Mseleni Joint Disease (MJD) is a crippling osteoarthropathy of unknown aetiology endemic to southern African Bantu-language speakers in a remote region of Northern KwaZulu-Natal, South Africa. Effective management of MJD has been hindered by limited insight into risk factors, explanatory models or treatment-seeking behaviours in those affected. Until MJD is better understood, disability, unemployment and dependence on social assistance grants and family income for subsistence will remain a reality for those affected. A mixed methods study was conducted with the aims of examining risk factors, explanatory models and treatment-seeking behaviours associated with MJD. The distribution, differential diagnosis and treatment of MJD were statistically analysed using medical records (n=723), MJD-patient surveys (n=37) and a meta-analysis. Socio-economic and cultural risk factors were assessed from surveys (n=99) and census publications. Interviews with MJD patients (n=6), nurses (n=7) and doctors (n=9) were qualitatively analysed for themes pertaining to perceptions, experiences and treatment-seeking for MJD. A point prevalence of 9% was estimated. Women were nearly twice as likely to have MJD than men (OR= 1.89; p=0.03) and the likelihood of MJD increased almost three-fold in those older than 50 years (OR= 2.83; p<0.01). Age was a confounder of the association between gender and MJD, as the sample was skewed in the representation of elderly women. MJD was only detected in patients older than 35 years, indicative of a later onset age than previously reported. The prevalence of MJD in settlements along tar and concrete roads, with access to public transport but limited piped water was suggestive of environmental risk factors or differential access to hospital-based care. Explanatory models of MJD were supernatural (witchcraft or ancestral displeasure); natural (nutritional deficiencies, 'genetics' and/or environmental); and/or social (gender-based practices and lifestyle). MJD patients described supernatural and natural aetiologies, and conceptualised disability as an inevitable reality. Consequently, patients reported taking few measures to prevent joint immobility, focussing instead on immediate symptomatic relief. Psychosocial and systemic barriers to treatment were suggestive of a disconnect between traditional African healing and Western biomedicine. This work demonstrates the value of the biocultural approach in identifying spatial, ecological, social and cultural processes that shape population patterns of health and disease.

Includes abstract. / Includes bibliographical references (p. 203-244). / The aetiology of obesity is complex, and in addition to intrinsic factors such as the biology of individuals (presented as genetics, age, gender) that contribute to the high obesity epidemic, there are behavioural determinants, along with economic, socio-cultural and environmental factors which are largely extrinsic, that either directly or indirectly influence the development of obesity, therefore are called “obesogenic” (Swinburn et al., 2005; Egger and Swinburn, 1997). In South Africa, these “obesogenic” factors have been only partially explored, and as such, there are gaps in our knowledge. We are also not certain of the extent to which the language, culture and age influence these afore-mentioned factors. As such, this dissertation focused on finding and adapting culturallysensitive and age-appropriate instruments to better understand these obesogenic factors in South African women and girls.

Bibliography: leaves 170-187. / Osteological, dental, and molecular analyses were conducted on remains from seven historical archaeological sites within South Africa. The emphasis was on the collection of lifestyle data for the purpose of adding to the unwritten history of indigenous South African peoples and to give voice to a once forgotten group of peoples. The demographic distribution reveals three different community dynamics: the Griqua sample are a pastoralist group incorporating some agricultural activities, the Colesberg individuals are an indigenous group resembling a migrant workers population living on the margins of society, and the Wolmaransstad demographics are suggestive of a Zabantu labouring community. All individuals are relatively healthy with low rates of dental disease and trauma and share similar growth patterns to living populations. However all of these individuals display high frequencies of porotic hyperostosis and cribra orbitalia, skeletal manifestations of iron deficiency anaemia. Many theories about the occurrence of anaemia are discussed and the hypothesis that, in these individuals, it is related to infection by the smallpox virus is investigated through the analysis of ancient DNA.

Includes bibliographical references (p. 228-241). / The present thesis examined the hypothesis that self-paced exercise performance and pacing strategies are regulated by a complex intelligent system in advance of a failure to maintain homeostasis in one or more physiological systems. In the first study, ten trained cyclists performed 20 km cycling time-trials in hot (35°C) and cool (15°C) conditions. The power output was reduced in the heat despite core temperatures that were sub-maximal and not different from those measured in the cool condition. Significantly, the reduction in power output was associated with a lower IEMG activity in the active muscle, suggesting that the brain recruited less muscle even at sub-maximal body temperatures. Thus, self-paced exercise in the heat was regulated in advance of thermoregulatory failure. This model was then applied to conditions where the oxygen content of the air was elevated (yperoxia). Eleven subjects performed 20km time-trails, and it was found that a higher power output was maintained throughput hyperoxic (F₁O₂0.21), and that the IEMG activity was elevated in hyperoxia. The subjective rating of perceived exertion (RPE), measured using the Borg scale, was similar in both this and the first study, despite differences in power output. It was suggested that the RPE may play a mediatory role.

