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SUMMARY:The origin of mitochondrial DNA mutations: population genetics and
  disease - Professor Patrick Chinnery\, Department of Clinical Neuroscienc
 es\, Cambridge Biomedical Campus
DTSTART:20210513T123000Z
DTEND:20210513T133000Z
UID:TALK150553@talks.cam.ac.uk
CONTACT:Caroline Newnham
DESCRIPTION:Since the first described disease-causing mitochondrial DNA (m
 tDNA) mutation in 1989\, mtDNA disorders have emerged as a major cause of 
 neuromuscular disease.  Epidemiological studies have shown that mtDNA muta
 tions account for ~2/3 of mitochondrial disorders\, affecting approximatel
 y 1:10\,000 of the population - but precisely how these mutations arise in
  the population and present in the neuromuscular clinic has remained a mys
 tery. \nUnlike the nuclear genome\, there are many copies of mtDNA within 
 each cell – with tens of thousands present in skeletal muscle fibres.  U
 ltimately\, a mtDNA mutation affects a single molecule.  Once a mutation o
 ccurs\, there is a mixed population of mtDNA within the cell (heteroplasmy
 )\, and recent deep sequencing has shown that low percentage level heterop
 lasmic mtDNA mutations are an almost universal finding in the healthy huma
 n population.  However\, the level of heteroplasmy can change during the m
 aternal inheritance of mtDNA.  In several mammalian species\, including hu
 mans\, there is a decrease in the amount of mtDNA within the developing fe
 male germ line at an early stage\, shortly after implantation of the blast
 ocyst.  This causes a genetic bottleneck leading to rapid shifts in the al
 lele frequency within the dividing and migrating cell population that ulti
 mately forms oocytes for the next generation.  This explains why low level
  heteroplasmies in the background population can reach high levels that ca
 use mitochondrial DNA diseases\, but this process is not entirely random. 
  Studying 53\,300 people from the 100\,000 Genomes Project\, we have shown
  evidence of selection for and against mtDNA variants in different regions
  of the mitochondrial genome. We also saw the signature of nuclear genetic
  control over the segregation pattern.  This has important implications fo
 r understanding how mtDNA variants reach high levels\, and ultimately shap
 e the landscape of mtDNA at the population level. Characterising the mecha
 nisms involved will not only cast light on the underlying biology\, but al
 so presents new opportunities to manipulate heteroplasmy during transmissi
 on or within tissues and organs during life.\n
LOCATION:Zoom meeting
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