Overview
Drug resistance evolution provides an excellent model for understanding adaptation in nature and has important bearings on public health policy. Our group demonstrated that high level pyrimethamine resistance has a single origin in SE Asia and that a selective sweep around dihydrofolate reductase (dhfr) has purged genetic variation around dhfr on chr 4. Subsequent intercontinental transfer of pyrimethamine resistance alleles from Asia to Africa resulted in plummeting efficacy of antifolate drugs. We have also investigated the role of copy number variation, showing multiple independent origins of copy number amplification in an ABC transporter, and demonstrating adaptive change in CNV during antifolate resistance evolution.
chr 4 surrounding dihydrofolate reductase driven
by pyrimethamine treatment in SE Asia. The same
resistance alleles subsequently spread across
sub-Saharan Africa (adapted from Nair et al. Mol
Biol Evol 2003 Sep;20(9):1526-36)
Thailand-Myanmar border. Multiple independent SNPs
in the kelch13 locus conferring resistance to artemisinin
have spread in the last 15 years