Once again, I saw too many talks to list them all.
In my opinion, today’s best session was titled “The Evolution of Molecular Function” with speakers Patrick Phillips, Jesse Bloom, and Joe Thornton. This symposium presented — and then demonstrated — a “functional synthesis” approach to molecular evolution.
Patrick began by talking about the history of genetics: statistical genetics and Mendelian genetics fragmented into many subfields over the past seventy years (pictured below).
Each subfield asks a unique — but separate — question about genes (pictured below). For example, population genetics explores how fitness is determined by the transmission of genes; whereas, molecular genetics explores how genes have effects on phenotype. Ultimately, an interdisciplenary synthesis provides a holistic understanding of the interplay between genes, gene transmission, gene effects, phenotypes, and fitness.
In the spirit of this “functional synthesis”, Jesse Bloom explained how H1N1 flu virus gained resistance to Oseltamivir (a.k.a. Tamiflu). Oseltamivir binds the neuraminidase active site, which inhbits H1N1 viral release from an infected cell. It is suspected that Tamiflu resistance began in 2006; as of 2009, almost all H1N1 strains are Tamiflu resistant. Resistance is conferred by the H274Y mutation. By itself, H274Y reduces the fitness of H1N1; it was therefore believed that the H274Y mutation would not spread through the flu population. Consequently, why did resistance to Tamiflu spread? Jesse speculates — in general — that some nuetral mutations can increase protein stability, thus creating a “stability buffer” enabling fitness-reducing mutations. For the case of H1N1 Tamiflu resistance, his hypothesis appears to be correct: Jesse revealed that the R194G mutation (a neutral mutation) compensates for the H274Y mutation, thus allowing H274Y to spread through the H1N1 population.
Finally, Joe Thornton talked about the evolution of steroid-hormone receptors. Whereas Jesse’s previous talk highlighted the interactions of just two molecular mutations, Joe showed how historical trajectories of many mutations led to the incredible diversity and specificity of extant proteins which bind steroid-hormones. Many of these mutations demonstrate Dollo’s Law, such that they cannot be undone without deleteriously affecting the protein. For more information, see (1) Thornton, Nature Review Genetics 2004, (2) Bridgham et al. Science 2006, (3) Keay et al. Endocrinology 2006, (4) Ortlund et al. Science 2007, (5) Bridgham et al. PLoS Genetics 2008, and (6) Laskowski et al., Nature Review Genetics 2008.
Okay, that’s it for today