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Genomics In The Journals: Jan 5, 2012

NEW YORK (GenomeWeb News) – In the Proceedings of the National Academy of Sciences online, a team from the US and China describes its strategy for finding short hairpin RNAs to effectively target pathogenic viruses such as HIV, hepatitis C, and influenza. By tiling the genomes of one influenza A virus strain, an HCV strain, and two HIV strains, researchers identified tens of thousands of candidate shRNAs. After assessing the activity of roughly 40,000 shRNAs against viral target sequences using a multiplex, fluorescent reporter-based assay, the group relied on cell culture experiments to follow-up on shRNAs with the most pronounced antiviral activity. They also inspected the sorts of shRNAs and target sequence properties that seem to influence this process.

Also in the early edition of PNAS, a look at how a liver microRNA called miR-122 contributes to hepatitis C virus survival in the host liver from researchers at the University of North Carolina at Chapel Hill and the University of Colorado. Findings from earlier studies suggested that the miRNA in question acts to spur on HCV activity in the liver. From their newest cell line experiments, researchers determined that this activity is the result of interactions between the HCV genome, miR-122, and a protein called Ago2. Rather than repressing viral RNA in the HCV genome, they found, Ago2 and proteins associated with it actually serve to stabilize and protect it.

"[T]he virus has usurped a process that usually down regulates gene expression to up regulate the stability of its RNA and expression of viral proteins needed for its lifecycle," UNC researcher Stanley Lemon, the study's senior author, said in a statement. "It's a classic example of how viruses subvert normally beneficial functions of the cell to their own nefarious purposes."

A research group from the US and the UK has detected a repeat expansion in the chromosome 9 gene C9ORF72 in a subset of suspected Alzheimer 's disease cases — work that they present in a correspondence article in the New England Journal of Medicine.

Using primers recognizing the six nucleotide-long expansion — which involves four guanines followed by two cytosine residues — the researchers did PCR-based screening on 771 individuals who appeared to have late-onset Alzheimer's disease and 223 unaffected siblings from more than 340 families sampled by the National Institute of Mental Health Alzheimer's Disease Genetics Consortium.

The search identified individuals from three families with C9ORF72 repeat expansions. Because these expansions have been reported in around 40 percent of familial amyotrophic lateral sclerosis cases and nearly one-third of familial frontotemporal dementia cases in the past, though, those involved in the study speculate that some of the apparent Alzheimer's cases tested may have been cases of frontotemporal dementia that were misdiagnosed.

"[T]he availability of a test for this genetic mutation may provide an opportunity to correct the misclassification of frontotemporal dementia as Alzheimer's disease in current and future patients," corresponding author Bryan Traynor, of the National Institute on Aging, and colleagues explain.

An international team led by researchers in Spain, Switzerland, and the US has found evidence underscoring the complexity of the human transcriptome: chimeric transcripts involving exons from more than one annotated gene.

As they report in PLoS ONE, the group used a combination of rapid amplification of cDNA ends, tiling arrays, deep RNA sequencing, and more to scrutinize the gene boundaries of hundreds of protein-coding genes on chromosomes 21 and 22 in human tissue samples and cell lines. Some 85 percent of the genes analyzed stretched beyond their currently annotated boundaries, the team reported. And the work uncovered verifiable transcripts comprised of sequences stitched together from multiple genes. The non-random nature of these connections, coupled with the evolutionary age and concerted expression of the genes involved, hint that at least some of the chimeric transcripts may be functional.

"The non-random nature of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network," the study's authors note.

Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.

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