Title |
Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum
|
---|---|
Published in |
Parasitology, August 2001
|
DOI | 10.1017/s0031182001007739 |
Pubmed ID | |
Authors |
S. PAGET-MCNICOL, A. SAUL |
Abstract |
A new method has been established to define the limits on a spontaneous mutation rate for a gene in Plasmodium falciparum. The method combines mathematical modelling and large-scale in vitro culturing and calculates the difference in mutant frequencies at 2 separate time-points. We measured the mutation rate at 2 positions in the dihydrofolate reductase (DHFR) gene of 3D7, a pyrimethamine-sensitive line of P. falciparum. This line was re-cloned and an effectively large population was treated with a selective pyrimethamine concentration of 40 nM. We detected point mutations at codon-46 (TTA to TCA) and codon-108 (AGC to AAC), resulting in serine replacing leucine and asparagine replacing serine respectively in the corresponding gene product. The substitutions caused a decrease in pyrimethamine sensitivity. By mathematical modelling we determined that the mutation rate at a given position in DHFR was low and occurred at less than 2.5 x 10(-9) mutations/DHFR gene/replication. This result has important implications for Plasmodium genetic diversity and antimalarial drug therapy by demonstrating that even with low mutation rates anti-malarial resistance will inevitably arise when mutant alleles are selected under drug pressure. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Germany | 1 | 2% |
Vietnam | 1 | 2% |
Unknown | 55 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 11 | 19% |
Student > Ph. D. Student | 7 | 12% |
Student > Master | 6 | 11% |
Student > Bachelor | 5 | 9% |
Other | 4 | 7% |
Other | 9 | 16% |
Unknown | 15 | 26% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 14 | 25% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 11% |
Biochemistry, Genetics and Molecular Biology | 6 | 11% |
Immunology and Microbiology | 5 | 9% |
Medicine and Dentistry | 4 | 7% |
Other | 7 | 12% |
Unknown | 15 | 26% |