16 research outputs found
Human genetic susceptibility to tuberculosis : the investigation of candidate genes influencing interferon gamma levels and other candidate genes affecting immunological pathways
Thesis (PhD (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2007.The infectious disease tuberculosis (TB) is one of the leading causes of death
worldwide. The idea that infectious diseases are the most important driving force in
natural selection and that they sustain frequent polymorphisms in the human genome
was formally suggested by Haldane in 1949. This hypothesis implicated the human
genetic component in the response to infectious disease. Today the involvement of host
genetics in TB has been proven unequivocally and, together with environmental factors
(e.g. nutrition and crowding) and the causative bacterium, Mycobacterium tuberculosis
(M.tuberculosis), may influence the outcome of disease. As is evident, TB is a complex
disease and the implication for studying genetic susceptibility is that a number of genes
will be involved.
Interferon gamma (IFN-7) is the major macrophage-activating cytokine during infection
with M.tuberculosis and its role has been well established in animal models and in
humans. This cytokine is produced by activated T helper 1 (Th1) cells. These Th1
responses can best deal with intracellular pathogens such as M.tuberculosis. We
selected twelve candidate genes based on the hypothesis that genes which regulate the
production of IFN-7 may influence TB susceptibility. We also selected polymorphisms
from 27 other candidate genes, which may affect immunological pathways involved in
TB, to investigate as susceptibility factors based on the following hypotheses: 1)
granulomatous diseases can share susceptibility genes; 2) gene expression studies done
by DNA-array analysis experiments may reveal TB susceptibility genes; 3) genomewide
linkage studies in TB can determine susceptibility loci and genes in this region are
possibly susceptibility factors; and 4) functional susceptibility polymorphisms in genes
involved in immune-mediated diseases other than TB may contribute to susceptibility to
TB.
This research tested the association of 136 genetic polymorphisms in 39 potentially
important genes with TB in the South African Coloured population. Well-designed
case-control association studies were used and we attempted to replicate these findings
in an independent sample set using family-based case-control designs (transmission
disequilibrium tests (TDTs)). In addition, haplotypes and linkage disequilibrium (LD)
in the candidate genes were also investigated.
During the case-control analyses we found significant associations for 6 single
nucleotide polymorphisms (SNPs) in the following genes: SH2 domain protein 1A, tolllike
receptor 2, class II major histocompatibility complex transactivator, interleukin 1
receptor antagonist, runt-related transcription factor 1 and tumour necrosis factor
superfamily, member 1B. Discrepant results were obtained during the TDT analyses.
The number of families available was small and for this reason we cannot conclude that
the case-control results were spurious. We also tested the association of haplotypes
with TB. Haplotypes in the interleukin 12, beta (IL12B) and toll-like receptor 4 genes
were nominally associated with TB in both the case-control and TDT analyses. We
observed strong LD for the genes in the South African Coloured population. In total 17
novel SNPs were identified and one novel allele was found for a microsatellite in
IL12B.
This research contributes to the increasing amount of information available on genes
involved in TB susceptibility, which in the future may help to predict high risk
individuals
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
Genetic resistance to Mycobacterium Tuberculosis infection and disease
CITATION: Möller, M. et al. 2018. Genetic resistance to Mycobacterium tuberculosis infection and disease. Frontier in Immunology, 9:2219, 1-13. doi:10.3389/fimmu.2018.02219.The original publication is available from https://www.frontiersin.org/journals/immunology#Natural history studies of tuberculosis (TB) have revealed a spectrum of clinical outcomes
after exposure to Mycobacterium tuberculosis, the cause of TB. Not all individuals
exposed to the bacteriumwill become diseased and depending on the infection pressure,
many will remain infection-free. Intriguingly, complete resistance to infection is observed
in some individuals (termed resisters) after intense, continuing M. tuberculosis exposure.
