Saturday, November 26, 2011

Positive selection, recombination hot spots and resistance to antimalarial drugs in P. Falciparum: the way to the treatment against malaria ?

Plasmodium Falciparum is a protozoan parasite that cause malaria in human. An estimated 781,000 people died from malaria in 2009 according to the World Health Organization. Different treatments exist against malaria since 1891 such as Atabrine, Chloroquine(CQ) or Artemisinin(ART) but there is not yet any vaccination possible and due to the evolution one can see an increasing in drug resistance of the Falciparum population.

Some information at genomic level are at a high importance to determine the resistance to antimalarial drugs. To study possible treatments, a group of researchers worked on Plasmodium Falciparum to detect variation in recombination rate, loci under recent positive selection and genes associated with drug responses. For this work, the researchers used the GWAS method (Genome-Wide Association Studies) which allows to define if a single-nucleotide polymorphism (SNPs) is associated with a trait, here the malaria.

The authors collected and adapted 189 independent P. falciparum: including 146 from Asia (specifically, Thailand and Cambodia), 26 from Africa, 14 from America and 3 from Papua New Guinea. Antimalarial drug resistance of Falciparum is different according to their localization, thus the choice of the authors is good but not well-balanced. Using population genetics methods and stratification methods, the authors showed that the parasites could be clustered into continental populations. Based on a PCA (Principal Component Analysis) we can see that the presence of SNPs could distinguish parasites with different phenotypes.

Population recombination maps were generated for all 14 chromosomes to detect variation in recombination rate. Recombination spots appeared to be conserved among population. The authors detected several loci with extremely high levels of recombination activity, including a locus at the end of chromosome 1 and a segment on chromosome 7 containing pfcrt (gene encoding the P. Falciparum CQ resistance transporter).

Three different methods were used to define loci under significant positive selection: relative extended haplotype homozygosity (REHH), integrated haplotype scores (iHS) and cross-population extended haplotype homozygosity XP-EHH. Using the REHH method, multiple loci under positive selection were detected such as: locus on chromosome 7 containing pfcrt, a locus on chromosome 11 containing the gene encoding P. Falciparum apical membrane antigen 1 (pfama-1) and a locus on chromosome 13 containing PF13_0271 which encodes an ATP-binding cassette (ABC) transporter. The pfama-1, pfcrt and new SNPs loci are detected using the iHS method. The XP-EHH compared the different populations and allowed the detection of selective sweep that drive some alleles to fixation in one population but remain polymorphic in others. A total of 11 genes under significant selection were detected by all three of the 3 methods.

The parasite half-maximum inhibitory concentration (IC50) measures the effectiveness of a compound in inhibiting biological or biochemical function. In the study, IC50 was measured to detect genes associated with drug responses. Multivariate analyses showed a strong positive correlation between IC50 values of mefloquine (MQ) and Dihydroartemisinin (DHA) and a general sensitivity to piperaquine (PQ) and DHA in all the parasites. The authors detected a higher resistant to the drugs on the Cambodian population.

This publication is very interesting, the authors identified many genes under positive selection, some of which could be drug or immune targets. With further studies, we can hope to obtain an effective treatment against the malaria. As a Nature publication, the authors could have been more attentive in small points such as changing the representative color of the different populations from one graph to the other.

Mu, J., Myers, R., Jiang, H., Liu, S., Ricklefs, S., Waisberg, M., Chotivanich, K., Wilairatana, P., Krudsood, S., White, N., Udomsangpetch, R., Cui, L., Ho, M., Ou, F., Li, H., Song, J., Li, G., Wang, X., Seila, S., Sokunthea, S., Socheat, D., Sturdevant, D., Porcella, S., Fairhurst, R., Wellems, T., Awadalla, P., & Su, X. (2010). Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs Nature Genetics, 42 (3), 268-271 DOI: 10.1038/ng.528

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