Selection strength and hitchhiking around two anti-malarial resistance genes

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.

Hitchhiking Mapping Reveals a Candidate Genomic Region for Natural Selection in Three-Spined Stickleback Chromosome VIII

“…In P. falciparum the region underlying selection around resistance loci depended strongly on the strength of selection. In the Laos population, experiencing weak selection for resistance to an antimalarial drug, the genome regions affected by hitchhiking were smaller (34-69 kb) than in the Thailand population influenced by strong selection (98-268 kb; Nash et al 2005). In our study, the selective sweep seems not to be restricted only to the loci in the vicinity of the candidate locus.…”

“…Unfortunately, estimation of the selection coefficient would require information of the mutation and recombination rates, as well as effective population size and this data is lacking at the moment. However, the selection in this genomic region might be fairly strong given that the size of the region is comparable to the Nash et al (2005) findings.…”

“…These examples show selective sweeps resulting from domestication (Clark et al 2004;Olsen et al 2006), artificial selection (Pollinger et al 2005;Sutter et al 2007), and pesticide treatment (Nair et al 2003;Nash et al 2005). In these cases selection is assumed to have The average of the equilibrium heterozygosity based on the observed number alleles (H EQ ) assuming either a step-wise mutation model (SMM) or a two-phase mutation model (TPM), and the expected heterozygosity (H E ).…”

Darwin and Genetics

“…These effects on linked neutral or nearly neutral variants can be used in statistical tests for the action of natural selection. This has enabled geneticists to detect and estimate the strength of selection acting on genes such as drug resistance genes in the human malaria parasite by using the variability of microsatellite markers (e.g., Nash et al 2005) to detect numerous examples of recent adaptations in human populations from their effects on patterns of variation at linked SNPs (e.g., Currat et al 2002;Sabeti et al 2002;Williamson et al 2007;Akey 2009) and to search for genes involved in responses to artificial selection (Walsh 2008).…”

Genetic architecture of resistance in Daphnia hosts against two species of host-specific parasites

“…This evidencetogether with the general notion that disease-related traits show high levels of polymorphisms in natural populations-has been used to emphasize the role of NFDS as a key mechanism of coevolution (references as before; for reviews, see (Thompson, 2005;SchmidHempel, 2011)). Other studies, however, stress the role of selective sweeps for host and parasite adaptation (Buckling and Rainey, 2002;Jiggins, 2003;Little et al, 2004;Nash et al, 2005;Obbard et al, 2011). To understand which model best explains coevolution in any given system requires, however, we must clarify the genetic architecture of host resistance.…”