After successful infection, the majority of individuals will develop latent TB infection
(LTBI). This infection state is currently (and perhaps imperfectly) defined by the presence
of a positive tuberculin skin test (TST) and/or interferon gamma release assay (IGRA),
but no detectable clinical disease symptoms. The majority of healthy individuals with
LTBI are resistant to clinical TB, indicating that infection is remarkably well-contained in
these non-progressors. The remaining 5–15% of LTBI positive individuals will progress to
active TB. Epidemiological investigations have indicated that the host genetic component
contributes to these infection and disease phenotypes, influencing both susceptibility and
resistance. Elucidating these genetic correlates is therefore a priority as it may translate
to new interventions to prevent, diagnose or treat TB. The most successful approaches
in resistance/susceptibility investigation have focused on specific infection and disease
phenotypes and the resister phenotype may hold the key to the discovery of actionable
genetic variants in TB infection and disease. This review will not only discuss lessons
from epidemiological studies, but will also focus on the contribution of epidemiology and
functional genetics to human genetic resistance to M. tuberculosis infection and disease.https://www.frontiersin.org/articles/10.3389/fimmu.2018.02219/fullhttps://doi.org/10.3389/fimmu.2018.02219Published review articlePublishers versio
High diversity, inbreeding and a dynamic Pleistocene demographic history revealed by African buffalo genomes
CITATION: De Jager, D., et al. 2021. High diversity, inbreeding and a dynamic Pleistocene demographic history revealed by African buffalo genomes. Scientific Reports, 11:4540, doi:/10.1038/s41598-021-83823-8.The original publication is available at https://www.nature.comPublication of this article was funded by the Stellenbosch University Open Access FundGenomes retain records of demographic changes and evolutionary forces that shape species and populations. Remnant populations of African buffalo (Syncerus caffer) in South Africa, with varied histories, provide an opportunity to investigate signatures left in their genomes by past events, both recent and ancient. Here, we produce 40 low coverage (7.14×) genome sequences of Cape buffalo (S. c. caffer) from four protected areas in South Africa. Genome-wide heterozygosity was the highest for any mammal for which these data are available, while differences in individual inbreeding coefficients reflected the severity of historical bottlenecks and current census sizes in each population. PSMC analysis revealed multiple changes in Ne between approximately one million and 20 thousand years ago, corresponding to paleoclimatic changes and Cape buffalo colonisation of southern Africa. The results of this study have implications for buffalo management and conservation, particularly in the context of the predicted increase in aridity and temperature in southern Africa over the next century as a result of climate change.https://www.nature.com/articles/s41598-021-83823-8Publisher's versio
A Mobile Holistic Enterprise Transformation Framework
Mobile phones and tablets shipments are surpassing those of the PC category, as well as in relation to Internet usage as of 2016; all details which have made mobile adoption a priority for many enterprises and a challenge for them as well. Many enterprises have fallen into a paradox of spending on creating and updating mobile services, and gaining less than expected in return.
Reasons for this include the lack of vision, and the lack of a clearly defined, well communicated mobile strategy. Enterprise Architecture ‘EA’ facilitates a successful transformation by controlling and managing the transitions in order to arrive at a clearly defined future state. It is regarded as the science of change to many. However, EA frameworks are very comprehensive and require weeks of training and resources, and are often too generic for mobile transformation.
Therefore, an EA-based mobile holistic enterprise framework has been developed to support enterprises in making mobile initiatives a priority. The proposed framework ensures a clearly defined, well-communicated, holistic future state that is continually evaluated, as opposed to many of the existing frameworks.
The proposed Mobile Holistic Enterprise Architecture Framework - ‘MHETF’ - is based on the realisation of the capabilities of smartphones that are aimed at individual average consumers (the backbone of the current mobile trend). The capabilities are categorised and translated into four sets of services categories for business use. They are linked to another two components of the framework which are: (i) the categorisation of goals and objectives that are incorporated into the Balanced Scorecard for evaluation at a later stage in planning, and continually referred to during transitions and (ii) the categorisation of the implementation forms (categorisation of end solutions’ functionalities).
