It can be useful to model the effect of mtDNA mutations at the level of individual genes, instead of just counting the number of mutated mtDNA molecules in the cell. To see why, consider a cell with 100% mutated mtDNA consisting of clonal expansions of two different mutations that have occurred on different genes. Call the mutants A and B. Mutant A may have a nonfunctional ND1 gene whereas mutant B has a nonfunctional tRNA-W gene. Even though all the mtDNA molecules in the cell are mutated in some way, all the mutant A mtDNA molecules contain functioning tRNA-W genes and all the mutant B molecules contain functioning ND1 genes, so the two mutant mtDNA molecules still complement each other and the cell function would be normal. To allow for this complementation of different mutant mtDNAs, we can assign to each mutation a profile indicating which genes, if any, are deleteriously affected by that mutation. We can do this with a logical vector with 37 elements (22 tRNAs, 13 protein genes, and 2 rRNAs). Table 48.1 gives an example of this for three specific mutations: the common deletion, the A3243G point mutation, and any silent point mutation. The columns of the table are arranged in the gene order on the human mtDNA genome, for simplicity in representing deletions that affect multiple genes. In the examples shown in Table 48.1, the common deletion removes a wide swath of genes, the relatively common A3243G point mutation affects only the L1 tRNA gene, and a neutral mutation affects no gene products.
The specification of the gene products affected by the simulated mutant will allow you to be more specific in the modeling of COX cells. COX staining is a very common laboratory method of detecting mitochondrial dysfunction in tissue samples. However, the COX staining only directly detects the presence of complex IV of the respiratory chain. This complex will be directly affected by mutations in the genes CO I, CO II, CO III, and also by any tRNA or rRNA mutation (see Table 48.1). This includes the majority of all known pathogenic point mutations and deletions, but not all. Specifying the gene products affected by the mutation allows the possibility of pathogenic mutations that will not produce COX- cells. By including this detail in your simulation you allow a very valuable comparison between the simulation and clinical data.
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