Evolutionary genetics of Leishmania species with a focus on South America

利什曼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）和各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物种复合体中的多个其他物种引起）的影响。在过去的十年里，在南美洲，VL或CL的病例负担和治疗结果都没有很大改善。例如，药物、疫苗和白蛉病媒控制的研究和开发工作进展不良。支持应用方法的基础知识也缺乏，包括对利什曼原虫物种进化遗传学的理解。该博士将解决这种缺乏基础知识，通过分析利什曼原虫物种的比较和人口分析，重点是在南美洲特有的物种，通过几个相关的分析。分析将开始与比较基因组学，通过完成所有利什曼原虫物种的高质量基因组，没有，或低质量的基因组组装，包括外群/非致病性物种在适当的情况下，使用牛津纳米孔技术（ONT）读取。ONT和Illumina目前已经提供了8个物种的数据。基金和联系人可用于获得DNA和测序多达20个物种。对所有30种利什曼原虫的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。第二个分析将集中于引起VL的物种L的群体遗传分析。婴儿在巴西，使用现有的数据集的约400株分布在整个巴西和南欧。我们未发表的分析表明，L。infantum是随着葡萄牙人的殖民而到达巴西的（~1600 CE）。学生利用这些数据来产生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。这个博士学位有可能从几个合作者那里获得更多的样本并进行测序，并为正在进行的L。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。第三次分析将重点关注大约7个物种的利什曼原虫Viannia分支，这些物种在南美洲导致CL。这项分析将开始与现有的数据，至少14 Viannia基因组的7个物种，以描述历史的杂交形成使用一个详尽的基因组规模的系统发育方法与单倍型分辨ONT组件。同样，在这个博士学位中，学生有可能参与现有数据（包括78个圭亚那利什曼原虫）的分析，和/或从几个合作者那里获得更多的样本并进行测序。与合作者的一些实地工作是可能的。这个博士将产生一个训练有素的专家在人口和比较基因组学，在南美利什曼原虫物种的基因组流行病学相当专业。

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.