|Type||Thesis or Dissertation - Doctor of Philosophy|
|Title||The population genetics and genomics of the African Salivarian trypanosomes|
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
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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.
|»||Gambia, The - Agricultural Census 2001-2002|