Genomic_and_transcriptomic_comparisons_of_closely_related_malaria_parasites_differing_in_virulence_and_sequestration_pattern

Malaria parasite species differ greatly in the harm they do to humans. While P. falciparum kills hundreds of thousands per year, P. vivax kills much less often and P. malariae is relatively benign. Strains of the rodent malaria parasite Plasmodium chabaudi show phenotypic variation in virulence during infections of laboratory mice. This makes it an excellent species to study genes which may be responsible for this trait. By understanding the mechanisms which underlie differences in virulence we can learn how parasites adapt to their hosts and how we might prevent disease. Here we present a complete reference genome sequence for the more virulent PcCB strain, and perform a detailed comparison with the genome of the less virulent PcAS strain. We found the greatest genomic variation in the subtelomeric regions, in particular amongst the sequences of the pir gene family, which has been associated with virulence and establishment of chronic infection. However, despite substantial variation at the sequence level, the repertoire of these genes has been largely maintained, highlighting the requirement for functional conservation as well as diversification in host-parasite interactions. We found that core genes involved in red blood cell invasion and sexual development have been under positive selection and these parallel phenotypic differences between parasite strains. These results provide the basis for a mechanistic understanding of the phenotypic differences between Plasmodium chabaudi strains, which might ultimately be translated into a better understanding of malaria parasites affecting humans.不同疟原虫物种对人类的致病危害差异悬殊。其中，恶性疟原虫（P. falciparum）每年可导致数十万人死亡，间日疟原虫（P. vivax）的致死率相对较低，而三日疟原虫（P. malariae）的致病性较为温和。啮齿类疟原虫查氏疟原虫（Plasmodium chabaudi）的不同毒株在感染实验小鼠时会表现出毒力的表型差异，这使其成为探究调控该性状相关基因的理想研究模型物种。 解析疟原虫毒力差异的潜在机制，有助于我们理解寄生虫适应宿主的方式，进而制定疾病防控策略。 本研究报道了高毒力PcCB菌株的完整参考基因组序列，并与低毒力PcAS菌株的基因组开展了细致的比对分析。 研究发现，基因组差异主要富集于亚端粒区域，尤其是与毒力和慢性感染建立相关的pir基因家族（pir gene family）的序列之间。尽管序列水平存在显著变异，但该基因家族的成员谱型整体保持稳定，这提示宿主-寄生虫互作过程中，既需要功能保守性，也需要基因多样化以适应宿主。 我们还发现，参与红细胞入侵和有性发育的核心基因受到正选择作用，这与不同疟原虫毒株的表型差异相互印证。 上述研究结果为解析查氏疟原虫不同毒株的表型差异提供了机制层面的依据，最终或可帮助我们更深入地认识感染人类的疟原虫物种。