scholarly journals Relevance of Higher-Order Epistasis in Drug Resistance

2020 ◽  
Vol 38 (1) ◽  
pp. 142-151
Author(s):  
Elena R Lozovsky ◽  
Rachel F Daniels ◽  
Gavin D Heffernan ◽  
David P Jacobus ◽  
Daniel L Hartl
Keyword(s):  
Artemisinin Combination Therapy ◽  
Higher Order ◽  
Intermittent Treatment ◽  
Third Order ◽  
Data Set ◽  
Epistatic Interactions ◽  
Lead Compounds ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Stepwise Evolution

Abstract We studied five chemically distinct but related 1,3,5-triazine antifolates with regard to their effects on growth of a set of mutants in dihydrofolate reductase. The mutants comprise a combinatorially complete data set of all 16 possible combinations of four amino acid replacements associated with resistance to pyrimethamine in the malaria parasite Plasmodium falciparum. Pyrimethamine was a mainstay medication for malaria for many years, and it is still in use in intermittent treatment during pregnancy or as a partner drug in artemisinin combination therapy. Our goal was to investigate the extent to which the alleles yield similar adaptive topographies and patterns of epistasis across chemically related drugs. We find that the adaptive topographies are indeed similar with the same or closely related alleles being fixed in computer simulations of stepwise evolution. For all but one of the drugs the topography features at least one suboptimal fitness peak. Our data are consistent with earlier results indicating that third order and higher epistatic interactions appear to contribute only modestly to the overall adaptive topography, and they are largely conserved. In regard to drug development, our data suggest that higher-order interactions are likely to be of little value as an advisory tool in the choice of lead compounds.

scholarly journals Detecting Heterogeneity of Substitution Along DNA and Protein Sequences

Genetics ◽  
1996 ◽  
Vol 143 (1) ◽  
pp. 589-602 ◽  
Author(s):  
Peter J E Goss ◽  
R C Lewontin
Keyword(s):  
Null Hypothesis ◽  
Nonuniform Distribution ◽  
Critical Values ◽  
Third Order ◽  
Variance Test ◽  
Data Set ◽  
Significance Level ◽  
Uniformly Most Powerful Test ◽  
Interval Lengths ◽  
Uniformly Most Powerful

Abstract Regions of differing constraint, mutation rate or recombination along a sequence of DNA or amino acids lead to a nonuniform distribution of polymorphism within species or fixed differences between species. The power of five tests to reject the null hypothesis of a uniform distribution is studied for four classes of alternate hypothesis. The tests explored are the variance of interval lengths; a modified variance test, which includes covariance between neighboring intervals; the length of the longest interval; the length of the shortest third-order interval; and a composite test. Although there is no uniformly most powerful test over the range of alternate hypotheses tested, the variance and modified variance tests usually have the highest power. Therefore, we recommend that one of these two tests be used to test departure from uniformity in all circumstances. Tables of critical values for the variance and modified variance tests are given. The critical values depend both on the number of events and the number of positions in the sequence. A computer program is available on request that calculates both the critical values for a specified number of events and number of positions as well as the significance level of a given data set.

scholarly journals Interactions between Merozoite Surface Proteins 1, 6, and 7 of the Malaria Parasite Plasmodium falciparum

2006 ◽  
Vol 281 (42) ◽  
pp. 31517-31527
Author(s):  
Christian W. Kauth ◽  
Ute Woehlbier ◽  
Michaela Kern ◽  
Zeleke Mekonnen ◽  
Rolf Lutz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Surface Proteins ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum
Sign in / Sign up

Export Citation Format

Share Document