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Malaria is a health problem for 40% of the world's population and is recognised as the world's major tropical disease, killing 4.7 million people annually. In the study of the disease to date apoptosis has been shown to be involved in the trade off relationships between parasite and mosquito host. Reduced fecundity in the infected mosquito has been postulated to be one such result of infection of the mosquito by the parasite that is beneficial to the parasite, in that it not only provides nutrients but results in increased biting rates and thus transmission of the parasite and as such is a target for novel control measures. The fecundity reduction has been shown by previous researchers to be the result of increased apoptotic activity in the follicular epithelia of the ovary induced by the parasite. During this study an in vitro assay was developed in an Anopheles cell line to study the effects of apoptosis induction. Following UV induced apoptosis, RT PCR demonstrated a reduced expression of DAD1, an anti-apoptotic gene. DAD1 was also tested using non- parasitized and parasitized mosquito RNA. In order to gain a better insight into the apoptotic machinery in Anopheles a range of bioinformatic tools were used. Whilst DAD1 has been characterised as having a role in N-linked glycosolation a study of its sequence homology to the Bc12 family was undertaken to identify putative BH domains and further characterise the gene.

From social impacts to genetic mutations, malaria has greatly affected our species. Plasmodium vivax, one of the causative agents of human malaria, is of particular interest due to its widespread global dispersion and seemingly benign effects, the significance of which are increasingly becoming more apparent. Molecular genetics can be applied to the analysis of past populations in an attempt to better understand the changing nature of disease over time. This project aimed to assess the extent that it is possible to use ancient DNA sequencing to study changes in the molecular diversity of P. vivax in medieval and post-medieval England. Historical records from this time suggest that P. vivax dramatically changed in virulence from the 13th to the 19th centuries, causing mortality levels in marshland areas to peak in the 1600's. The analysis of ancient Plasmodium DNA extracted from the bones of individuals dating to these centuries allows us to explore changes in parasite structure and virulence, while also assessing the extent to which it is possible to use ancient DNA techniques to study changes in the molecular diversity of the parasite. As P. vivax leaves no pathological change in bone, biomolecular techniques provide the only method for a conclusive retrospective diagnosis. Ancient DNA extracted from the rib bones of 159 skeletons was screened for the presence of P. vivax using optimized PCR systems and DNA sequencing. Segments of the malarial 18S rRNA and cytochrome b genes, and the human mtDNA HVR1 regions were amplified, cloned and sequenced. There was no evidence for the presence of P. vivax in any of the bones, however P. falciparum DNA was detected in one, possibly two, bones and human DNA detected in 16 bones. This suggests poor pathogen DNA survival and/or inadequate current techniques. The results of this study highlight specific areas of aDNA research that need to be addressed to increase the effectiveness and utility of aDNA research. These include sample contamination, preferential microbial DNA amplification, PCR specificity, and the incorporation and survival of pathogen and endogenous DNA in bone. Ancient DNA techniques have great potential to make significant contributions to palaeodisease research. However, further development is needed before they can reliably and efficiently be applied to P. vivax aDNA studies.

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Malaria is the most important vector-borne disease in Yemen, the country with the highest incidence of malaria in the Arabian Peninsula. A 24-month study in two villages in Taiz region mvestigated vectorial as-cts of malaria transmission. In pyrethrum knockdown (PKD) and light trap (LT) catches, eight species were identified from a total of 3,407 anophelines. Vhe study has provided 3fl important vectorial evidence base on malaria transmission in Yemen, to inform future control strategies.

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Malaria is a major public health concern for the one-third of the human population esti- mated to be exposed to the threat of the most virulent species, Plasmodium falciparum. Modern molecular and computational tools from population genetics may help to better understand and fight the burden of drug resistant malaria. Malaria biology is substantially different from the underlying paradigm of standard population genetics models, most notably because malaria has both a asexual haploid phase and a sexual diploid phase where selfing (i.e. mating between genetically identical parasites) is possible. It is therefore fundamental to understand if commonly used population genetics methods are robust to the deviations from standard expectations imposed by the malaria life-cycle. We build novel models of malaria population genetics and provide guidelines to interpret empirical studies of the spread of drug resistance. Using realistic models of epistasis between genes involved in drug resistance we suggest that all signals of linkage disequilibrium (LD) are possible and that researchers should be confident in reporting a lack of statistical association between genes involved in resistance to antimalarials. We also suggest that researchers should be cautious in interpreting changes in the prevalence of drug resistance after control interventions as reductions in transmission can cause a change in prevalence without concomitant change in frequency of resistance. We provide guidelines to better design and interpret studies related to estimating effective population size (Ne). We use computational simulations to study scenarios that can approximate control and elimination interventions (i.e. where a significant part of the population is killed). For Ne estimation our results suggest that researchers must increase the number of individuals and loci genotyped in order to have sufficiently precise Ne estimates. LD-based Ne estimators are more appropriate for early detection of control and elimination interventions than temporal-based Ne estimators. Long- term estimators based on heterozygosity should not be used to make inferences about contemporary demographic processes. We also applied our analysis to disease vectors and we concluded that LD-based estimation is able to detect demographic seasonality patterns (i.e. changes in population size due to variations imposed by wet and dry seasons) whereas temporal estimators will provide averages over longer periods of time. We also studied selection detection using FsT-outlier approaches. Our results suggest that temporal FST might not be appropriate for early detection of genes involved in drug resistance (e.g. in the case of artesunate derivatives). We also provide software and guidelines to better design and interpret studies (also across other taxa) of selection based on FsT-outlier approaches. Most notably our results suggest that sampling only one or two SNPs per locus (as it is done in many empirical studies) might not be sufficient to detect areas of the genome under selection, and that at least 4 SNPs per loci should be genotyped.

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