Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites
Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites
复制标题
DOI：
10.1101/gr.105163.110
复制
发表时间：
2010-11-01
期刊：
影响因子：
7
通讯作者：
Winzeler, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Dharia, Neekesh V.;Plouffe, David;Winzeler, Elizabeth A.
在这里，我们充分表征了14个恶性疟原虫患者分离株的基因组最近从伊基托斯地区使用基因组扫描，一种基于微阵列的技术，描绘了大部分的单碱基变化，插入缺失，拷贝数变异区分两个克隆的编码区。我们表明，寄生虫种群在秘鲁亚马逊承担有限数量的基因型和低重组频率。尽管一些菌株基本上是克隆性的，但我们看到亚端粒高度可变基因和内部变异基因的突变频率很高，这表明突变发生在自交或有丝分裂复制过程中。这些数据还表明，一个或两个减数分裂分离不同的分离株，表明分离自不同个体的恶性疟原虫克隆在一定的地理区域可能是有用的连锁分析或数量性状基因座研究。通过对不同分离株的成对比较，我们发现了顶质体基因组中的点突变，这些点突变与其他物种中赋予克林霉素抗性的已知突变接近，但在疟疾寄生虫中是迄今为止未知的。随后的药物敏感性试验显示，携带这些突变之一的菌株中克林霉素EC50增加了100倍以上。亚马逊地区存在克林霉素耐药性寄生虫的证据表明，卫生政策应该改变，不再使用奎宁+克林霉素治疗孕妇和婴儿的疟疾，并且应该重新考虑开发新的林可酰胺类疟疾抗生素。[补充材料可在http://www.genome.org在线获得。来自本研究的微阵列数据已提交至NCBI基因表达综合库（http：//www.ncbi.nlm.nih.gov/geo），登录号为GSE 22861，也可在http：//www.scripps.edu/cb/winzeler/resources/pf_peru。]
Here, we fully characterize the genomes of 14 Plasmodium falciparum patient isolates taken recently from the Iquitos region using genome scanning, a microarray-based technique that delineates the majority of single-base changes, indels, and copy number variants distinguishing the coding regions of two clones. We show that the parasite population in the Peruvian Amazon bears a limited number of genotypes and low recombination frequencies. Despite the essentially clonal nature of some isolates, we see high frequencies of mutations in subtelomeric highly variable genes and internal var genes, indicating mutations arising during self-mating or mitotic replication. The data also reveal that one or two meioses separate different isolates, showing that P. falciparum clones isolated from different individuals in defined geographical regions could be useful in linkage analyses or quantitative trait locus studies. Through pairwise comparisons of different isolates we discovered point mutations in the apicoplast genome that are close to known mutations that confer clindamycin resistance in other species, but which were hitherto unknown in malaria parasites. Subsequent drug sensitivity testing revealed over 100-fold increase of clindamycin EC50 in strains harboring one of these mutations. This evidence of clindamycin-resistant parasites in the Amazon suggests that a shift should be made in health policy away from quinine + clindamycin therapy for malaria in pregnant women and infants, and that the development of new lincosamide antibiotics for malaria should be reconsidered.[Supplemental material is available online at http://www.genome.org. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE22861 and are also at http://www.scripps.edu/cb/winzeler/resources/pf_peru.]