Using whole genome sequence data to develop molecular barcodes to profile Plasmodium malaria parasites

点击翻译按钮获取中文摘要

Malaria is an important disease caused by parasites of the Plasmodium genus. Whilst theincidence of malaria has decreased in recent years, the burden still remains significant,with approximately 212 million new cases of malaria in 2015. Imported malaria canjeopardise disease control and elimination, and its prevalence is likely to increase due togreater travel. When assessing whether a country has successfully eliminated malaria,there is a need to distinguish imported cases from the cases transmitted locally. Amolecular barcode has been developed for P. falciparum parasites to predict thegeographical region of parasite origin, to high (>90%) accuracy. The barcode wasdeveloped by investigating the genetic variation within two parasite organelles, themitochondrion and the apicoplast. These organelles are present within all Plasmodiumparasite species, and both contain specific sequences of DNA. There is regional geneticdiversity within these genomes, and this diversity can be used within the barcode topredict the origin of the parasite.The barcode developed could prove to be an important tool for malaria control, but thereare limitations, which if overcome would improve its performance. P. falciparum parasitesare the main cause of malaria-related deaths worldwide, however there are many otherhuman-infective Plasmodium species, including P. vivax, P. malariae, P. knowlesi, P.ovale wallikeri and P. ovale curtisi. I propose to broaden the scope of the barcode byincluding additional genetic markers to profile multiple Plasmodium species. In addition,the previous barcode was developed using parasite samples from West Africa, EastAfrica, Southeast Asia and a limited set of countries in South America and Oceania.Therefore, I will aim to broaden the geographical scope of the barcode by inputting datafrom currently underrepresented regions. The barcode was also less efficient at predictingsamples from East Africa which were occasionally mistaken for parasites from WestAfrica, this is thought to be due to the high levels of genetic diversity within East AfricanPlasmodium parasites. I will address this issue by using more samples from East Africa toappreciate the high levels of genetic diversity within this region.2A further complication in disease control is the emergence of drug resistance toArtemisinin Combination Therapy (ACT), which is the current first line of treatment foruncomplicated P. falciparum malaria. Specific genetic regions known to be associated withACT resistance may be incorporated into the barcode to allow for the detection of drugresistant parasites. Combined with the geographical information within the barcode, thisallows for tracking the spread of drug resistant parasites, which may aid as a revolutionarytool for malaria control in the near future.During the process of this project, strong bioinformatics skills will be gained to analyselarge sets of genetic sequence data, this will develop my quantitative skills, fitting in withthe 'Quantitative Skills for Large Data Sets' MRC research theme. Many Plasmodiumsamples will be investigated for genetic diversity using whole genome sequencing; this willtrain me within the field of genomics, enhancing my skills on whole organism physiology.Finally, the aim of the project is to develop a platform known as a molecular barcode,which can track the movement and spread of Plasmodium parasites globally. I will aim toincorporate the barcode into a diagnostic tool that can be used in the evaluation ofcomplex malaria interventions and control programmes.