Putting RFMix and ADMIXTURE to the test in a complex admixed population

CITATION: Uren, C., Hoal, E. G. & Moller, M. 2020. Putting RFMix and ADMIXTURE to the test in a complex admixed population. BMC Genetics, 21:40, doi:10.1186/s12863-020-00845-3.The original publication is available at https://bmcinfectdis.biomedcentral.comPublication of this article was funded by the Stellenbosch University Open Access FundBackground: Global and local ancestry inference in admixed human populations can be performed using computational tools implementing distinct algorithms. The development and resulting accuracy of these tools has been tested largely on populations with relatively straightforward admixture histories but little is known about how well they perform in more complex admixture scenarios. Results: Using simulations, we show that RFMix outperforms ADMIXTURE in determining global ancestry proportions even in a complex 5-way admixed population, in addition to assigning local ancestry with an accuracy of 89%. The ability of RFMix to determine global and local ancestry to a high degree of accuracy, particularly in admixed populations provides the opportunity for more accurate association analyses. Conclusion: This study highlights the utility of the extension of computational tools to become more compatible to genetically structured populations, as well as the need to expand the sampling of diverse world-wide populations. This is particularly noteworthy as modern-day societies are becoming increasingly genetically complex and some genetic tools and commonly used ancestral populations are less appropriate. Based on these caveats and the results presented here, we suggest that RFMix be used for both global and local ancestry estimation in worldwide complex admixture scenarios particularly when including these estimates in association studies.https://bmcgenet.biomedcentral.com/articles/10.1186/s12863-020-00845-3Publisher's versio

Investigating southern African genetic diversity and its role in TB susceptibility

Thesis (PhD)--Stellenbosch University, 2017.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

Inferring recombination patterns in African populations.

Although several high-resolution recombination maps exist for European-descent populations, the recombination landscape of African populations remains relatively understudied. Given that there is high genetic divergence among groups in Africa, it is possible that recombination hotspots also diverge significantly. Both limitations and opportunities exist for developing recombination maps for these populations. In this review, we discuss various recombination inference methods, and the strengths and weaknesses of these methods in analyzing recombination in African-descent populations. Furthermore, we provide a decision tree and recommendations for which inference method to use in various research contexts. Establishing an appropriate methodology for recombination rate inference in a particular study will improve the accuracy of various downstream analyses including but not limited to local ancestry inference, haplotype phasing, fine-mapping of GWAS loci and genome assemblies

Population structure and infectious disease risk in southern Africa.

The KhoeSan populations are the earliest known indigenous inhabitants of southern Africa. The relatively recent expansion of Bantu-speaking agropastoralists, as well as European colonial settlement along the south-west coast, dramatically changed patterns of genetic diversity in a region which had been largely isolated for thousands of years. Owing to this 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. Here, we consolidate information from various population genetic studies that characterize admixture patterns in southern Africa with an aim to better understand differences in adverse disease phenotypes observed among groups. Our review confirms that ancestry has a direct impact on an individual's immune response to infectious diseases. In addition, we emphasize the importance of collaborative research, especially for populations in southern Africa that have a high incidence of potentially fatal infectious diseases such as HIV and tuberculosis

Population structure and infectious disease risk in southern Africa.

The KhoeSan populations are the earliest known indigenous inhabitants of southern Africa. The relatively recent expansion of Bantu-speaking agropastoralists, as well as European colonial settlement along the south-west coast, dramatically changed patterns of genetic diversity in a region which had been largely isolated for thousands of years. Owing to this 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. Here, we consolidate information from various population genetic studies that characterize admixture patterns in southern Africa with an aim to better understand differences in adverse disease phenotypes observed among groups. Our review confirms that ancestry has a direct impact on an individual's immune response to infectious diseases. In addition, we emphasize the importance of collaborative research, especially for populations in southern Africa that have a high incidence of potentially fatal infectious diseases such as HIV and tuberculosis

A post-GWAS analysis of predicted regulatory variants and tuberculosis susceptibility.

Utilizing data from published tuberculosis (TB) genome-wide association studies (GWAS), we use a bioinformatics pipeline to detect all polymorphisms in linkage disequilibrium (LD) with variants previously implicated in TB disease susceptibility. The probability that these variants had a predicted regulatory function was estimated using RegulomeDB and Ensembl's Variant Effect Predictor. Subsequent genotyping of these 133 predicted regulatory polymorphisms was performed in 400 admixed South African TB cases and 366 healthy controls in a population-based case-control association study to fine-map the causal variant. We detected associations between tuberculosis susceptibility and six intronic polymorphisms located in MARCO, IFNGR2, ASHAS2, ACACA, NISCH and TLR10. Our post-GWAS approach demonstrates the feasibility of combining multiple TB GWAS datasets with linkage information to identify regulatory variants associated with this infectious disease

The ancestral proportions and the accuracy of the inferred local ancestry for the SAC.

The ancestral proportions and the accuracy of the inferred local ancestry for the SAC.</p