Identifying nuclear genetic modifiers of the m.3243A>G mutation

Róisín Boggan is a first year PhD student in the WCMR who is trying to identify nuclear genetic modifiers of the m.3243A>G mutation. Following her talk as part of our weekly ‘Research in Progress’ meeting, Róisín tells us more.

There are many genetic causes of mitochondrial disease. The most common disease-causing heteroplasmic mutation is an A-to-G transition at position 3243 in the mitochondrial genome; known as m.3243A>G. There is a wide range of observable disease types that can be caused by m.3243A>G, which suggests that m.3243A>G-related disease is influenced by factors other than this mitochondrial mutation.

Using patient data from the MRC Mitochondrial Disease Patient Cohort, Dr Sarah Pickett was able to demonstrate that the variation that we see in the disease traits of m.3243A>G can in part be explained by unknown additive genetic factors from the nucleus. My project is working to identify these unknown nuclear factors, and establish how they relate to different disease traits.

Single nucleotide polymorphisms (SNPs) are the most common form of variation in the genome, and occur at about 1 in 1000 nucleotides. There are roughly 3.2 billion nucleotides in the genome, so the frequency of SNPs allows them to be used as flags for sections of DNA. Using SNPs in this way, I will be searching through the nuclear DNA to identify regions that show links to disease phenotypes.

To facilitate this search of the genome, it has been necessary to develop a stringent quality control pipeline to ensure that the SNP flags I am using are reliable and of good quality. This process has involved a number of steps, such as looking at the internal structure and variance of the data, as well as statistically checking reported familial relationships.

Upcoming work will utilize this quality-controlled data set to begin family-based and population-based searches of the genome to uncover disease-associated regions.