared the protein the first global regulator of RNA editing.

"What we've determined is that this protein's ability to alter editing of mRNAs is not specific to just a few genes, but instead, its ability to bind to mRNAs is required for proper RNA editing of most mRNAs," said Michael C. Washburn, a graduate student in the IU College of Arts and Sciences' Department of Biology and first author on the paper with Boyko Kakaradov of the University of California, San Diego.

Working in the laboratory of Heather A. Hundley, corresponding author on the paper and an assistant professor of biochemistry and molecular biology in the IU School of Medicine's Medical Sciences Program at Bloomington, Washburn and undergraduate Medical Sciences program student Emily Wheeler collaborated with the team from UCSD to show that the region of ADR-1 protein that binds to target mRNAs in C. elegans is also required for regulating editing. This region is present in many human proteins, and a protein similar to ADR-1 is specifically expressed in human neurons.

"So it is likely that a similar mechanism exists to regulate editing in humans," Hundley said. "Further work in our lab will be aimed at understanding the detailed mechanism of how these proteins regulate editing, in turn providing an inroad to developing therapeutics that modulate editing for the treatment of human diseases."

C. elegans is a microscopic worm that like humans highly expresses a family of proteins in the nervous system called ADARsadenosine deaminases that act on RNAa family that includes ADR-1.

ADARs change specific nucleotides (molecular building blocks for DNA and RNA) in RNA, in a process called adenosine-to-inosine editing, or A-to-I editing, that diversifies genetic information to specify different amino acids, splice sites and structures. Scientists currently estimate there are between 400,000 and 1 million A-to-I editing events in noncoding regions of the human transcriptome.

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A key facilitator of mRNA editing uncovered

Researchers from the University of Washington and the HudsonAlpha Institute for Biotechnology have developed a new method for organizing and prioritizing genetic data. The Combined Annotation-Dependent Depletion, or CADD, method will assist scientists in their search for disease-causing mutation events in human genomes.

The new method is the subject of a paper titled "A general framework for estimating the relative pathogenicity of human genetic variants," published in Nature Genetics.

Current methods of organizing human genetic variation look at just one or a few factors and use only a small subset of the information available. For example, the Encyclopedia Of DNA Elements, or ENCODE, catalogs various types of functional elements in human genomes, while sequence conservation looks for similar or identical sequences that have survived across different species through hundreds of millions of years of evolution. CADD brings all of these data together, and more, into one score in order to provide a ranking that helps researchers discern which variants may be linked to disease and which ones may not.

"CADD will substantially improve our ability to identify disease-causal mutations, will continue to get better as genomic databases grow, and is an important analytical advance needed to better exploit the information content of whole-genome sequences in both clinical and research settings," said Gregory M. Cooper, Ph.D., faculty investigator at HudsonAlpha and one of the collaborators on CADD.

The goal in developing the new approach was to take the overwhelming amount of data available and distill it down into a single score that can be more easily evaluated by a researcher or clinician. To accomplish that, CADD compares and contrasts the properties of 15 million genetic variants separating humans from chimpanzees with 15 million simulated variants. Variants observed in humans have survived natural selection, which tends to remove harmful, disease-causing variants, while simulated variants are not exposed to selection. Thus, by comparing observed to simulated variants, CADD is able to identify those properties that make a variant harmful or disease-causing. C scores have been pre-computed for all 8.6 billion possible single nucleotide variants and are freely available for researchers.

"We didn't know what to expect," Cooper said, "but we were pleasantly surprised that CADD was able not only to be applicable to mutations everywhere in the genome but in fact do a substantially better job in nearly every test that we performed than other metrics."

The CADD method is unique from other algorithms in that it assigns scores to mutations anywhere in human genomes, not just the less-than two percent that encode proteins (the "exome"). This unique attribute will be crucial as whole-genome sequencing becomes routine in both clinical and research settings.

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The above story is based on materials provided by HudsonAlpha Institute for Biotechnology. Note: Materials may be edited for content and length.

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Ranking disease-causal mutations within whole genome sequences