The population genetics and genomics of the African Salivarian trypanosomes

QH426 Genetics

Duffy, Craig William ; MacLeod, Annette

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: trypanosomes, population genetics, Africa, microsatellite, T. brucei, T. congolense, T. vivax, nagana, human African trypanosomiasis, sleeping sickness, parasitology;   

Others  :  http://theses.gla.ac.uk/3157/1/2012DuffyCWPhD.pdf

来源: University of Glasgow

【 摘 要 】

The African Salivarian trypanosomes are the causative agents of both Human African Trypanosomiasis, or sleeping sickness, and Animal African Trypanosomiasis, more widely known as Nagana. Primarily spread through the tsetse fly vector both diseases are distributed across the sub-Saharan tsetse belt, afflicting some of the poorest communities in the world. Three species of trypanosomes are predominantly responsible for these two diseases. T. brucei, which is comprised of the three morphologically identical sub-species T. b. brucei, T. b. gambiense (further separated into two subgroups) and T. b. rhodesiense, with the latter two sub-species exclusively responsible for infections in humans. The animal infective species T. congolense, comprised of the Forest, Kilifi and Savannah subtypes, and T. vivax meanwhile are responsible for millions of livestock and wild animal infections across the continent, with severe downstream economic consequences.A crucial component in understanding the diseases caused by these parasites is through understanding the diversity present in the field, as it is ultimately the combination of host, vector and parasite diversity that gives rises to the disease phenotypes observed during clinical diagnosis and treatment. In order to truly understand the role of such diversity in the field it is necessary to know how individuals within a population interact with one another, if they do at all. Mating between individuals allows for the direct interaction of genomes, allowing for the generation of new chromosomal sequences through meiotic recombination and new chromosomal pairings through bi-parental inheritance of genetic material. Identified as a non-obligatory process in T. brucei the importance of mating in natural trypanosome populations is both a controversial and understudied topic despite the significant role of the process in shaping the evolutionary development of these clinically important parasites.In order to further investigate the genetic diversity and role of mating in the trypanosomes populations from The Gambia, Uganda and Malawi have been examined through the use of microsatellite markers specific to the genomes of T. brucei, T. congolense and T. vivax. The results presented here demonstrate drastically different levels of diversity in the respective populations and evidence for a spectrum of genetic exchange, with both highly clonal and frequently mating populations identified in this manner.T. vivax, sampled from horses, donkeys and cattle in The Gambia would appear to most closely fit with the traditional views of clonality in trypanosomes, extensive clonal reproduction of a single genotype, significant disagreement with Hardy-Weinberg principles and the presence of significant linkage between the loci examined. These results, which closely resemble those observed for T. b. gambiense Group 1, suggest that genetic exchange may be absent or rare in T. vivax, which may lead to the eventual divergence of independent populations as they slowly accumulate unique mutations. The apparent dominant clonality of T. vivax is a sharp contrast to the situation observed for T. congolense in The Gambia, with strong evidence for frequent mating and a high rate of inbreeding. That this evidence originated from the same sample sets used in the T. vivax studies presented here highlights the differences between these two species and the requirement for further work independent of the studies into T. brucei.The final half of this thesis has focused upon the population genetics and genomics of T. brucei, the species responsible for sleeping sickness in humans. Examination of five of T. b. rhodesiense populations, four from Uganda and one from Malawi has demonstrated the potential for variation in the population structure within a single species. The Ugandan populations are dominated by clonality; with repeated bottlenecks reducing the genetic diversity present as the parasites has spread northwards. The Malawi population, genetically distinct from the populations of Uganda, instead appears to favour genetic exchange over clonality, with a genetically diverse population and only a limited number of repeated genotypes. This provides the first evidence of mating playing a significant role in a field population of human infective trypanosomes, introducing a significant role for meiotic recombination and chromosomal reassortment which may drastically alter the way in which these parasites respond to selective pressures and evolutionary forces. Finally, this thesis has aimed to bridge the gap between traditional low resolution studies and the developing field of genomics by examining the SNP variation present between three laboratory strains of T. brucei, providing the building blocks in understanding genome wide variation in trypanosomes. Utilising these data, and through sequencing of progeny generated in the process of constructing the TREU 927 genetic map, it has been possible to partially reassemble the haplotypes for the megabase chromosomes of this strain, previously selected as the T. brucei genome reference strain. Collected together these data provide an important resource of genomic variation for both laboratory studies and as a baseline for future investigations into the genomic diversity of field populations.In summary this thesis has demonstrated the variable nature and versatile role of genetic exchange in the trypanosomes, bringing together data not only from the human infective sub-species of T. brucei but from the animal infective species T. congolense and T. vivax. Finally in looking to the future this work has begun the process of transitioning from the relatively low density microsatellite markers by examining high density SNP variation in common laboratory strains, the first step towards future adoption of these markers for the purpose of population genomics.