A Systematic Map of Genetic Variation in Plasmodium falciparum

PLoS Pathogens

Elizabeth A Winzeler¹  Claire Kidgell¹  Jeffrey R Johnson¹  Johanna Daily²  Dyann F Wirth²  Sarah K Volkman²  Soulyemane Mboup³  Ousmane Sarr³  Omar Ndir³  Serge Batalov⁴  David Plouffe⁴  Karine G. Le Roch⁴  Yingyao Zhou⁴  Justin O Borevitz⁵ 

[1] Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America;Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, United States of America;Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal;Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America;Plant Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America

关键词: Plasmodium;    Malarial parasites;    Antimicrobial resistance;    Gene amplification;    Malaria;    Antimalarials;    Immune system proteins;    Gene mapping;   

DOI  :  10.1371/journal.ppat.0020057

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Discovering novel genes involved in immune evasion and drug resistance in the human malaria parasite, Plasmodium falciparum, is of critical importance to global health. Such knowledge may assist in the development of new effective vaccines and in the appropriate use of antimalarial drugs. By performing a full-genome scan of allelic variability in 14 field and laboratory strains of P. falciparum, we comprehensively identified ≈500 genes evolving at higher than neutral rates. The majority of the most variable genes have paralogs within the P. falciparum genome and may be subject to a different evolutionary clock than those without. The group of 211 variable genes without paralogs contains most known immunogens and a few drug targets, consistent with the idea that the human immune system and drug use is driving parasite evolution. We also reveal gene-amplification events including one surrounding pfmdr1, the P. falciparum multidrug-resistance gene, and a previously uncharacterized amplification centered around the P. falciparum GTP cyclohydrolase gene, the first enzyme in the folate biosynthesis pathway. Although GTP cyclohydrolase is not the known target of any current drugs, downstream members of the pathway are targeted by several widely used antimalarials. We speculate that an amplification of the GTP cyclohydrolase enzyme in the folate biosynthesis pathway may increase flux through this pathway and facilitate parasite resistance to antifolate drugs.

【 授权许可】

CC BY