Multi-population genomic analysis of malaria parasites indicates local selection and differentiation at the gdv1 locus regulating sexual development

Abstract

Parasites infect hosts in widely varying environments, encountering diverse challenges for adaptation. To identify malaria parasite genes under locally divergent selection across a large endemic region with a wide spectrum of transmission intensity, genome sequences were obtained from 284 clinical Plasmodium falciparum infections from four newly sampled locations in Senegal, The Gambia, Mali and Guinea. Combining these with previous data from seven other sites in West Africa enabled a multi-population analysis to identify discrete loci under varying local selection. A genome-wide scan showed the most exceptional geographical divergence to be at the early gametocyte gene locus gdv1 which is essential for parasite sexual development and transmission. We identified a major structural dimorphism with alternative 1.5 kb and 1.0 kb sequence deletions at different positions of the 3′-intergenic region, in tight linkage disequilibrium with the most highly differentiated single nucleotide polymorphism, one of the alleles being very frequent in Senegal and The Gambia but rare in the other locations. Long non-coding RNA transcripts were previously shown to include the entire antisense of the gdv1 coding sequence and the portion of the intergenic region with allelic deletions, suggesting adaptive regulation of parasite sexual development and transmission in response to local conditions.

Major subpopulations of Plasmodium falciparum in sub-Saharan Africa

“…With higher density of genomic variants from next generation sequencing technologies, a better resolution of African P. falciparum populations is now possible. SNP markers for specific local populations or across several sites within geographic blocs have enabled the description of genomic variation and signatures of selection in Africa (6,7). However, the ancestry, current structure and gene flow between P. falciparum across Africa remains unclear.…”

Shifts in P. falciparum genetic structure and gametocyte markers in the transition to elimination

“…Alternatively, higher gametocyte conversion rates may have been selected by reductions in the Anopheline population driven by vector campaigns deployed during the elimination initiative, such as intra-door residual spraying. Further studies are required to assess if changes in sexual differentiation after sharp declines of malaria transmission are mainly driven by plastic responses or adaptive selection of Pf genes such as pfgdv1 [27][28][29] . Independently of the mechanisms used by the parasite, the higher investment in gametocyte production observed in this study suggest that reactive focal MDA approaches with gametocytocidic antimalarials such as primaquine, coupled with glucose-6-phosphate dehydrogenase de ciency testing, 30 may increase the impact of strategies aiming to interrupt or prevent the reestablishment of malaria transmission.…”

Population Genomics Of Plasmodium Falciparum And Malaria Control Implications In Abidjan (Cote D’ivoire)

“…During the past decade, genomics and genetics studies have been conducted to identify P. falciparum markers associated with disease severity, resistance to drugs and escape to the human immune system. These studies provide valuable informations for malaria control [5][6][7] . Hence, a population genomics study of P. falciparum in a single endemic population of Gambia identified new genes under balancing selection, such as the apical membrane antigen 1 gene (ama1) which encodes a prime vaccine candidate [8] .…”