Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 32, Pages 13052-13057Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1210585109
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Funding
- Bill and Melinda Gates Foundation
- National Institutes of Health (NIH) [1R01AI075080-01A1]
- Ellison Medical Foundation
- Exxon-Mobil Foundation
- NIH Fogarty International Center
- National Institute of Allergy and Infectious Diseases, and Broad Scientific Planning and Allocation of Resources Committee (SPARC)
- National Science Foundation Graduate Research Fellowship
- Burroughs Wellcome Foundation
- Packard Foundation
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Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite-the deadliest of those that cause malaria-is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites' in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.
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