Biomedical Engineering Reference
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and inconsistent mutations contained in the multiple sequence alignment. The
approach is different from other efforts because it does not assume that the se-
quences have a single common structure. In this sense alidot combines struc-
ture prediction and motif search (15). An implementation of this algorithm is
available from http://www.tbi.univie.ac.at/. This approach to surveying func-
tional structures goes beyond search software such as RNAmot (34) in that it
does not require any a priori knowledge of the functional structure motifs and it
goes beyond searches for regions that are especially thermodynamically stable
or well-defined (68) in that it returns a specific prediction for a structure if and
only if there is sufficient evidence for structural conservation.
Of course, it is not possible to determine the function of a conserved struc-
ture or structural element without additional experimental input. Nevertheless,
knowledge about their location can be used to guide, for instance, deletion stud-
ies (90). Knowledge of both protein coding regions and functional RNA struc-
tures in the viral genome is needed, e.g., to rationally design attenuated mutants
for vaccine development.
Structure predictions of a set of sequences are conveniently summarized in
the form of Hogeweg-style mountain plots (61) (see Figure 3).
The computation of consensus and conserved RNA structures has been used
to compile an Atlas of potentially functional RNA motifs in RNA virus ge-
nomes. Detailed data are available at present for Picornaviridae (148), Hepatitis
B virus (73,129), and Flaviviridae (136).
5.
DISCUSSION
Structural genomics, the systematic determination of all macromolecular
structures represented in a genome is at present focused almost exclusively on
proteins. Over the past two decades it has become clear, however, that a variety
of RNA molecules have important, and sometimes essential, biological func-
tions beyond their roles as rRNAs, tRNAs, or mRNAs. Given a handful of re-
lated RNA sequences, reliable methods now exist to predict conserved
functional RNA structures within these RNAs. Because of their small size and
fast evolution, the genomes of RNA viruses supply fertile ground for such ap-
proaches, and databases of functional viral RNA structures are being built.
These functional RNA motifs in the viral genome are just as essential as the
encoded proteins, and thus just as promising targets for development of drugs
and vaccines (90,151).
The importance of regulatory functions mediated by RNA has only now
found more attention through recent studies on the phenomenon of RNA inter-
ference (11,45,49). A recent study (138) showed, furthermore, that non-coding
RNA motives may act as potent "danger motifs" that trigger an adaptive immune
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