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Mitochondrial Heteroplasmy

Discussion in 'Mitochondrial Rx' started by Jason Coates, Jul 3, 2018.

  1. Jason Coates

    Jason Coates Losing the Shade.


    Vital mitochondrial DNA (mtDNA) populations exist in cells and may consist of heteroplasmic mixtures of mtDNA types. The evolution of these heteroplasmic populations through development, ageing, and generations is central to genetic diseases, but is poorly understood in mammals. Here we dissect these population dynamics using a dataset of unprecedented size and temporal span, comprising 1947 single-cell oocyte and 899 somatic measurements of heteroplasmy change throughout lifetimes and generations in two genetically distinct mouse models. We provide a novel and detailed quantitative characterisation of the linear increase in heteroplasmy variance throughout mammalian life courses in oocytes and pups. We find that differences in mean heteroplasmy are induced between generations, and the heteroplasmy of germline and somatic precursors diverge early in development, with a haplotype-specific direction of segregation. We develop stochastic theory predicting the implications of these dynamics for ageing and disease manifestation and discuss its application to human mtDNA dynamics.
  2. Jason Coates

    Jason Coates Losing the Shade.

    A mathematical model that can predict the nature of the mitochondrial DNA a child will inherit from its mother was part of a study that also found that maternal age counts in mitochondrial health, too.

    This part of the study, in mice, showed that the older the mother, the higher is the risk that mutated, disease-causing mitochondrial DNA will be passed along to offspring.

    The study, “Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations,” was published in the journal Nature Communications.

    Most cells have multiple mitochondria, which house the mitochondrial DNA (mtDNA) — an integral component of the cell’s energy-producing machine.

    mtDNA can acquire mutations over time, which can lead to different mtDNA sequences within different mitochondria of the same cell. This phenomenon, called heteroplasmy, occurs when a cell has some mitochondria with a mutation in its mtDNA and some that does not.

    Heteroplasmy can influence the inheritance and onset of serious mitochondrial diseases, which develop due to mutations in key mitochondrial genes.

    People inherit their mitochondria from their mothers. If the mother has heteroplasmy, it can be difficult to determine how this will affect an unborn child.

    In particular, scientists don’t know how heteroplasmy changes over time in women, and whether the risk of transmitting a disease-carrying mitochondrial mutation increases or decreases.

    Researchers in Europe analyzed mtDNA segregation in two mouse lines with heteroplasmy, using mothers with a range of ages. Measurements were then taken from 1,947 oocytes [immature egg cells] and 899 pups.

    Using this extensive data, they were able to create a mathematical model that was descriptive of mtDNA inheritance — they transfer of mitochondrial DNA from mother to offspring, taking maternal age into account.

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