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Report provided to the Human Fertilisation and Embryology Authority, April 2011 - page 9 / 45





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replicative advantage3. A heteroplasmic mother can produce oocytes (and children) that have dramatically different proportions, from 0-100%, of normal and abnormal mtDNA, compared to each other and to her. This germline mosaicism occurs because the germline is thought to arise from very few cells at a time when mtDNA copy number is especially low. Some women carriers can have low or even undetectable heteroplasmy within their adult somatic tissues but very high abnormal loads or even homoplasmy in all their oocytes4. It is also possible that de novo mutations in mtDNA may occur in the germline at any stage.

      • 2.2.6

        Nuclear-mitochondrial interactions: Mitochondrial dynamics and function depend on nuclear-encoded genes. Therefore defects in the interaction between nucleus and mitochondria can lead to defects in replication, transcription or activity of mitochondria, or perhaps to the triggering of apoptosis (programmed cell death) or autophagy (where the cell begins to digest part of itself). Any of these processes could also in theory contribute to altered segregation of abnormal and normal mitochondria. This incompatibility can explain why certain cytoplasmic hybrids, where the nuclear and mtDNA genomes within a cell are from different species, fail to thrive.

      • 2.2.7

        Differing phenotypes: Specific disease-causing mtDNA mutations vary significantly in the degree of mitochondrial dysfunction, and therefore the severity of the phenotype they produce. This variation is further compounded by the degree of heteroplasmy and the possible differing levels of heteroplasmy in different tissues. There have been some reports that certain mtDNA mutations lead to preferential replication of abnormal mtDNA ie, there is selection for abnormal mtDNA even though it might be expected that they should be selected against. These instances are unusual and have only been noted for a few rare types of mtDNA mutation.

3 4 For example, Certain D-loop mutations are likely to compromise replication efficiency. Similar bottlenecks can also explain why genotyping some tissues, notably blood, can be unreliable. At any one moment, the majority of blood cells may be derived from very few, or perhaps even a single haematopoietic (blood) stem cell. Page 9 of 45

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