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Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration
Thesis (MSc)--Stellenbosch University, 2025.
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Stellenbosch : Stellenbosch University
2025
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| _version_ | 1867614029408632832 |
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| access_status_str | Open Access |
| author | Collins, Megan |
| author2 | Pearce, Brendon Clive |
| author_browse | Collins, Megan Pearce, Brendon Clive |
| author_facet | Pearce, Brendon Clive Collins, Megan |
| author_sort | Collins, Megan |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/132107 |
| institution | Stellenbosch University (South Africa) |
| last_indexed | 2026-06-10T12:45:32.686Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/132107 Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration Collins, Megan Pearce, Brendon Clive Stellenbosch University. Faculty of Agrisciences. Dept. of Genetics. Mitochondrial DNA Mitochondrial pathology -- Genetic aspects Proteins -- Structure -- Computer simulation Mutation (Biology) -- Data processing Transfer RNA UCTD Thesis (MSc)--Stellenbosch University, 2025. Collins, M. 2025. Investigating Mitochondrial DNA Mutations Driving Dysfunction and Intervertebral Disc Degeneration. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/bc34b646-b505-4dac-9aba-cf8ec00bede4 ENGLISH ABSTRACT: Lower back pain is a chronic disorder responsible for debilitation and reducing quality of life for millions of individuals worldwide. Studies have shown that LBP due to disc degeneration is one of the leading causes of disability. Mitochondrial dysfunction has been associated with disc degeneration and, furthermore, disc degeneration has been associated with LBP, however, the association between these mtDNA mutations and disc degeneration has not yet been assessed. The aim of this study was to investigate mitochondrial DNA mutations (mtDNA) associated with general mitochondrial dysfunction and their subsequent association with lower back pain (LBP) due to intervertebral disc degeneration (IVDD) in a South African cohort. This study sought to establish a neutral list of mtDNA mutations associated with general mitochondrial dysfunction so as to further assess their association with disc degeneration. A total of 56 mutations were identified for downstream analysis. From the generated list, the relevant protein subunits and tRNA secondary structures containing these mutations were modelled, in silico, to assess if and how the mutations altered the structure of these molecules. Mutations in protein coding genes were assessed by modelling the individual protein subunit as well as modelling the relevant mitochondrial respiratory chain complex that the subunit forms part of. From this data, hypotheses could be made about how these mutations cause dysfunction, and a subsequent genotyping assay could be chosen. After modelling, a total of 16 mutations were selected as part of the genotyping assay. The 16 mutations chosen for downstream analysis was then assessed in a South African cohort for their potential association with intervertebral disc degeneration. Genotypic data was generated for 60 case individuals and 102 control individuals. Statistical analyses were conducted to assess Hardy-Weinberg Equilibrium, allele frequencies, fixation indices, G-statistics, linkage disequilibrium and haplotype analysis. Logistic regression was also performed to assess for association of the mutations with disc degeneration. From this pilot study, monomorphic and polymorphic mutations were identified in a South African cohort. No significant associations were observed, however, three mutations, namely A10398G, C6223T and A8536G appeared to have high mutant allele frequencies when compared to the other mutations that were polymorphic. This indicates, that had the study cohort been larger, it is possible that these mutations may have been significant. The data generated also provided some genetic insight into which mutations could aid future studies in terms variant selection for further investigation regarding intervertebral disc degeneration within the South African context. AFRIKAANSE OPSOMMING: Laer rugpyn is 'n chroniese toestand wat verantwoordelik is vir verswakking en 'n verminderde lewensgehalte vir miljoene mense wêreldwyd. Studies het getoon dat laer rugpyn (LBP) as gevolg van skyfdegenerasie een van die hoofredes vir gestremdheid is. Mitochondriale disfunksie is verbind met skyfdegenerasie, en verder is skyfdegenerasie geassosieer met LBP. Die verband tussen hierdie mtDNA-mutasies en skyfdegenerasie is egter nog nie geëvalueer nie. Die doel van hierdie studie was om mitochondriale DNA-mutasies (mtDNA) wat met algemene mitochondriale disfunksie geassosieer word, te ondersoek, sowel as hul daaropvolgende verband met laer rugpyn as gevolg van intervertebrale skyfdegenerasie (IVDD) in 'n Suid-Afrikaanse groep. Hierdie studie het gepoog om 'n neutrale lys mtDNA-mutasies wat met algemene mitochondriale disfunksie geassosieer word, op te stel om hul verband met skyfdegenerasie verder te assesseer. Altesaam 56 mutasies is geïdentifiseer vir verdere ontleding. Van die gegenereerde lys is die betrokke proteïensubeenhede en tRNA-sekondêre strukture wat hierdie mutasies bevat, in silico gemodelleer om te bepaal of en hoe die mutasies die struktuur van hierdie molekules verander het. Mutasies in proteïenkoderende gene is beoordeel deur die individuele proteïensubeenheid te modelleer, sowel as die mitochondriale respiratoriese kettingkompleks waarvan die subeenheid deel vorm. Uit hierdie data kon hipoteses gemaak word oor hoe hierdie mutasies disfunksie veroorsaak, en 'n gepaste genotiperingstoets kon gekies word. Na modellering is altesaam 16 mutasies gekies vir die genotiperingstoets. Die 16 mutasies wat vir verdere ontleding gekies is, is toe in 'n Suid-Afrikaanse groep beoordeel vir hul potensiële verband met intervertebrale skyfdegenerasie. Genotipiese data is gegenereer vir 60 gevalle-individue en 102 kontrole-individue. Statistiese analises is uitgevoer om Hardy-Weinberg- ewewig, alleelfrekwensies, fiksasie-indekse, G-statistieke, skakelingswanbalans en haplotipe-analise te beoordeel. Logistieke regressie is ook uitgevoer om die verband tussen die mutasies en skyfdegenerasie te beoordeel. Uit hierdie loodsstudie is monomorfiese en polimorfiese mutasies in 'n Suid-Afrikaanse groep geïdentifiseer. Geen beduidende verbande is waargeneem nie, maar drie mutasies, naamlik A10398G, C6223T en A8536G, het hoë mutante alleelfrekwensies getoon in vergelyking met ander mutasies wat polimorfies was. Dit dui daarop dat, indien die studiepopulasie groter was, hierdie mutasies moontlik betekenisvol kon wees. Die data wat gegenereer is, het ook genetiese insig verskaf in watter mutasies toekomstige studies kan help met variantekeuse vir verdere ondersoek na intervertebrale skyfdegenerasie binne die Suid-Afrikaanse konteks. Masters 2025-05-23T14:01:00Z 2025-05-23T14:01:00Z 2025-03 Thesis https://scholar.sun.ac.za/handle/10019.1/132107 Stellenbosch University xii, 156 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Mitochondrial DNA Mitochondrial pathology -- Genetic aspects Proteins -- Structure -- Computer simulation Mutation (Biology) -- Data processing Transfer RNA UCTD Collins, Megan Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration |
| title | Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration |
| title_full | Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration |
| title_fullStr | Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration |
| title_full_unstemmed | Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration |
| title_short | Investigating mitochondrial DNA mutations driving dysfunction and intervertebral disc degeneration |
| title_sort | investigating mitochondrial dna mutations driving dysfunction and intervertebral disc degeneration |
| topic | Mitochondrial DNA Mitochondrial pathology -- Genetic aspects Proteins -- Structure -- Computer simulation Mutation (Biology) -- Data processing Transfer RNA UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/132107 |
| work_keys_str_mv | AT collinsmegan investigatingmitochondrialdnamutationsdrivingdysfunctionandintervertebraldiscdegeneration |