Every person inherits their mitochondrial DNA—the energy-producing machinery inside cells—exclusively from their mother, and subtle variations in this DNA influence how long we live and our risk of age-related diseases like kidney and liver failure. Yet scientists do not understand how these variants are selected or filtered as they pass from mother to child. Researchers at this lab recently analysed mitochondrial DNA from 358,916 people in UK Biobank and found that common variants affect organ function and lifespan. They also showed, using the 100,000 Genomes Project, that the mother’s nuclear genome somehow shapes which mitochondrial variants her children inherit—but the timing and mechanism remain unknown. This project will determine exactly when and how that selection happens. Using mice (whose mitochondrial inheritance closely mirrors humans), the team will track variant transmission across four stages: egg development, egg maturation, fertilisation, and early embryo growth. They will measure variant proportions in thousands of single cells, identify the nuclear genes responsible using single-cell genomics, and then experimentally modify those genes to confirm causation. This is fundamental science. It will reveal the cellular machinery that has shaped human mitochondrial DNA diversity over generations. Understanding these mechanisms could eventually help predict which mitochondrial variants are likely to spread in populations, with long-term implications for common age-related diseases—but no immediate clinical application is expected.
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Mitochondria are the main source of energy within cells. They are made from over ~1100 proteins which are coded by two different genomes: nuclear DNA and mitochondrial DNA (mtDNA). MtDNA is only inherited from our mother, and codes for 13 mitochondrial proteins that are essential for cell energy production. In humans, mtDNA varies considerably between different people (called mtDNA single nucleotide variants, or mtSNVs). Studying mtDNA in 358,916 individuals in UK Biobank, we have recently shown that mtSNVs influence how healthy organs function, including the kidney and liver, how long we live, and whether we develop common age-related diseases. Thus, knowing how mtDNA variants arise in the human population has important implications for understanding who we are and how we function during life. Analysing data from the 100,000 genomes project, we have shown that our mtDNA is shaped, or 'selected' as it is transmitted from a mother to each child under the influence of the nuclear genome, but it is not known precisely when and how this occurs. In this project we aim to determine the main mechanisms. We will study mice because we have shown that the mechanisms of mtDNA inheritance are very similar to humans, and the experiments we propose are neither feasible nor technically possible in humans. Harnessing new genetic and single-cell techniques, we will study the transmission of mtSNVs at four stages: when egg cells develop, when they mature, around fertilisation, and in early embryonic development. First, we will generate mice transmitting mtSNVs. Next, we will determine whether there is selection at each of the four stages by measuring heteroplasmy in thousands of single cells. We will then use single-cell functional genomic approaches to determine the most likely nuclear genes involved in modulating mtDNA transmission. Finally, we will modify these genes in mice to show that they directly influence mtSNV inheritance. This work will advance our understanding of the fundamental cellular mechanisms driving human mtDNA evolution and genetic diversity in the human population, with implications for health and lifespan.
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