High recombination rates and hotspots in a Plasmodium falciparum genetic cross

Abstract

BackgroundThe human malaria parasite Plasmodium falciparum survives pressures from the host immune system and antimalarial drugs by modifying its genome. Genetic recombination and nucleotide substitution are the two major mechanisms that the parasite employs to generate genome diversity. A better understanding of these mechanisms may provide important information for studying parasite evolution, immune evasion and drug resistance.ResultsHere, we used a high-density tiling array to estimate the genetic recombination rate among 32 progeny of a P. falciparum genetic cross (7G8 × GB4). We detected 638 recombination events and constructed a high-resolution genetic map. Comparing genetic and physical maps, we obtained an overall recombination rate of 9.6 kb per centimorgan and identified 54 candidate recombination hotspots. Similar to centromeres in other organisms, the sequences of P. falciparum centromeres are found in chromosome regions largely devoid of recombination activity. Motifs enriched in hotspots were also identified, including a 12-bp G/C-rich motif with 3-bp periodicity that may interact with a protein containing 11 predicted zinc finger arrays.ConclusionsThese results show that the P. falciparum genome has a high recombination rate, although it also follows the overall rule of meiosis in eukaryotes with an average of approximately one crossover per chromosome per meiosis. GC-rich repetitive motifs identified in the hotspot sequences may play a role in the high recombination rate observed. The lack of recombination activity in centromeric regions is consistent with the observations of reduced recombination near the centromeres of other organisms.

Antimalarial Drug Resistance: A Threat to Malaria Elimination

“…In addition, in high transmission areas, patients have multiple strain infections transmitted to the mosquito vector. Crossing over of genes during meiosis in the mosquito can then break up resistance and compensatory mutations, and this greater opportunity for recombination will result in increased parasite diversity and direct competition between different parasite strains, with less opportunity for resistant alleles to become fixed (Jiang et al 2011;Takala-Harrison and Laufer 2015). This is not the case in low transmission areas where multiple infections are much less common, infected individuals are less preimmune, usually more prone to be symptomatic, and, as a consequence, to be treated with possible poor-quality antimalarial drugs, incomplete treatment courses, or (artemisinin) monotherapies.…”

DNA Repair Mechanisms and Their Biological Roles in the Malaria Parasite Plasmodium falciparum

“…Analyses of parasite populations (119) and genetic crosses (74,77) showed that the subtelomeric regions have a high rate of recombination during the sexual stages. Further studies are needed to ascertain whether these events occur during meiosis or the numerous subsequent mitotic divisions in the mosquito vector.…”

“…Several other studies, nonetheless, have explored outcomes of meiotic recombination. P. falciparum genetic cross studies have analyzed the segregation of chromosomal markers (SNPs and microsatellites) spread out over the genome between geographically distinct parasite clones: 3D7 ϫ HB3 (79), HB3 ϫ Dd2 (73,74,(80)(81)(82), and 7G8 ϫ GB4 (77,83,84). These were instrumental in mapping the dihydrofolate reductase gene (dhfr) (85) and P. falciparum chloroquine resistance transporter gene (pfcrt) (86) that are key drug resistance loci and identifying key determinants of host cell tropism (77,83,84).…”

“…To date, no Mlh3 ortholog has been identified in P. falciparum. During meiotic recombination, each chromosome averages one crossover (73,74,77) and has a genetic map unit distance of ϳ10 kb (77) to ϳ15 kb (73) per centimorgan. Meiosis is followed by many rounds of DNA replication inside oocysts to form thousands of genomes that segregate into individual haploid sporozoites (66,78).…”

Multifunctional Involvement of a C2H2 Zinc Finger Protein (PbZfp) in Malaria Transmission, Histone Modification, and Susceptibility to DNA Damage Response

“…Genetic mapping and hotspot identification have also been performed in Plasmodium spp. (30)(31)(32)(33). Previously, our laboratory identified and investigated the role of molecules involved in HR.…”