How is inheritance of mitochondrial genetic disease influenced by the biology of the oocyte?

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a maternally-inherited mitochondrial disorder that predominantly affects the nervous system. In severe cases, MELAS appears in childhood and causes progressive, life-limiting neurological impairment for which cures are currently lacking. The severity of disease symptoms is largely determined by the level of heteroplasmy for the pathogenic mtDNA m.3243A>G variant present in oocytes at the time of conception. The goal of this project is to determine how transmission of the m.3243A>G variant is shaped by the biochemical demands of generating and transmitting a haploid maternal genome during mammalian oogenesis. Unravelling the interplay between accurate transmission of the maternal nuclear genome and transmission of the m.3243A>G variant will shed new light on the selection pressures that shape heteroplasmy levels and hence the risk of MELAS in the human population. The findings will also underpin the development of tailored approaches to improve reproductive outcomes for women undergoing MD treatment to reduce transmission of the m.3243 variant. This is a joint project with Newcastle University, UK.