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Report provided to the Human Fertilisation and Embryology Authority, April 2011 - page 8 / 45





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during very early development of the embryo post implantation. Only after this do mtDNA copy numbers increase, in a cell type specific manner.

      • 2.2.3

        mtDNA replication: mtDNA replication and transcription depend on regulatory proteins encoded by nuclear genes. It is not clear how mtDNA copy number is regulated, and whether this is strictly dependent on demand, as abnormal mtDNA that does not function properly can be replicated to the same degree as normal mtDNA. It is also apparent that mtDNA replication does not occur in the early preimplantation embryo, with some evidence in the mouse suggesting that it begins at the blastocyst stage. The high numbers of mitochondria in oocytes are almost certainly essential to enable embryonic cells to inherit sufficient numbers of mtDNA copies that will be needed at later stages of development.

      • 2.2.4

        Heteroplasmy: Where abnormal mtDNA coexists in a cell with normal mtDNA, the cell is called heteroplasmic2. Where all copies of mtDNA in a cell are either all abnormal or all normal, the cell is called homoplasmic. The severity of most mitochondrial genetic diseases is dictated by the proportion of abnormal to normal mitochondria within the cells. The proportion may also change over time. Thus many of these diseases may manifest late or increase in severity with age. There may also be variations in heteroplasmy between tissues, perhaps resulting in specific manifestations of the disease according to the most affected organ or system. Homoplasmy for abnormal mtDNA is generally associated with more severe disease.

2.2.5 Mitochondrial bottleneck: Where an early embryo is heteroplasmic, a mitochondrial „bottleneckā€Ÿ arises because of a combination of low mtDNA copy number per cell and small founding cell populations for each tissue type during early embryogenesis. This means that, simply by chance, it is likely that different cell types will have different proportions of abnormal and normal mtDNA. It is possible that replication of mtDNA can further skew the proportions in subsequent development, especially if one form has a

2 Because of errors in replication, variant mtDNA sequences are common in all cells. Therefore heteroplasmy is the norm. However, most of these variants or polymorphisms will be benign. For this reason, the term heteroplasmy generally refers to situations where both disease-causing and normal mtDNA are present.

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