Selection strength and hitchhiking around two anti-malarial resistance genes

Proceedings of the Royal Society B: Biological Sciences - Tập 272 Số 1568 - Trang 1153-1161 - 2005
Denae Nash1,2, Shalini Nair2, Mayfong Mayxay3,4, Paul N. Newton4, Jean-Paul Guthmann5, Nicholas J. White6,7,8, Tim Anderson2
1Our Lady of the Lake UniversitySan Antonio, TX 78207, USA
2Southwest Foundation for Biomedical Research (SFBR), PO Box 760549, San Antonio, TX 78245, USA
3Faculty of Medicine, National University of LaosVientiane, Lao PDR
4Wellcome Trust-Mahosot-Oxford Tropical Medicine Research Collaboration, Mahosot HospitalVientiane, Lao PDR
5Epicentre (Médecins Sans Frontières-France)8 rue Saint Sabin, 75011 Paris, France
6Centre for Clinical Vaccinology and Tropical Medicine, Churchill HospitalOxford OX3 7LJ, UK
7Faculty of Tropical Medicine, Mahidol UniversityBangkok, Thailand
8Shoklo Malaria Research Unit (SMRU), Mae Sot, Tak, Thailand

Tóm tắt

Neutral mutations may hitchhike to high frequency when they are situated close to sites under positive selection, generating local reductions in genetic diversity. This process is thought to be an important determinant of levels of genomic variation in natural populations. The size of genome regions affected by genetic hitchhiking is expected to be dependent on the strength of selection, but there is little empirical data supporting this prediction. Here, we compare microsatellite variation around two drug resistance genes (chloroquine resistance transporter (pfcrt), chromosome 7, and dihydrofolate reductase (dhfr), chromosome 4) in malaria parasite populations exposed to strong (Thailand) or weak selection (Laos) by anti-malarial drugs. In each population, we examined the point mutations underlying resistance and length variation at 22 (chromosome 4) or 25 (chromosome 7) microsatellite markers across these chromosomes. All parasites from Thailand carried the K76T mutation inpfcrtconferring resistance to chloroquine (CQ) and 2–4 mutations indhfrconferring resistance to pyrimethamine. By contrast, we found both wild-type and resistant alleles at both genes in Laos. There were dramatic differences in the extent of hitchhiking in the two countries. The size of genome regions affected was smaller in Laos than in Thailand. We observed significant reduction in variation relative to sensitive parasites for 34–64 kb (2–4 cM) in Laos on chromosome 4, compared with 98–137 kb (6–8 cM) in Thailand. Similarly, on chromosome 7, we observed reduced variation for 34–69 kb (2–4 cM) aroundpfcrtin Laos, but for 195–268 kb (11–16 cM) in Thailand. Reduction in genetic variation was also less extreme in Laos than in Thailand. Most loci were monomorphic in a 12 kb region surrounding both genes on resistant chromosomes from Thailand, whereas in Laos, even loci immediately proximal to selective sites showed some variation on resistant chromosomes. Finally, linkage disequilibrium (LD) decayed more rapidly around resistantpfcrtanddhfralleles from Laos than from Thailand. These results demonstrate that different realizations of the same selective sweeps may vary considerably in size and shape, in a manner broadly consistent with selection history. From a practical perspective, genomic regions containing resistance genes may be most effectively located by genome-wide association in populations exposed to strong drug selection. However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations.

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Proceedings of the Royal Society B: Biological Sciences

Tập 272 Số 1568

1153-1161

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