Project description:We used a high-density tiling array to estimate genetic recombination rate among 32 independent recombinant progeny of a P. falciparum genetic cross (7G8 M-CM-^W GB4). We detected 3184 segregating multi-probe single-feature polymorphisms (mSFPs) and 638 recombination events (496 excluding those from subtelomeric regions). These data, in combination with results from 254 previously reported microsatellites, enabled us to construct a high-resolution genetic map. Comparing genetic and physical maps, we obtained an overall recombination rate of 9.6 kb/cM (12.8 kb/cM excluding subtelomeric regions) and identified 54 hotspots, some of which occurred in genes encoding surface antigens or proteins with repetitive motifs that might play a role in genetic recombination in the parasite. Motifs enriched in hotspots were also identified. In agreement with results from a previous cross (HB3 M-BM-4 Dd2), there was positive correlation between sizes of individual chromosomes and their recombination events. These results show that the P. falciparum genome is highly recombinogenic, providing an important genetic basis for parasite survival under various selection pressures. GC-rich repetitive motifs identified in the hotspot sequences may play a role in the high recombination frequency observed. Ten microgram of genomic DNA, extracted and purified from 3D7 (reference), thirty-two P. falciparum independent recombinant progeny of the 7G8 x GB4 cross, and the two parental lines (Hayton, 2008), were hybridized to the PFSANGER GenechipM-BM-. (Affymetrix, Inc., Santa Clara, CA, USA). The scanned image CEL files were first processed using the RMA method, then averaged and compared with reference genome 3D7, and lastly assigned either 7G8 or GB4 alleles based on similarities to the two parental lines. Total of 35 genomic DNA samples (biological replicates: 6 for 3D7, 4 for 7G8, 4 for GB4, and 2 for Pf_WE2). The supplementary file 'GSE25656_QuantNormData_Log2_AllSamples.txt' contains the RMA-normalized data for all of the samples. The supplementary files 'GSE25656_chr*' contain the parental allele assignment of each chromosome and include probe-level annotation.

Project description:Malaria represents a major public health problem in Africa [1]. In the East African highlands, even in high-altitude areas previously considered too cold to support vector population and parasite transmission [2], frequent malaria epidemics have been reported since the 1980M-bM-^@M-^Ys [3]. Plasmodium falciparum infections have been detected in areas as high as 1,600-2,400m above sea level in Africa [4], albeit there is a marked gradient of parasite prevalence along the altitude transect [5-7]. Both the historical absence of malaria in the African highlands and now the intensive malaria control efforts put in place after the recent outbreaks have reduced malaria prevalence and incidence [8], rendering the East African highlands particularly prone to epidemic malaria due to the lack of the protective immunity, and causing significant human mortality amongst all age groups [9]. Therefore, malaria transmission monitoring in the East African highlands becomes a particularly important public health issue.Despite the overall lower immunity of the population in these historically malaria-free areas, the many successive outbreaks since the 1980M-bM-^@M-^Ys may have generated some level of immunity against P. falciparum amongst highland residents. The antibody response to Plasmodium is cumulative and long lasting, developing after repeated exposures to the parasite and persisting for months or years after infection was resolved. The antibody response to Plasmodium varies amongst individuals of different age groups (i.e. toddlers, children and adults) as well as amongst individuals of same age groups from areas of different parasite prevalence [10]. The repertoire of targets of the antibody response also expands after multiple infections, with the number of recognized antigens being correlated to parasite prevalence, age and immunity to clinical malaria [11,12]. Serological studies bring forth indirect evidence of human exposure to the parasite, and can reliably assess its prevalence and transmission intensity in an endemic area [13-15]. However, the vast majority of serological studies of malaria have been, hereto, limited to a small number of the parasiteM-bM-^@M-^Ys antigens. The work we present here is an expansion of the study published by Badu et al. [16], in which the antibody response to the 19kDa fragment of merozoite surface protein 1 (MSP-119) was examined in populations from two endemic areas in the western Kenyan highlands. There, the tremendous variations of malaria transmission intensity in a small spatial scale are caused by substantial differences in altitude, topography and other environmental conditions [6,7,17,18]. We now expand our antibody profiling survey to include 854 P. falciparum proteins by using high-throughput proteomic microarray technology. Protein microarrays have been used to explore the humoral response to P. falciparum in other African settings [19-24], but this is the broadest characterization of the antibody responses of the population of western Kenyan highlands to date. In the present study we: i) determined the serological reactivity against P. falciparum (Pf) in subjects residing in a low transmission area, and detected hotspots of transmission; ii) examined the dynamics of antibody response to hundreds of Pf proteins generated by sera from toddlers, older children and adults residing in two endemic areas differing in transmission intensities, during two distinct malaria seasons, and compared the intensity, breadth and antigenic targets of these responses; and iii) identified candidate Pf antigenic markers that could provide more sensitive serological surveillance to detect micro-geographic variations in malaria transmission levels and differentiate hotspots of infection in low endemic areas. (references provided in the 'readme.txt') Antibody profiling was performed on sera from residents of western Kenyan highlands against Plasmodium falciparum. One-hundred and ten age-stratified serum samples collected during the dry and the wet seasons, from residents of two locations with differing parasite transmission levels (uphill and valley bottom), and 10 unexposed USA controls were probed on a protein microarray displaying 854 unique proteins of P. falciparum.

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Plasmodium falciparum

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