The framework is supported by EA inter-operability and maturity models to ensure continuity and alignment with the existing initiatives, the enterprise’s strategic objectives, and the change required in the scope of transformation. An evaluation for the available enterprise architecture frameworks was carried out and resulted in the selection of The Open Group Architecture Framework (TOGAF). The decision was also commended by the participants in the case study evaluation due to their familiarity with this framework, which is being adopted as the Saudi E Government Standard in contrast to the other major frameworks of Zachman and Federal Enterprise Architecture (FEA). MHETF has been applied to three case studies in the Kingdom of Saudi Arabia; two applications for a leading national outsourcing company, and the third for
the outpatient clinics in a large hospital in the capital city of Riyadh. The results have shown major improvements in the four goal areas of mobile transformation; productivity, processes, satisfaction improvement and facilitating new opportunities. Eventually, the final evolution has
shown that the participants are satisfied with the framework overall, and indicates that the framework changed their perspective of the power of mobile applications significantly, is relatively easy to understand, and that they are planning to adopt it for future mobile initiatives
African wild dogs (Lycaon pictus) from the Kruger National Park, South Africa are currently not inbred but have low genomic diversity
African wild dogs (Lycaon pictus) have undergone severe population reductions and are listed as endangered on the International Union for Conservation of Nature Red List. Small, isolated populations have the potential to suffer from threats to their genetic diversity that may impact species viability and future survival. This study provides the first set of population-wide genomic data to address conservation concerns for this endangered species. Whole genome sequencing data were generated for 71 free-ranging African wild dogs from the Kruger National Park (KNP), South Africa, and used to estimate important population genomic parameters. Genomic diversity metrics revealed that variation levels were low; however, this African wild dog population showed low levels of inbreeding. Very few first- and second-order relationships were observed in this cohort, with most relationships falling into the third-order or distant category. Patterns of homozygosity could have resulted from historical inbreeding or a loss in genome variation due to a population bottleneck. Although the results suggest that this stronghold African wild dog population maintains low levels of inbreeding, likely due to their cooperative breeding system, it may lead to a continuous population decline when a reduced number of suitable mates are available. Consequently, the low genomic variation may influence species viability over time. This study highlights the importance of assessing population genomic parameters to set conservation priorities. Future studies should include the investigation of the potential of this endangered species.https://www.nature.com/srepdm2022Veterinary Tropical Disease
Characterizing epidemiological and genotypic features of Mycobacterium bovis infection in wild dogs (Lycaon pictus)
Mycobacterium bovis (M. bovis) infects a wide range of wildlife species and has recently been discovered in the endangered African wild dog (Lycaon pictus). This study aimed to characterize the epidemiology of tuberculosis (TB) in wild dogs in endemic areas of South Africa. We describe 12 TB cases in wild dogs from Kruger National Park (KNP), Hluhluwe–iMfolozi Park (HiP) and a private facility in Hoedspruit from 2015 to 2017. Spoligotyping was used to identify the disease-causing M. bovis strain in these cases, and whole-genome sequencing was performed on 5 M. bovis isolates (KNP = 2 and HiP = 3) to investigate genomic diversity as well as the relationship to other isolates found in these geographical areas. Three distinct strain types were responsible for the M. bovis infections in this species. The SB0121 strain was observed in wild dogs from KNP, whereas SB0130 was responsible for infection in wild dogs from HiP. A novel strain, SB2681, was also identified in the HiP wild dogs. Whole-genome sequence analysis suggests that different infection sources exist among these wild dogs and that inter-species transmission most likely occurred between wildlife predators and prey located within shared geographical areas. This study highlights the importance of regular disease surveillance to identify and characterize potential threats for successful control of infection and protection of endangered species.The South African Medical Research Council and the National Research Foundation.http://wileyonlinelibrary.com/journal/tbedhj2022Paraclinical Science
Human genetic susceptibility to tuberculosis : the investigation of candidate genes influencing interferon gamma levels and other candidate genes affecting immunological pathways
Thesis (PhD (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2007.The infectious disease tuberculosis (TB) is one of the leading causes of death
worldwide. The idea that infectious diseases are the most important driving force in
natural selection and that they sustain frequent polymorphisms in the human genome
was formally suggested by Haldane in 1949. This hypothesis implicated the human
genetic component in the response to infectious disease. Today the involvement of host
genetics in TB has been proven unequivocally and, together with environmental factors
(e.g. nutrition and crowding) and the causative bacterium, Mycobacterium tuberculosis
(M.tuberculosis), may influence the outcome of disease. As is evident, TB is a complex
disease and the implication for studying genetic susceptibility is that a number of genes
will be involved.
Interferon gamma (IFN-7) is the major macrophage-activating cytokine during infection
with M.tuberculosis and its role has been well established in animal models and in
humans. This cytokine is produced by activated T helper 1 (Th1) cells. These Th1
responses can best deal with intracellular pathogens such as M.tuberculosis. We
selected twelve candidate genes based on the hypothesis that genes which regulate the
production of IFN-7 may influence TB susceptibility. We also selected polymorphisms
from 27 other candidate genes, which may affect immunological pathways involved in
TB, to investigate as susceptibility factors based on the following hypotheses: 1)
granulomatous diseases can share susceptibility genes; 2) gene expression studies done
by DNA-array analysis experiments may reveal TB susceptibility genes; 3) genomewide
linkage studies in TB can determine susceptibility loci and genes in this region are
possibly susceptibility factors; and 4) functional susceptibility polymorphisms in genes
involved in immune-mediated diseases other than TB may contribute to susceptibility to
TB.
