Selection strength and hitchhiking around two anti-malarial resistance genes - PubMed (original) (raw)

Comparative Study

Selection strength and hitchhiking around two anti-malarial resistance genes

Denae Nash et al. Proc Biol Sci. 2005.

Abstract

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 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.

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Figures

Figure 1

Figure 1

Map showing sample collection sites in Thailand and Laos.

Figure 2

Figure 2

Patterns of genetic variation around pfcrt and dhfr. (a) and (b) show _H_e (±1 s.d.) plotted against position on the chromosomes relative to pfcrt (chromosome 7) and dhfr (chromosome 4). The markers are ordered along the _x_-axis, which is not linear. Chromosomes bearing wild-type alleles are shown in grey, those bearing resistant alleles are shown in red (Laos) or black (Thailand). The distance from pfcrt and dhfr at which _H_e differs significantly (p<0.01) between wild-type and resistant chromosomes is shown in the bars underneath the graph. Significance values were derived by permutation: black, p<0.001; stippled, p<0.01.

Figure 3

Figure 3

Decline in linkage disequilibrium around pfcrt and dhfr. (a) and (b) show the decline in LD around wild-type and resistant alleles at pfcrt and dhfr. The _x_-axes are shown to scale. In (b), resistant alleles bearing between one and four mutations are grouped. These graphs are shown with the _x_-axis drawn to scale. LD is measured using EHH (±1 s.d.). (c) EHH plotted around dhfr alleles bearing different resistance mutations. EHH surrounding resistant alleles from Thailand is shown in black and those from Laos in red, while EHH decay around sensitive alleles is shown in grey. Four-letter codes indicate amino acids present at positions 51, 59, 108 and 164, while underlined letters are those underlying resistance. These codes are marked on the graph for clarity. Data describing EHH decline are not shown for the NCNI allele, as there were only three parasites carrying this allele.

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