Genomic and Genetic Approaches to Studying Antimalarial Drug Resistance and Plasmodium Biology

• Published in: Trends in parasitology Vol. 37; no. 6; pp. 476 - 492
• Main Authors: Okombo, John, Kanai, Mariko, Deni, Ioanna, Fidock, David A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2021
• Subjects: drug resistance; gene editing; genetic crosses; genomics; inducible expression; Plasmodium falciparum malaria; genomics; inducible expression; drug resistance; genetic crosses; gene editing; Plasmodium falciparum malaria
• ISSN: 1471-4922; 1471-5007
• DOI: 10.1016/j.pt.2021.02.007

Recent progress in genomics and molecular genetics has empowered novel approaches to study gene functions in disease-causing pathogens. In the human malaria parasite Plasmodium falciparum, the application of genome-based analyses, site-directed genome editing, and genetic systems that allow for temporal and quantitative regulation of gene and protein expression have been invaluable in defining the genetic basis of antimalarial resistance and elucidating candidate targets to accelerate drug discovery efforts. Using examples from recent studies, we review applications of some of these approaches in advancing our understanding of Plasmodium biology and illustrate their contributions and limitations in characterizing parasite genomic loci associated with antimalarial drug responses.
CRISPR/Cas9 and other site-specific gene-editing techniques enable rapid and efficient generation of knockouts, targeted integrants, and allelic replacements of genes associated with malaria pathogenesis and drug resistance.Regulatable genetic systems that quantitatively and temporally modulate expression levels facilitate mechanistic studies, especially those involving essential genes, and help distinguish on-target from off-target effects.New or refined whole-genome-based strategies, such as functional genomic screens and genetic crosses in humanized mice, now accompany traditional techniques, including genome-wide association studies (GWAS) and gene editing to identify and characterize genetic determinants of resistance.