Includes bibliographical references (p. 216-249). / The temperature responses to exercise have been a much investigated topic of intense research interest over the past 50 years. More recently, the effects of fluid ingestion on temperature regulation have been the focus of this area. The aim of this thesis is to undertake research to evaluate what has become the established dogma in this field and to determine whether a new model might better explain thermoregulation in humans during endurance exercise.

Includes bibliographical references (leaves 115-128). / Generally, the factors contributing to success or failure of axon regeneration lie in the intrinsic properties of the injured neurons, as well as the surrounding microenvironment of the transected axon. Mammalian neurons may lack the intrinsic ability to survive after trauma, or to re-express genes required for axonal regrowth. Moreover, several proteins inhibitory to neurite growth, such as Tenascin-R (TN-R) and Nogo-A, have been identified in mammals. These proteins are associated with oligodendrocytes and myelin and are considered major inhibitory components of the CNS environment.

Genome-wide association study (GWAS) has emerged as an effective method for detecting genetic polymorphisms associated with expressed phenotypes. Over the past decade, GWAS of human traits and diseases has revolutionized the field of complex disease genetics, identifying hundreds of genetic variants associated with several different phenotypes, ranging from metabolic diseases to cardiovascular and neuropsychiatric conditions. These associations have provided fundamental insights into the genetic architecture of disease susceptibility and led to initial forays into clinical applications, particularly in creation of genetic risk scores for improved disease risk prediction and identification of new drug targets for novel drug development. Despite this gratifying success, however, for almost all complex traits, the identified genetic loci explain only a small proportion, generally less than half, of the estimated heritability. A number of alternative explanations have been offered for this, including undetected genetic effects, unaccounted-for environmental factors, and gene–gene and gene–environment interaction effects. Although there is no consensus on these explanations, it is universally acknowledged that a substantial proportion of the trait heritability is attributable to existence of a large number of undetected genetic variants distributed across the entire allele frequency spectrum, each of which has very small to modest effect on the phenotype, and non host-DNA factors that contribute to phenotypic variation. In parallel to host GWAS, the advent of next-generation sequencing technologies (NGS) that enable culture-independent profiling of microbial communities has led to the rediscovery of the microbiome - the collective genome of the microorganisms that inhabit the body - and the emergence of microbiome-wide association studies. These studies have linked the gut microbiome to a variety of human conditions, ranging from neurological conditions, such as Parkinson's disease and autism, to metabolic diseases, such as obesity, diabetes, and cardiovascular disease. Given the critical importance of the microbiome in host phenotype, it is clear that in order to more comprehensively understand the basis of host phenotypic status, both the host's genotype and microbiome information have to be examined. This thesis explores the dissection of microbial taxa and host genetic polymorphisms associated with human complex traits and diseases, and the interaction of human host genetic polymorphisms with the microbiome. Then, a Bayesian statistical framework, based on the Dirichlet process random effects model, is proposed for identifying microbial species associated with host phenotype. The proposed method uses a weighted combination of phylogenetic and radial basis function kernels to model microbial taxa effects, and a non-parametrically defined latent variable to model latent heterogeneity among samples. Philosophically, the non-parametric specification amounts to the addition of an infinite amount of prior information about all fine details of the parameters being modelled; thus represents an attractive strategy. The utility of the method is demonstrated through simulation experiments and application to real microbiome datasets for schizophrenia, HIV/AIDS, and atherosclerosis diseases, where it is shown that the method is not only robust but also has high statistical power for association inference, resulting in a framework that can contribute to our understanding of the link between the microbiome and human diseases. Understanding the human genetic predisposing factors in concert with this link will make human GWAS fulfil its translational potential, from patient stratifcation and disease risk prediction to identification of new biology and drug discovery.

Includes bibliographical references. / Musculotendinous stiffness or elasticity is difficult to measure in vivo. Therefore, various procedures have been used in an attempt to quantify the contribution of the elastic properties of muscle and tendon to stretch shortening cycle performance. The results are variable, perhaps as a result of the different techniques utilised. Although several studies have suggested an association between a more compliant muscle-tendon complex, and enhanced stretch shortening cycle performance, this interpretation is not conclusive and needs further testing with particular attention being focused on the non-invasive, in vivo measurement of musculotendinous stiffness. Accordingly, the primary goal of this dissertation was to identify the relationship between the mechanical characteristics of the muscle-tendon complex, in particular tendon stiffness, and stretch shortening cycle muscle function.

Includes bibliographical references (p. 177-213). / The aim of this thesis was to examine the effect of various antecedent exposures and physiological pertubations on the relationship between the perceptual (perceived exertion), the physiological (metabolic milieu), and the performance (overall exercise performance) during both open and closed loop exercise at either a self-placed or constant workload.

