Investigating southern African genetic diversity and its role in TB susceptibility

Uren, Caitlin (2017-12)

Thesis (PhD)--Stellenbosch University, 2017.

Thesis

ENGLISH ABSTRACT: Recent genetic studies have established that the KhoeSan populations of southern Africa are the earliest known indigenous inhabitants of the region and distinct from all other African populations. Owing to the region’s unique history, population structure in southern Africa reflects both the underlying KhoeSan genetic diversity as well as differential recent admixture. This population structure has a wide range of biomedical and sociocultural implications such as changes in disease risk profiles: there is a known correlation between ancestry and tuberculosis (TB) susceptibility. Research presented in this thesis consolidates information from various population genetic studies that characterized admixture patterns in southern Africa with the aim to improve the understanding of differences in adverse disease phenotypes observed among populations. Further to previous studies, genome-wide polymorphism data from more than 20 southern African populations were analysed to investigate the fine-scale population structure in the area. The analyses revealed fine-scale population structure in and around the Kalahari Desert, which does not always correspond to linguistic or subsistence categories, but rather reflects the role of ecogeographic boundaries. In addition, we showed that the Khoe adopted their pastoralism through a process of largely cultural diffusion rather than demic diffusion as previously thought. The proportion and origin of KhoeSan genetic ancestry in southern African populations is of particular relevance to disease, because the KhoeSan exhibit greater variation in genetic diversity than other African populations, including unusual variation in genes with demonstrable immune function. Utilizing data from several TB genome-wide association studies (GWAS), a bioinformatics pipeline was employed to detect regulatory polymorphisms in linkage disequilibrium with variants previously implicated in TB susceptibility. A total of 133 predicted regulatory variants were found. Association analyses were performed in TB cases and healthy controls and yielded six intronic functionally relevant variants. The post-GWAS approach, which included ancestry as a confounder, demonstrated the feasibility of combining multiple TB GWAS datasets with linkage information to identify regulatory variants associated with TB susceptibility. In addition to classical association studies, selection scans have the ability to identify genomic regions associated with a phenotype. Signals of natural selection in southern African populations was studied using high-coverage exome sequence data. Selection signals were identified in genes associated with immune response to foreign pathogens introduced from the 12th century onwards. In addition, signals of selection were identified in pathways associated with focal adhesion and ECM receptor interaction. It is clear that there are distinct immune-related signals of positive selection present in southern African populations. This research not only provided insight into the genetic basis and biology of human TB susceptibility, but also harnessed the unique ancestry present in southern African populations. The addition of population genetics information was shown to greatly shape and improve our investigations of TB susceptibility and may also apply to other phenotypes unique to southern Africa. Since the era of personalised medicine is imminent, more investigations of understudied southern African populations most severely affected by TB are required.

AFRIKAANSE OPSOMMING: Onlangse genetiese studies het vasgestel dat die KhoeSan bevolking van suider-Afrika die vroegste bekende inheemse inwoners van die streek was, en dat hul kenmerkend van ander Afrika-bevolkings verskil. Op grond van die streek se unieke geskiedenis, weerspieël die bevolkingstruktuur van suider-Afrika beide die onderliggende genetiese diversiteit van die KhoeSan, asook differensiële onlangse vermenging. Hierdie bevolkingstruktuur het ‘n verskeidenheid van biomediese asook sosiokulturele implikasies, soos verandering in siekterisikoprofiele: dit bekend is dat daar ‘n assosiasie is tussen toenemende KhoeSan afkoms en tuberkulose (TB). Navorsing uiteengesit in hierdie proefskrif konsolideer inligting uit verskeie bevolkingsgenetika studies, waarin vermengingspatrone in suider-Afrika omgeskryf is met die doel om verskille in siektefenotipes beter te begryp. Om die fynskaalse bevolkingstruktuur in the area te ondersoek, is genoomwye polimorfisme-data van meer as 20 bevolkings van suider-Afrika ontleed. Die analise het kleine aspekte van die bevolkingstruktuur in en rondom die Kalahari-woestyn ontbloot, wat nie altyd ooreengestem het met taalkundige en lewensbestaans kategorieë, soos voorheen voorgestel nie. Dit het eerder die rol van geografiese versperrings en die ekologie van die groter Kalahari-kom weerspieël. Ons toon aan dat die Khoe hulle pastorale bestaanstrategie eerder deur ‘n proses van grotendeels kulturele diffusie aangeneem het en nie, soos wat voorheen aanvaar is, as gevolg van vermenging, vervanging of verplasing nie. Die genetiese bydrae van die KhoeSan tot die bevolkings van suider-Afrika is veral belangrik in die konteks van siekte, aangesien die KhoeSan meer variasie in genetiese diversiteit het as ander Afrika bevolkings. Dit sluit ongewone variasie in gene met bewysde immuunfunksies in. Deur gebruik te maak van data van verskeie genoomwye assosiasiestudies (GWAS) oor TB, is ‘n bioinformatikapyplyn aangestel om regulatoriese polimorfismes in koppelingsdisekwilibirum met veranderlikes voorheen aangedui in TB-kwesbaarheid op te spoor. ‘n Bevolkingsgebaseerde gevallekontrole-assosiasiestudie van 133 voorspelde regulatoriese variante is in TB-gevalle asook gesonde kontroles uitgevoer. Assosiasies met ses introniese veranderlikes is waargeneem. Die post-GWAS-benadering, wat afkoms as ‘n invloed ingesluit het, demonstreer die uitvoerbaarheid daarvan om meervoudige TB GWASdatastelsels met koppelingsinligting te kombineer om regulatoriese veranderlikes geassosieerd met hierdie aansteeklike siekte te identifiseer. Bykomend tot klassieke assosiasiestudies, kan skanderings van natuurlike seleksie areas in die genoom identifiseer wat met ‘n fenotipe geassosieer is. Aanduidings van natuurlike seleksie in bevolkings van suider-Afrika is bestudeer deur die gebruik van hoë dekking eksoom-volgordebepaling data. Seleksieseine is geïdentifiseer in immuunrespons-gene geassosieer met patogene wat vanaf die 12de eeu na suider-Afrika gebring is. Positiewe seleksie is geïdentifiseer in “focal adhesion” and “ECM receptor interaction” paaie. Dit is duidelik dat daar unieke immuunverwante aanduidings van positiewe seleksie in bevolkings van suider-Afrika teenwoordig is. Hierdie navorsing het nie net insig tot die genetiese basis en biologie van TB-vatbaarheid bygedra nie, maar het ook die unieke afkoms van bevolkings van suider-Afrika ingespan. Die toevoeging van bevolkingsgenetika verbeter nie net ons studies van TB-vatbaarheid nie, maar kan ook op ander unieke fenotipes in suider-Afrika van toepassing wees. Met die naderende era van persoonlike medisyne, is meer ondersoeke van onderbestudeerde bevolkings van suider-Afrika, wat die meeste deur TB geaffekteer word, nodig.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/102591
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