Ochola, Harold
Using genomics and population genetics to understand genetic variation in Malawi Plasmodium falciparum clinical isolates.
PhD thesis, University of Liverpool.
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Abstract
The natural selection imposed by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum, leading to an ever-changing landscape of genetic variation. We have carried out whole-genome sequencing of 93 P. falciparum clinical isolates from Malawi and used population genetic methods to investigate the genetic diversity and regions under selection. In addition, by computing XP-EHH, PCA and FST we have compared the Malawi isolates to five dispersed others (Kenya, Mali, Burkina Faso, Cambodia and Thailand), and identified genes potentially under positive directional selection. Geographic stratification of genetic diversity in the populations followed continental lines and small population differences were observed within Africa. Positive directional selection signals were identified at or near pfdhps, pfcrt, pfmdr1 and pfgch1 (known drug targets) and in several merozoite invasion ligands (e.g., msp3.8, trap and ama1). We discuss the role of drug selection in promoting fixation of alleles between populations with differing adaptation to local drug pressure. Analysis of copy number variation in Malawi provides a detailed catalogue of new and previously identified gene deletions and duplications with critical roles in cytoadherence, gametocytogenesis, invasion and drug response. This work provides the first genome-wide scan of selection and CNV in Malawi to guide future studies in investigating parasite evolution, changing malaria epidemiology, and monitoring and evaluating impact of malaria interventions as they are deployed.
| Item Type: | Thesis (PhD) |
|---|---|
| Additional Information: | Date: 2013-08 (completed) |
| Subjects: | ?? QL ?? ?? R1 ?? |
| Divisions: | Faculty of Health and Life Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 31 Jul 2014 11:01 |
| Last Modified: | 17 Dec 2022 01:36 |
| DOI: | 10.17638/00015753 |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/15753 |
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