Evolutionary genetics of Leishmania species with a focus on South America

利什曼原虫原虫对世界上几个人口众多的地区造成重大危害，主要影响东非、中东、印度次大陆和南美洲的穷人。巴西和南美洲其他地区受到内脏利什曼病（VL，由婴儿利什曼原虫引起）和多种形式的皮肤利什曼病（CL，由墨西哥利什曼原虫、巴西利什曼原虫和Viannia物种复合体中的多种其他物种引起）的影响。在过去十年中，南美的VL或CL的病例负担和治疗结果都没有得到很大改善。相对于所造成的危害，对利什曼病的研究被忽视了。例如，药物、疫苗和沙蝇病媒控制的研究和开发进展不佳。支持应用方法的基础知识也缺乏，包括对利什曼原虫物种的进化遗传学的理解。本博士将通过对利什曼原虫物种的比较分析和种群分析，重点关注南美洲特有的物种，通过几项相关分析，解决这一基础知识的缺乏问题。分析将从比较基因组学开始，通过使用牛津纳米孔技术（ONT）读取，完成所有没有或低质量基因组组装的利什曼原虫物种的高质量基因组，包括适当的外群/非致病性物种。ONT和Illumina的8个物种的数据现已可用。资金和联系人可以获得DNA并对多达20多个物种进行测序。对所有30种利什曼原虫进行比较基因组学分析将有助于更好地了解这些寄生虫的分子进化。第二项分析将利用分布在巴西和南欧的约400个菌株的现有数据集，对巴西引起vl的物种L. infantum进行群体遗传分析。我们未发表的分析表明，L. infantum是随着葡萄牙人的殖民（约1600年）来到巴西的。该学生将利用这些数据制作巴西该物种的遗传多样性、种群结构、扩散和繁殖动态的种群遗传模型。在这个博士学位中，有可能从几个合作者那里获得进一步的样本并对其进行测序，并为正在进行的乳杆菌婴儿突变对狗和人类宿主疾病严重程度和/或耐药性的影响的分析做出贡献。第三个分析将集中在大约7个物种的利什曼原虫（Leishmania Viannia）分支上，它们导致了南美洲的CL。该分析将从七个物种的至少14个Viannia基因组的现有数据开始，使用详尽的基因组尺度系统发育方法和单倍型解析的ONT组装来描述杂交形成的历史。同样，在这个博士学位课程中，学生有可能参与现有数据的分析（包括78个古颜利什曼原虫），和/或从几个合作者那里获得进一步的样本并对其进行测序。与合作者进行一些实地工作是可能的。该博士学位将培养一名在人口和比较基因组学方面训练有素的专家，在南美利什曼原虫物种的基因组流行病学方面具有相当的专业知识。

Evolutionary genetics of Leishmania species with a focus on South AmericaLeishmania protozoans cause significant harm to several regions of the world with large populations, primarily affecting the poor in East Africa, the Middle East, the Indian subcontinent, and South America. Brazil and other regions of South America are affected by both visceral leishmaniasis (VL, caused by Leishmania infantum) and cutaneous leishmaniasis in a variety of forms (CL, caused by Leishmania mexicana, Leishmania braziliensis and multiple other species in the Viannia species complex). Neither case burdens nor treatment outcomes for VL or CL have improved very much in South America over the last decade.Research in leishmaniasis is neglected, relative to the harm caused. For example, research and development of drugs, vaccines and sand fly vector control is poorly developed. The fundamental knowledge underpinning the applied approaches are also lacking, including an understanding of the evolutionary genetics of Leishmania species. This PhD will address this lack of fundamental knowledge, though analysis of comparative and population analysis of Leishmania species, focusing on species that are endemic in South America, via several related analyses.Analysis will begin with comparative genomics, by completing high-quality genomes for all Leishmania species that have no, or low-quality genome assemblies, including outgroup/non-pathogenic species where appropriate, using Oxford Nanopore technology (ONT) reads. ONT and Illumina data for eight species are available now. Funds and contacts are available to obtain DNA and sequence up to 20 more species. Comparative genomics analyses of all of 30 Leishmania species will lead to a better understanding of molecular evolution in these parasites. The second analyses will focus on population-genetic analysis of the VL-causing species L. infantum in Brazil, using an existing data set of ~400 strains distributed throughout Brazil and southern Europe. Our unpublished analysis shows that L. infantum arrived in Brazil with the colonisation by the Portuguese (~1600 CE). The student with utilise this data to produce population genetic models of the genetic diversity, population structure, dispersal, and breeding dynamics of this species in Brazil. There is potential within this PhD, to obtain and sequence further samples from several collaborators, and to contribute to ongoing analysis of the effects of L. infantum mutations on disease severity in dog and human hosts and/or to drug resistance.The third analyses will focus on the Leishmania Viannia clade of approximately seven species, which cause CL in South America. This analysis will begin with existing data of at least 14 Viannia genomes from the seven species to describe the history of hybrid formation using an exhaustive genome-scale phylogenetic approach with haplotype-resolved ONT assemblies. Again, within this PhD there is there is potential for the student to take part in analysis of existing data (including 78 Leishmania guyanensis), and/or to obtain and sequence further samples from several collaborators. Some field work with collaborators would be possible.This PhD will produce a highly-trained expert in population and comparative genomics, with considerable expertise in the genomic epidemiology of Leishmania species of South America.