Phenotypic and Genotypic Variation of a Fungal Pathogen Powered by Codon Ambiguity and Degenerate Translation

The term “genetic code” is associated with a measure of ambiguity.  For molecular biologists, “genetic code” has historically referred to a table that provides for each messenger RNA ribonucleotide triplet the corresponding amino acid that is incorporated into the growing end of a nascent polypeptide chain, i.e. the translation from RNA sequence to protein sequence.  In colloquial parlance, “genetic code” is frequently used to refer to all or part of the deoxribonucleotide sequence of a genome.  A recent paper, published online ahead of print in Proceedings of the National Academy of Sciences (Bezerra et al., PNAS, 2013) demonstrates that this semantic ambiguity can have a counterpart in the ribosomal interpretation of the genetic code, using the technical molecular biological meaning of the latter term. (more…)

Influenza A Virus: Is Virulence Attributable to Virulence Factors?

Influenza A viruses continue to be of enormous interest to biomedical researchers and clinicians alike.  In addition to the annual influenza epidemics, which have been inferred to cause substantial excess mortality, there is the ever-present threat of a global pandemic due to several features of influenza virus biology.  A high mutation rate associated with a segmented negative-sense RNA genome that facilitates recombination confers on these orthomyxoviruses a prodigious ability to evolve in ways that confound and evade the human immune system.  The ability of influenza viruses to infect domesticated mammals, such as pigs, as well as birds, both wild and domesticated, provides additional opportunities for the virus to try out new genetic combinations and to disseminate around the globe by means both dependent and independent of human travel.

A recent paper by Jagger et al. (Science 2012) reveals that influenza A viruses are also, not surprisingly, capable of exploiting rather subtle and ingenious genetic “tricks” to maximize the value of every base pair in a total of a mere 13.5 kilobases of genome.  These authors have discovered a new influenza gene product, PA-X, that represents a fusion protein incorporating 191 amino-terminal amino acids of the well-known RNA-dependent RNA polymerase (PA) protein and another carboxy-terminal 61 amino acids of a protein from a reading frame shifted by one nucleotide downstream.  They present evidence from multiple experiments suggesting that the frameshift is related to a highly conserved codon that is rarely employed in mammalian and avian genomes and therefore interacts with a cognate tRNA of relatively low concentration in the cytosol.  The longer-than-average wait for this tRNA to be recruited to the ribosome makes a frameshift mutation more probable. (more…)

A Medical Application of Phylogenetic Analysis

A couple of months ago, my institution hosted a one-day symposium on phylogenetics. One of the speakers was John Avise, a member of the National Academy of Sciences and the individual generally credited with originating the field of phylogeography. His talk and those of two other speakers were focused on subjects most typically regarded as part of biology, not medicine. However, the fourth lecturer on the program applied some of the same methods and patterns of thought to the interactions between HIV and its human hosts, thereby illustrating the potential relevance of phylogenetic analysis to matters of clinical significance. A recent paper in Science (Harris et al., 2010) provides another such example.

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen of major significance in many countries. According to Maryn McKenna (2010), author of a recent book on this pathogen, there are almost 19,000 deaths and almost 370,000 hospitalizations annually attributable to MRSA infections in the United States. The yearly total costs for these infections are estimated to be in the billions of dollars. (more…)

Phenotypic noise and the evolution of virulence

Commentary on: M. Ackermann, B. Stecher, N. E. Freed, P. Songhet, W.-D. Hardt, and M. Doebeli (2008) Self-destructive cooperation mediated by phenotype noise. Nature 454:987-9

One of the most exciting developments in microbial population biology over the past few years is the recognition that high levels of phenotypic noise – in which genetically identical microbes express different genes and manifest different phenotypes despite a common environment – is widespread in bacterial populations and that this noise plays an important role in bacterial evolutionary ecology (e.g. Elowitz et al. 2002, Balaban et al. 2004, Rosenfeld et al. 2005, Acar et al. 2008, Veening et al. 2008). I have always thought that the best explanations for this phenomenon involve bet hedging in uncertain environments (Seger and Brockmann 1987), and indeed this bet-hedging perspective has been well supported by mathematical modeling (e.g. Thattai and van Oudenaarden 2004, Kussell et al. 2005).

But in this week’s issue of Nature, Martin Ackermann and colleagues propose an alternative explanation (more…)