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Malaria Genomes Illustrate Differences, Selection Pressure Even in Closely Related Strains

NEW YORK (GenomeWeb) – Sequencing studies of the malaria parasite, Plasmodium falciparum, have revealed that there are differences between populations from very different geographic locations — like Africa and Asia — due to variations in whether the parasite is endemic to the area, the drug regimen used, mosquito susceptibility, and innate and acquired immune responses.

Now, a new study published in BMC Genomics has found that even among strains circulating in the same general geographic location, there are regions of the genome under specific selective pressure that cause strains to vary.

Researchers from the London School of Hygiene and Tropical Medicine, the University of Ghana, and the Wellcome Trust Sanger Institute sequenced malaria genomes from 85 clinical isolates collected from two sites in Ghana in order to test for selection that could occur due to seasonality differences of transmission, antimalarial drugs, or other factors. In one area, Kintampo, which is located in central Ghana, malarial transmission occurs year-round, while in Navrongo, located near the northern border, transmission is seasonal.

From the 85 samples, the team identified 121,712 SNPs, 65 percent of which were located in genes. Diversity was analyzed for each isolate, and the researchers found similar diversity across isolates and between the two regions.

The researchers also did a principal component analysis of the SNPs, and overall, they found very little differentiation between the two populations.

A deeper look at long-range haplotype information, however, "indicated that selection has probably been operating on multiple other loci," the authors wrote. To evaluate this, the team looked for areas with higher-than-expected integrated haplotype scores. An integrated haplotype score measures the extent of positive selection occurring in a genome.

The researchers identified 13 chromosomal regions with two or more SNPs above the top 0.1 percent of the randomly expected distribution. The largest region with the most supporting evidence spanned 303 kb on chromosome 6, while a second region spanned 50 kb on chromosome 11 and contained SNPs within the AMA1 antigen gene. Both of those regions have also been detected in other malaria samples from West Africa.

Higher-than-expected integrated haplotype scores were also seen around the antifolate drug target genes DHFR and DHPS and the chloroquine resistance transporter gene CRT. However, only the DHPS gene had a signature in both population samples. There was no detectable signature around the multi-drug resistance MDR1 gene.

Next, the team compared the average haplotype length associated with each SNP in the two populations and found evidence of selection in four chromosomal loci — one in the Kintampo population and three in the Navrongo population.

Most of the genes in those regions have an unknown function; however, one gene, TRAP, is a "leading vaccine candidate antigen," and another encodes for a protein that is "essential for mosquito transmission," the authors wrote.

Thus, "even in a situation of closely situated populations with very similar population structure and shared selection signatures, analysis across heterogeneous environments has potential to refine the mapping of important loci under temporally or spatially varying selection, including those of potential relevance to epidemiology and control of infection," the authors concluded.