Malaria Genomics in the Era of Eradication

Abstract

The first reference genome assembly for the Plasmodium falciparum malaria parasite was completed over a decade ago, and the impact of this and other genomic resources on malaria research has been significant. Genomic resources for other malaria parasites are being established, even as P. falciparum continues to be the focus of development of new genomic methods and applications. Here we review the impact and applications of genomic data on malaria research, and discuss future needs and directions as genomic data generation becomes less expensive and more decentralized. Specifically, we focus on how population genomic strategies can be utilized to advance the malaria eradication agenda.

Figure 1.

Range of transmission intensity. A schematic representing signals detected from mosquito, human, and parasite populations that are anticipated as transmission intensity declines. As the transmission intensity decreases from high to low levels, changes in mosquito (entomological inoculation rate [EIR]; human complexity of infection [COI]), and parasite (genotyping) indicators are anticipated to change. With relatively high transmission (e.g., EIR > 1), we see high COI levels and a predominance of polygenomic infections as assessed through genotyping methods. As transmission decreases to more moderate (e.g., EIR from 0.1 to 1) or lower levels (e.g., EIR from 0.01 to 0.1), we detect decreases in COI and increases in the proportion of individuals harboring monogenomic infections. Eventually as transmission intensity is very low (e.g., EIR from 0 to 0.01) we detect evidence of COI = 1 and clonal parasite populations among monogenomic infections detected using genotyping methods.

Figure 2.

Intervention effect on parasite population. This schematic represents the potential impact of different interventions (e.g., bednets, vaccines, or drugs) on allele frequencies in the parasite population. The different colored circles represent a specific locus of interest such as an allele or haplotype that may be subject to selection by a vaccine (green circle) or drug (red circle). As a vaccine (e.g., a monovalent protein subunit vaccine like RTS,S) is applied, there may be reduction in specific parasite types that harbor the target locus (e.g., the circumsporozoite [CS] locus that matches the type found in the vaccine), thus reducing parasite types with that specific locus from the parasite population. As a drug is applied, there may be selection for a specific drug resistance locus resulting in an increase in the frequency of parasite types that harbor that specific drug-resistant variant. For comparison, use of a bednet might reduce the overall parasite types (represented by fewer circles that are proportionally reduced), but may not specifically select for or against any particular locus or allele within parasites in that population.

Figure 3.

Anticorrelated drug resistance—an evolutionary loop. This schematic represents a potential evolutionary loop whereby two different drugs (A in red and B in blue) act on the same locus with each drug selecting a different variant or haplotype than the alternate drug. For example, as drug A (red) is applied to the parasite population, the haplotype conferring resistance to A will increase in frequency in the population. If the alternate drug (B, blue) is applied to this population, the alternate haplotype conferring resistance to B will increase in the population. This creates a population with increased resistance to B, but increased susceptibility to the alternate drug A. Application of drug A will now reverse the dynamics of the haplotype frequency such that the variant that confers resistance to A will again increase in frequency in the population. This alternating use of paired drugs with anticorrelated resistance will thus create an evolutionary loop.

Figure 4.

Expected changes in derived allele frequency. A simulation of expected changes in derived allele frequency (DAF) over time in a population with 1000 individuals for alleles that are selectively neutral (gray lines) or that confer a 1% fitness advantage (red lines). Time is measured in generations.