本日、午後3時半から、Dan Hartl教授の遺伝研セミナーが行われ、教授が座長を務めました。
The 1538th Biological Symposium>
Tuesday, October 25, 2011 15:30 - 16:30
Place: Seminar room - Library 3F:B301
Speaker: Daniel L. Hartl (Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA)
Title: Evolvability in Sequence Space
Summary:
The therapeutic utility of most first-line antimalarial drugs has been compromised by the evolution of resistance, examples including chloroquine, atovaquone, pyrimethamine, and most recently artemisinin. Both chloroquine resistance and pyrimethamine resistance are associated with multiple amino acid replacements in the target protein. The antimalarials pyrimethamine and chlorcycloguanil target the metabolic enzyme dihydrofolate reductase (DHFR), part of a bifunctional enzyme needed for the synthesis of tetrahydrofolate used in purine and amino acid biosynthesis. We have studied evolutionary pathways in the evolution of DHFR for resistance to both pyrimethamine and chlorcycloguanil, using an approach in which all possible intermediates are created by site-directed mutagenesis and assayed for their level of resistance. The studies were carried out in transgenic bacteria and yeast carrying the coding sequence of the parasite DHFR. Evolutionary trajectories were determined using probabilities of fixation based on the relative levels of resistance. While both pyrimethamine and chlorcycloguanil target the active site of DHFR, the evolutionary landscapes for resistance are not congruent. Our results bear generally on mechanisms of protein evolution in sequence space and the ruggedness of evolutionary landscapes. They also help explain observed patterns of DHFR polymorphism in natural populations and why the most resistant forms of the parasite are confined to areas of low malaria transmission. I will also describe the "morbidostat," a new continuous-culture device that automatically selects for ever-increasing levels of antibiotic resistance, and show how the morbidostat can be used to measure the reproducibility of evolution in sequence space.
Chair person: Takashi Gojobori
Note:English seminar
