Nucleotide methylation and neurocognitive phenotypes

Flitton, Miles (2018) Nucleotide methylation and neurocognitive phenotypes. PhD thesis, University of Nottingham.

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Epigenetic modifications are under increasing scrutiny in research of health and disease states. The most commonly researched epigenetic modification, DNA methylation, is associated with familial forms of dementia, developmental delay syndromes, and disparate cognitive phenotypes. This thesis investigates the relationship between nucleotide methylation and brain disease using three distinct approaches.

The majority of the thesis focuses on a genetic variant located within a DNA methyltransferase, DNMT3L R278G, which had previously been associated with intelligence scores in a Scottish birth cohort. Data was utilised from the Oxford Project To Investigate Memory and Aging, specifically the VITACOG cohort of individuals who have mild cognitive impairment and who received B vitamin treatment over a two-year period. It was discovered that minor allele carriers of the R278G variant who received B vitamin treatment showed improved visuospatial associative memory, but diminished verbal semantic memory. These effects were reflected in rates of brain atrophy for these individuals over the course of the two-year study. In silico modelling suggests that the R278G variant disrupts the DNMT3A-3L complex required for de novo methylation.

Investigation of genetic variants in methylation genes was by examining next-generation sequencing data from the UK10K project for multiple intellectual disability and autism spectrum disorder cohorts. Thirty DNA and RNA methylation genes were investigated to identify rare coding variants these cohorts. Case-control analysis of these intellectual disability and autism cohorts compared to the TwinsUK general population controls identified four rare missense variants associated with risk for disease. As these variants were found only in individuals with intellectual disability comorbid with psychiatric disease, the findings suggest that these variants contribute to disease risk for a specific clinical population.

DNA methylation is a dynamic process where demethylation of 5mC results in the formation of further methylation marks including 5hmC and 5caC. An optimised immunohistochemical method was used to detect 5hmC and 5caC modifications in multiple regions of human brain tissue. Initial characterisation confirmed the near-ubiquitous presence of 5hmC in the human brain. Further, substantial 5caC staining was recorded in the human cerebellum that was absent in all other brain regions, signifying an as-of-yet unidentified relationship between this methylation mark and cerebellar function.

Taken together, the different strands of investigation carried out in this thesis have substantiated the importance of nucleotide methylation in dementia progression, intellectual disability, and healthy brain function. Our use of well-curated cohort studies provides the basis for further investigation into methylation patterns and their role in the pathogenesis of multiple brain diseases.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Knight, Helen Miranda
Macdonald, Ian
Keywords: Epigenetic modifications; DNA methylation; Nucleotide methylation; Brain diseases
Subjects: Q Science > QP Physiology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 52582
Depositing User: Flitton, Miles
Date Deposited: 11 Apr 2019 14:25
Last Modified: 13 Dec 2020 04:30

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