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…)

The Focus of Selection, the Locus of Response, and Epigenetic Evasion

 

An interesting hypothesis in the evolutionary genetics of treating infections and cancers is that if the therapeutic agent does not directly target the pathogen or tumor, then the pathogen or tumor will be less likely to evolve resistance to that agent.  While early work on inhibitors of angiogenesis as potential cancer therapeutics suggested that such treatment did not elicit resistance by the tumor cells (Boehm et al., 1997), a recent study by Conley et al. (2012) raises doubts about the reliability of this notion in the context of antiangiogenic therapy for human breast cancer. (more…)

Levels of Selection, Logical Schemes, Selfish Genes, and Misleading Memes

Both Nature and Science are currently celebrating the 100th anniversary of the birth of an icon of logic, computer science, and mathematical biology: Alan Turing.  In reading Andrew Hodges’s spectacular biography of Turing (1983) many years ago I came to appreciate that the subject of the book was both a deeply creative and extraordinarily rigorous thinker.  Although Turing is known for seminal achievements in mathematical logic and computer science, his most directly practical and immediately consequential contribution was his facilitation of the Allied cause in World War II through his guidance of the effort to break the Nazi military code.  This effort called primarily on his prodigious talents for far-reaching inference and it was in reading about this effort that I was prompted to consider a concept that might be called “maximum deduction.”  Turing and his able colleagues needed to make every possible deductive inference (or at least very close to every possible inference) supported by the available data on German military communications in order to solve a problem of immense and immediate impact (the saving of Allied ships from devastating German submarine attacks). (more…)

Phenotypic Variation Due to Epigenetic and Environmental Variation

Natural selection depends on heritable phenotypic variation.  The most obvious source of phenotypic variation is genotypic variation.  A new study, by Casanueva et al. in Science (2012) suggests that in addition to genotypic variation, variation in life history and stochastic variations in gene expression can substantially affect phenotypic variation.

These authors studied mutation penetrance in Caenorhabditis elegans  overexpressing a transgenic transcription factor (heat shock factor 1 or HSF-1) that controls the expression of genes encoding proteins that are involved in stress responses.  The worms expressing high levels of the HSF-1 transgene (hsf-1) were previously shown to be better able to cope with diverse environmental stresses than otherwise identical worms not expressing the HSF-1 transgene. 

Casanueva et al. then crossed HSF-1 transgenic worms with worms that harbored a variety of mutations that affect embryonic or post-embryonic development .  In the majority of these crosses, the overexpression of HSF-1 was associated with reduced penetrance of these genetic variants. (more…)