Kidgell Claire, Volkman Sarah K, Daily Johanna, Borevitz Justin O, Plouffe David, Zhou Yingyao, Johnson Jeffrey R, Le Roch Karine, Sarr Ousmane, Ndir Omar, Mboup Soulyemane, Batalov Serge, Wirth Dyann F, Winzeler Elizabeth A
Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA.
PLoS Pathog. 2006 Jun;2(6):e57. doi: 10.1371/journal.ppat.0020057. Epub 2006 Jun 23.
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 approximately 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.
在人类疟原虫恶性疟原虫中发现参与免疫逃逸和耐药性的新基因对全球健康至关重要。这些知识可能有助于开发新的有效疫苗以及合理使用抗疟药物。通过对14个恶性疟原虫野外和实验室菌株的等位基因变异进行全基因组扫描，我们全面鉴定出约500个以高于中性速率进化的基因。大多数变异最大的基因在恶性疟原虫基因组中有旁系同源物，其进化时钟可能与没有旁系同源物的基因不同。211个无旁系同源物的可变基因群体包含大多数已知免疫原和一些药物靶点，这与人类免疫系统和药物使用正在推动寄生虫进化的观点一致。我们还揭示了基因扩增事件，包括围绕pfmdr1（恶性疟原虫多药耐药基因）的一个事件，以及一个以恶性疟原虫GTP环水解酶基因（叶酸生物合成途径中的首个酶）为中心的此前未表征的扩增事件。尽管GTP环水解酶不是任何现有药物的已知靶点，但该途径的下游成员是几种广泛使用的抗疟药物的靶点。我们推测叶酸生物合成途径中GTP环水解酶的扩增可能会增加该途径的通量，并促进寄生虫对抗叶酸药物产生耐药性。
