Somatic mutation and regulatory genomic variation in the human brain: relevance to neurodegenerative disease.
Professor Jonathan Mill, Complex Disease Epigenomics Group, University of Exeter Medical School
Assistant Professor Jia Nee Foo, Lee Kong Chian School of Medicine, Nanyang Technological University.
About the Programme:
The University of Exeter (UoE) and Nanyang Technological University (NTU), Singapore are offering six fully funded postgraduate studentships to undertake collaborative research projects at the two institutions, leading to PhD degrees (split-site) to be conferred either by the UoE or NTU.
Students pursuing these postgraduate research projects will benefit from the unique opportunity to conduct their research at both institutions. Students will be registered at one or other institution, where they will be based for the majority of their time, but will spend at least 12 and not more than 18 months at the partner institution over the duration of the programme. The frequency and length of stays at each institution will be agreed with successful candidates prior to offers being made.
Neurodegenerative diseases represent a major healthcare burden worldwide and the most common cause of morbidity and disability in the elderly. As the population ages, the social and economic burden of these these diseases will increase further.
This PhD project will focus on Alzheimer’s disease (AD), a chronic neurodegenerative disorder that is characterized by progressive cortical neuropathology and cognitive decline, and Parkinson’s disease (PD), a long-term degenerative disorder of the basal ganglia that primarily affects the motor system.
Although the neuropathological signatures of AD and PD are well characterized in post-mortem human brain, the specific mechanisms involved in the onset and progression of these debilitating conditions are still unknown; an improved understanding of these processes is vital to enable the design of effective therapies.
There has been considerable success in identifying genetic risk factors for both AD and PD, although little is known about the functional mechanisms by which risk variants mediate disease susceptibility. Increased understanding about the functional
complexity of the genome has led to growing recognition about the likely role of somatic and non-sequence-based regulatory variation in health and disease.
In Exeter, Professor Mill’s group has established a program of research to explore the role of epigenomic and transcriptomic processes in neurodegenerative diseases and the extent to which these mediate the effects of disease-associated genetic variation. Beyond germline genomic variation, somatic mutations that occur during post-zygotic cell division or that accumulate with age in post-mitotic neurons of the brain provide another possible mechanism underlying neurological disorders. In Singapore, Dr Foo’s group has established a program of work to profile somatic mosaicism in post-mortem brain and to evaluate their role in neurodegenerative phenotypes.
The primary goal of this studentship will be to use the novel genomic profiling approaches established in our groups to explore the role of both somatic mutations and regulatory genomic variation in AD and PD. The study will use human post-mortem brain samples to explore the accumulation of novel somatic mutations, epigenomic dysregulation and transcriptional changes in disease-relevant regions of the brain. We have developed fluorescence-activated nuclei sorting (FANS) methods to purify populations of nuclei from neurons and other cell types in the brain for subsequent genomic profiling.
In Professor Mill’s laboratory, purified neural nuclei will be used for regulatory genomic profiling (DNA modifications, histone modifications, gene expression, and alternative splicing) using the cutting-edge genomics facilities at the University of Exeter. In Dr Foo’s laboratory, single-cell genomics approaches such as the Fluidigm C1 system will be used to screen for somatic mutations in various cell populations in the same postmortem brain tissue. Systems biology approaches will be used to integrate multi-omic data, drawing on expertise in both Exeter and Singapore. Novel genomic changes and pathways will be validated in larger collections of brain tissues and functionally characterized in mouse, organoid and induced pluripotent stem cell models.
The proposed project is scalable and can be applied to address multiple questions related to neurodevelopment and neurodegeneration, depending on the availability of post-mortem brain tissue samples. With the anticipation of establishing a future brain bank in Singapore/Asia, we hope to develop and optimize these methods within the coming five years. Future work will enable us to compare and understand differences between the genomic underpinnings of neurodegenerative disease in European and Asian populations.
To apply for the project, visit: http://www.exeter.ac.uk/studying/funding/award/?id=3055
3 year studentship providing tuition fees and an annual stipend allowance at Research Council rates, currently £14,777 per year for 2018-19