Consortial Project 3

Genome diversity in malaria-endemic regions

Consortial Project 3 uses resequencing to identify new genetic diversity in genes known to be associated with resistance to severe malaria, within and across malaria-endemic populations.

Study sites

• Burkina Faso: Centre National de Recherche et de Formation sur le Paludisme
• Cameroon: University of Buea
• Gambia: MRC Laboratories
• Ghana: Noguchi Memorial Institute for Medical Research
• Ghana: Navrongo Health Research Centre
• Kenya: KEMRI-Wellcome Reseach Programme
• Malawi: Blantyre Malaria Project
• Malawi: Malawi-Liverpool-Wellcome Programme
• Mali: University of Bamako
• Papua New Guinea: Papua New Guinea Institute for Medical Research
• Tanzania: Joint Malaria Programme, Kilimanjaro Christian Medical Centre
• Tanzania: Muhimbili University of Allied and Health Sciences
• Vietnam: Oxford University Clinical Research Unit

Scientific rationale

Whereas the genome-wide association (GWA) studies of Consortial Project 1 look systematically and unbiasedly at known single nucleotide polymorphisms (SNPs) across the genome, Consortial Project 3 takes a directed approach, comprehensively mining the full sequence of known or putative malaria resistance genes. By resequencing entire genes rather than genotyping at discrete nucleotides, this approach provides a comprehensive catalogue of genetic diversity in the targeted region of the tested population. It reveals new SNPs (and other genetic variants) while also assessing the status of known SNPs. Importantly, resequencing can expose the functional polymorphism in a gene that alters malaria susceptibility, whereas genotyping simply points at genomic regions that associate with resistance, without information about the identity or mechanism of the functional variant.

Genes of interest for analysis in Consortial Project 3 are selected on the basis of a previously demonstrated role in resistance to malaria or on association 'hits' inferred from Consortial Project 1 GWA studies. Importantly, the Consortial Project 3 resequencing pipeline also provides an efficient mechanism for resolving Consortial Project 1 hits in distinct populations. Conversely, new SNPs identified in Consortial Project 3 will inform future genotyping and GWA studies. Consortial Project 3 resequencing efforts will also provide novel insights into the unique and common features of the genetic population structure within and across the African and Southeast Asian populations that we are studying.

Data generation

Our pilot efforts, currently in the development and data collection phase, focus on resequencing well-characterised malaria resistance genes in 48 samples from each partner site. These genes include the alpha-globin and beta-globin gene clusters, G6PD and SLC4A1. We are optimistic that soon new, high-throughput sequencing technology can be leveraged to greatly increase the Consortial Project 3 resequencing capacity, while also greatly reducing the cost of this approach.