Thursday, August 06, 2009

Decoding the Structure of the HIV Genome

The title of the press release on Biology News Net caught my eye: UNC researchers decode structure of an entire HIV genome. I clicked the link on my aggregator and read the first two paragraphs.
The structure of an entire HIV genome has been decoded for the first time by researchers at the University of North Carolina at Chapel Hill. The results have widespread implications for understanding the strategies that viruses, like the one that causes AIDS, use to infect humans.

The study, the cover story in the Aug. 6, 2009, issue of the journal Nature, also opens the door for further research which could accelerate the development of antiviral drugs.
By the time I finished the article I thought I had a pretty good idea of what they were talking about but, just to be sure, I visited the Nature website to read the actual scientific paper.
Watts, J.M., Dang, K.K., Gorelick, R.J., Leonard, C.W., Bess Jr., J.W., Swanstrom, R., Burch, C.L. and Weeks, K.M. (2009) Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460:705-710 [doi: 10.1038/nature08237]

Single-stranded RNA viruses encompass broad classes of infectious agents and cause the common cold, cancer, AIDS and other serious health threats. Viral replication is regulated at many levels, including the use of conserved genomic RNA structures. Most potential regulatory elements in viral RNA genomes are uncharacterized. Here we report the structure of an entire HIV-1 genome at single nucleotide resolution using SHAPE, a high-throughput RNA analysis technology. The genome encodes protein structure at two levels. In addition to the correspondence between RNA and protein primary sequences, a correlation exists between high levels of RNA structure and sequences that encode inter-domain loops in HIV proteins. This correlation suggests that RNA structure modulates ribosome elongation to promote native protein folding. Some simple genome elements previously shown to be important, including the ribosomal gag-pol frameshift stem-loop, are components of larger RNA motifs. We also identify organizational principles for unstructured RNA regions, including splice site acceptors and hypervariable regions. These results emphasize that the HIV-1 genome and, potentially, many coding RNAs are punctuated by previously unrecognized regulatory motifs and that extensive RNA structure constitutes an important component of the genetic code.
The authors determined the two- and in some cases the three-dimensional structure of the HIV RNA genome. In other words, they figured out the way RNA folds to form regions of secondary structure (double-stranded RNA). This RNA molecule functions as a complex messenger RNA and the secondary structure plays a role in regulating how the molecule is translated.

The press release doesn't really convey this result very well, especially in the opening paragraph. Part of the problem is misue of the word "decode." We're familiar with journalists who use "decode" to mean "nucleotide sequence" as in "Scientists decoded the human genome." This elevates "decode" to an entirely new meaning.

In fairness, this confusion over the word "decode" is exacerbated by the language used by the authors in the paper.
Our discovery that the peptide loops that link independently folded protein domains are encoded by highly structured RNA indicates that these and probably other mRNAs encode protein structure at a second level beyond specifying the amino acid sequence. In this view, higher-order RNA structure directly encodes protein structure, especially at domain junctions. The extraordinary density of information encoded in the structure of large RNA molecules (Figs 1, 2 and 4d) represents another level of the genetic code, one which we understand the least at present. This work makes clear that there is much to be discovered by broad structural analyses of RNA genomes and intact mRNAs.
I'm not sure this language is helpful.

UPDATE: The press release from Scientific American is different: HIV genome structure decoded.
It might not be super high-res, but researchers at the University of North Carolina at Chapel Hill have described the first full structure of the HIV-1 genome.

The paper, published online today in Nature, maps out the virus' genome down to a one-nucleotide resolution with the help of a technique call SHAPE—selective 2'-hydroxyl acylation analyzed by primer extension—to paint the full, previously unknown picture of the virus (Scientific American is part of Nature Publishing Group).

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