This research tested the association of 136 genetic polymorphisms in 39 potentially
important genes with TB in the South African Coloured population. Well-designed
case-control association studies were used and we attempted to replicate these findings
in an independent sample set using family-based case-control designs (transmission
disequilibrium tests (TDTs)). In addition, haplotypes and linkage disequilibrium (LD)
in the candidate genes were also investigated.
During the case-control analyses we found significant associations for 6 single
nucleotide polymorphisms (SNPs) in the following genes: SH2 domain protein 1A, tolllike
receptor 2, class II major histocompatibility complex transactivator, interleukin 1
receptor antagonist, runt-related transcription factor 1 and tumour necrosis factor
superfamily, member 1B. Discrepant results were obtained during the TDT analyses.
The number of families available was small and for this reason we cannot conclude that
the case-control results were spurious. We also tested the association of haplotypes
with TB. Haplotypes in the interleukin 12, beta (IL12B) and toll-like receptor 4 genes
were nominally associated with TB in both the case-control and TDT analyses. We
observed strong LD for the genes in the South African Coloured population. In total 17
novel SNPs were identified and one novel allele was found for a microsatellite in
IL12B.
This research contributes to the increasing amount of information available on genes
involved in TB susceptibility, which in the future may help to predict high risk
individuals
TLR1, 2, 4, 6 and 9 variants associated with tuberculosis susceptibility: a systematic review and meta-analysis
CITATION: Schurz, H., et al. 2015. TLR1, 2, 4, 6 and 9 variants associated with tuberculosis susceptibility: a systematic review and meta-analysis. PLoS ONE,
10(10):1-24, doi:10.1371/journal.pone.0139711.The original publication is available at http://journals.plos.org/plosoneBackground:
Studies investigating the influence of toll-like receptor (TLR) polymorphisms and tuberculosis susceptibility have yielded varying and often contradictory results in different ethnic groups. A meta-analysis was conducted to investigate the relationship between TLR variants and susceptibility to tuberculosis, both across and within specific ethnic groups.
Methods:
An extensive database search was performed for studies investigating the relationship between TLR and tuberculosis (TB) susceptibility. Data was subsequently extracted from included studies and statistically analysed.
Results:
32 articles involving 18907 individuals were included in this meta-analysis, and data was extracted for 14 TLR polymorphisms. Various genetic models were employed. An increased risk of TB was found for individuals with the TLR2 rs3804100 CC and the TLR9 rs352139 GA and GG genotypes, while decreased risk was identified for those with the AG genotype of TLR1 rs4833095. The T allele of TLR6 rs5743810 conferred protection across all ethnic groups. TLR2 rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group. The T allele of TLR4 rs4986791 was also found to increase the risk of TB in the Asian subgroup. All other TLR gene variants investigated were not found to be associated with TB in this meta-analysis.
Discussion:
Although general associations were identified, most TLR variants showed no significant association with TB, indicating that additional studies investigating a wider range of pattern recognition receptors is required to gain a better understanding of this complex diseasehttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139711Publisher's versio
A new tool for prioritization of sequence variants from whole exome sequencing data
CITATION: Glanzmann, B. et al. 2016. A new tool for prioritization of sequence variants from whole exome sequencing data. Source Code for biology and Medicine, 11:10, doi:10.1186/s13029-016-0056-8.The original publication is available at http://scfbm.biomedcentral.com/Publication of this article was funded by the Stellenbosch University Open Access Fund.Background: Whole exome sequencing (WES) has provided a means for researchers to gain access to a highly
enriched subset of the human genome in which to search for variants that are likely to be pathogenic and possibly
provide important insights into disease mechanisms. In developing countries, bioinformatics capacity and expertise
is severely limited and wet bench scientists are required to take on the challenging task of understanding and
implementing the barrage of bioinformatics tools that are available to them.
Results: We designed a novel method for the filtration of WES data called TAPERâ„¢ (Tool for Automated selection
and Prioritization for Efficient Retrieval of sequence variants).
Conclusions: TAPERâ„¢ implements a set of logical steps by which to prioritize candidate variants that could be
associated with disease and this is aimed for implementation in biomedical laboratories with limited bioinformatics
capacity. TAPERâ„¢ is free, can be setup on a Windows operating system (from Windows 7 and above) and does not
require any programming knowledge. In summary, we have developed a freely available tool that simplifies variant
prioritization from WES data in order to facilitate discovery of disease-causing genes.Publishers versio