Evolutionary genetics of Leishmania species with a focus on South America

利什曼原生动物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既有内脏利什曼病(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、巴西利什曼原虫和万年虫物种复合体中的多种其他物种引起)。在过去的十年里，南美洲的VL或CL的病例负担和治疗结果都没有太大的改善。相对于造成的危害，对利什曼病的研究被忽视了。例如，药物、疫苗和沙蝇媒介控制的研发不发达。支持应用方法的基础知识也是缺乏的，包括对利什曼原虫物种进化遗传学的理解。本博士将通过对利什曼原虫物种的比较和种群分析，通过几个相关的分析，解决这种基础知识的缺乏。分析将从比较基因组学开始，使用牛津纳米孔技术(ONT)完成所有没有或低质量基因组组合的利什曼原虫物种的高质量基因组，包括适当的外群/非致病物种。目前已有8个物种的ONT和Illumina数据。资金和联系人可以用来获取DNA并对多达20个物种进行测序。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。第二个分析将重点放在巴西引起VL的物种L.infantum的种群遗传分析上，使用分布在巴西和南欧的约400个菌株的现有数据集。我们未发表的分析表明，L.infantum是随着葡萄牙人的殖民(公元1600年)来到巴西的。这名学生利用这些数据建立了该物种在巴西的遗传多样性、种群结构、扩散和繁殖动态的种群遗传模型。在这个博士中，有可能从几个合作者那里获得更多的样本并进行排序，并为正在进行的分析婴儿利什曼原虫突变对狗和人类宿主的疾病严重性和/或抗药性的影响做出贡献。第三项分析将集中在大约七个物种的利什曼原虫分支上，这是导致南美洲CL的原因。这项分析将从七个物种的至少14个万寿菊基因组的现有数据开始，使用单倍型解析的ONT组装的详尽基因组规模系统发育方法来描述杂交形成的历史。同样，在这个博士学位中，学生有可能参与现有数据的分析(包括78个古扬利什曼原虫)，和/或从几个合作者那里获得更多的样本并进行排序。这一博士学位将培养出一位训练有素的人口和比较基因组学专家，在南美洲利什曼原虫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.