Schistosoma mansoni is a metazoan parasite that infects millions of people across the developing world. I applied coalescence models to genome-wide single nucleotide polymorphisms (SNPs) from ten global isolates of S. mansoni and an isolate of the closely related Schistosoma rodhaini to infer the dates of: i) the speciation between S. mansoni and S. rodhaini; ii) the spread of S. mansoni across sub-Saharan Africa; and iii) the migration to the New World. Further, I used this sequence data to document signatures of directional selection between S. mansoni and S. rodhaini to uncover genes involved in host adaptation and under balancing selection in S. mansoni. I conducted a field study in Uganda to collect epidemiological data from primary schools that had been subject to contrasting intensities and durations of Mass Drug Administration (MDA). Children in endemic areas were examined for S. mansoni up to three days before and after treatment with praziquantel. I fitted a mixed-effects model to the egg count data and found that individuals from schools that were treated most intensively had a lower estimated mean egg reduction rate compared with individuals from less intensively treated schools, suggesting that more rounds of MDA may be resulting in S. mansoni parasites that are better tolerating anthelmintic treatment. Finally, I collected S. mansoni miracidia from patients in Uganda and developed a novel method for generating whole-genome sequences. In total, 213 miracidia from 35 patients were sequenced. Using a dataset of 5.4 million SNPs, I documented the population structure, characterised regions of the genome under selection and associated SNPs against the clearance phenotype. I uncovered the strongest signal of selection and the highest association with host clearance phenotype in a region at the beginning of chromosome 2 that contains two calcium channels; variants in this region may therefore be underlying the observed reduction in praziquantel efficacy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:754687 |
| Date | January 2017 |
| Creators | Crellen, Thomas |
| Contributors | Webster, Joanne ; Cotton, James ; Aanensen, David |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/61692 |
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