Sunday, 23 September 2018

Aging in the Variance: increasing variation between egg-cells with age

DNA in mitochondria, the powerhouses of the cell, is passed down from mother to child. But there are many mitochondria in each cell, and these mitochondria may have different genetic features. If a mother carries a mixture of mitochondrial DNA (mtDNA) types, this can make it hard to say which features their children will inherit. For mothers carrying a disease-causing mtDNA mutation, this makes family planning and clinical therapies challenging.

In particular, the role of a mother's age has long been a mystery. Is the probability of a child inheriting a particular mtDNA feature higher when mothers are younger or older? An answer to this question could help plan clinical strategies to improve fertility and prevent the inheritance of deadly mitochondrial disease.



Joerg Burgstaller and colleagues (see our blog entry here) previously made a type of mouse that contains two (apparently benignly differing) types of mitochondria (and their genetic material mtDNA) in every cell. This means that their egg-cells that make the next generation also have both types of mtDNA present. Our latest paper investigates how the proportion of the two types of mtDNA varies within the ovary, finding that cells become more and more variable with time.

To address this, we worked with our excellent collaborators with a combination of maths, statistics, and experiment. Our collaborators used cutting-edge technology to reveal the proportions of two-types of mtDNA in the egg cells of mother mice at a wide range of ages, and in the litters of offspring the mothers produced. This experimental work was the largest-scale study of mammalian mtDNA that we're aware of, involving thousands of observations throughout lifetimes and between generations. In concert, we developed a mathematical model describing the changes to, and inheritance of, mtDNA from mother to offspring. We combined the model and data to learn how different biological processes affect mtDNA through and between generations.

We found that the cell-to-cell variability in the proportions of the two types of mtDNA dramatically increased as mothers aged. This means that the probability of inheriting more extreme -- both lower and higher -- levels of a genetic feature increases for older mothers. We also found that different mtDNA mixtures were inherited in different ways - with some mtDNA types favoured for inheritance and some disfavoured. We used our findings to create a way to predict how the risk that offspring would inherit disease-causing mtDNA features changes over time. Moving forward, we're aiming to harness these powerful ways of using large datasets to describe and predict the dynamics of mtDNA inheritance in humans, and to learn what it is about these mtDNA types that predicts their evolution across generations. You can read the article “Large-scale genetic analysis reveals mammalian mtDNA heteroplasmy dynamics and variance increase through lifetimes and generations” for free in Nature Communications here. Iain, Joerg and Nick