African populations are vastly underrepresented in genetic studies despite having the most genetic variation globally and facing wide-ranging environmental exposures. Most of these studies have been conducted in populations of European (EUR) ancestry using GWAS arrays that represent the genetic variation in these populations. Thus, the prediction accuracy of polygenic risk scores (PRS) derived from EUR ancestry populations is less accurate in populations of non-European ancestry, and least accurate in African (AFR) ancestry populations. The extent to which PRS prediction accuracy varies within AFR ancestry populations has not, however, been previously investigated. This study had two aims: the first was to investigate the contribution of common variants to the risk of schizophrenia in the South African Xhosa (SAX) population through genome-wide association study (GWAS) analysis, and to determine if PRS derived from EUR and East Asian (EAS) ancestry populations from the Psychiatric Genomics Consortium (PGC) Schizophrenia Working Group were generalizable to SAX. The second aim was to assess the generalizability of PRS for non-psychiatric phenotypes that were derived from EUR ancestry individuals from the UK Biobank (UKB, n = ~350,000) in the Uganda General Population Cohort (GPC, n = 4,778) and the South African Drakenstein Child Health Study (DHCS, n = 638). To address the first aim, a GWAS was conducted in 2,086 Xhosa individuals from South Africa with and without schizophrenia (ncases = 1,038; ncontrols = 1,048) using a custom-designed Affymetrix GWAS array designed to capture variation in the Xhosa population. The schizophrenia GWAS in SAX yielded one SNP (rs35172303 ; P = 4.74e-08, OR = 0.6004, 95%CI:[0.499,0.721]) in ZFP3 that met genome-wide significance. The association of variants in ZFP3 from the schizophrenia GWAS is consistent with those from an earlier exomesequence study in SAX undertaken by colleagues, but this gene has not previously been associated with schizophrenia in large-scale schizophrenia GWAS of predominantly EUR ancestry. After characterizing the genetic architecture of schizophrenia in SAX, it was found that the heritability was enriched across functional categories involved in the regulation of gene expression. Then, the accuracy of PRS derived from PGC Schizophrenia Working Group from both EUR and EAS ancestries in predicting schizophrenia in SAX was quantified. There was low PRS prediction accuracy using PGC-derived summary statistics in SAX (PGC-EUR: max R2 = 0.0057, P = 0.008; PGC-EAS: max R2 = 0.0059, P = 0.007). These findings are consistent with previous findings that showed that PRS predication accuracy is low when discovery and target cohorts come from different ancestral backgrounds. For the second aim, PRS prediction accuracy was quantified in simulations using data from the African Genome Variation project (AGVP) to represent continental AFR diversity. Samples were categorised by geographical region into West, East and South Africa cohorts. Each cohort was divided into a discovery and target datasets. The West and East African discovery data was used to predict the simulated phenotype in the three target cohorts. Using UKB EUR ancestry individuals, PRS prediction accuracy was assessed for 34 anthropometric and blood panel traits in the Uganda GPC, and then meta-analysed UKB with PAGE (Population Architecture using Genomics and Epidemiology, comprising about 50,000 Latino/Hispanic and African-American individuals) and BBJ (Biobank Japan, n = ~162,000) to assess how the inclusion of diverse sample impacts PRS prediction accuracy. Simulations were limited by sample size but showed that PRS prediction accuracy was highest when the discovery and target cohorts were matched by African region, and for phenotypes with the sparsest genetic architecture. Using empirical data from UKB and the Uganda GPC, a low prediction accuracy was observed across all 34 quantitative traits in GPC when using GWAS data from UKB. There was differential prediction accuracy across AFR ancestry groups within UKB, i.e. the prediction accuracy was highest for the Ethiopian and admixed populations, and lowest for southern African populations. When comparing PRS prediction accuracy of East African individuals from the UKB to that of individuals from GPC, the prediction accuracy was lowest in the Ugandan GPC population, indicating that the difference in environments between the two groups may be contributing to the difference in PRS accuracy. Moreover, the cross-ancestry meta-analyses showed that the inclusion of diverse samples in large scale studies improves PRS prediction accuracy, most especially for phenotypes with population-enriched variants. It was demonstrated for the first time in this thesis that EUR ancestry-derived PRS prediction accuracy varied within continental AFR ancestry groups, and tracks with population history and the evolution of humans. The higher prediction accuracy observed in Ethiopians can be explained by their genetic proximity to Europeans as a result of the back to Africa migration, whereas the southern African populations (including SAX) are more proximal to the ancestral populations that never left the continent. It is therefore imperative to not only include more African samples in future large-scale studies, but to have samples that adequately represent the genetic and environmental diversity on the African continent.