Selection strength and hitchhiking around two anti-malarial resistance genes.
AffiliationSouthwest Foundation for Biomedical Research (SFBR), San Antonio, TX 78245, USA.
MetadataShow full item record
AbstractNeutral 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 in pfcrt conferring resistance to chloroquine (CQ) and 2-4 mutations in dhfr conferring 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) around pfcrt in 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 resistant pfcrt and dhfr alleles 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.
- A selective sweep driven by pyrimethamine treatment in southeast asian malaria parasites.
- Authors: Nair S, Williams JT, Brockman A, Paiphun L, Mayxay M, Newton PN, Guthmann JP, Smithuis FM, Hien TT, White NJ, Nosten F, Anderson TJ
- Issue date: 2003 Sep
- Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistance alleles in a population from central Africa.
- Authors: McCollum AM, Basco LK, Tahar R, Udhayakumar V, Escalante AA
- Issue date: 2008 Nov
- Reduced heterozygosity at intragenic and flanking microsatellites of pfcrt gene establishes natural selection based molecular evolution of chloroquine-resistant Plasmodium falciparum in India.
- Authors: Mallick PK, Singh R, Singh OP, Singh AK, Bhasin VK, Valecha N
- Issue date: 2013 Dec
- Analyses of genetic variations at microsatellite loci present in-and-around the Pfcrt gene in Indian Plasmodium falciparum.
- Authors: Chauhan K, Pande V, Das A
- Issue date: 2013 Dec
- Characteristics of genetic hitchhiking around dihydrofolate reductase gene associated with pyrimethamine resistance in Plasmodium falciparum isolates from India.
- Authors: Lumb V, Das MK, Singh N, Dev V, Wajihullah, Sharma YD
- Issue date: 2009 Dec