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The conclusion that the disorder is caused by a mutation in the mitochondrial genome is supported by the pedigree and the observation of variable expression in affected members of the same family. The disorder is passed only from affected mothers to offspring; when fathers are affected, none of their children have the trait (as seen in the children of II-2 and III-6). This outcome is expected of traits determined by mutations in mtDNA, because mitochondria are in the cytoplasm and usually inherited only from a single (in humans, the maternal) parent.

The facts that some offspring of affected mothers do not show the trait (III-9 and IV-5) and that expression varies from one person to another suggest that affected persons are heteroplasmic, with both mutant and wild-type mitochondria. Random segregation of mitochondria in meiosis may produce gametes having different proportions of mutant and wild-type sequences, resulting in different degrees of phenotypic expression among the offspring. Most likely, symptoms of the disorder develop when some minimum proportion of the mitochondria are mutant. Just by chance, some of the gametes produced by an affected mother contain few mutant mitochondria and result in offspring that lack the disorder.

Another possible explanation for the disorder is that it results from an autosomal dominant gene. When an affected (heterozygous) person mates with an unaffected (homozygous) person, about half of the offspring are expected to have the trait, but just by chance some affected parents will have no affected offspring. It is possible that individuals II-2 and III-6 in the pedigree just happened to be male and their sex is unrelated to the mode of transmission. The variable expression could be explained by variable expressivity (see p. 000 in Chapter 3).

2. Suppose that a new organelle is discovered in an obscure group of protists. This organelle contains a small DNA genome and some scientists are arguing that, like chloroplasts and mitochondria, this organelle originated as a free-living eubacterium that entered into an endosymbiotic relation with the protist. Outline a research plan to determine if the new organelle evolved from a free-living eubac-terium. What kinds of data would you collect and what predictions would you make if the theory is correct?

We could examine the structure, organization, and sequences of the organelle genome. If the organelle shows only characteristics of eukaryotic DNA, then it most likely has a eukaryotic origin but, if it displays some characteristics of eubacterial DNA, then this finding supports the theory of a eubacterial origin. However, on the basis of our knowledge of mitochondrial and chloroplast genomes, we should not expect the organelle genome to be entirely eubacterial in its characteristics.

We could start by examining the overall characteristics of the organelle DNA. If it has a eubacterial origin, we might expect that the organelle genome will consist of a circular molecule and will lack histone proteins. We might then sequence the organelle DNA to determine its gene content and organization. The presence of any group II introns would suggest a eubacterial origin, because these introns have been found only in eubacterial genomes and genomes derived from eubacteria. The presence of any pre-mRNA introns, on the other hand, would suggest a eukaryotic origin, because these introns have been found only in nuclear eukaryotic genomes. If the organelle genome has a eubacterial origin, we might expect to see polycistronic mRNA, the absence of a 5' cap, and inhibition of translation by those antibiotics that typically inhibit eubacterial translation.

Finally, we could compare the DNA sequences found in the organelle genome with homologous sequences from eubacteria and eukaryotic genomes. If the theory of an endosymbiotic origin is correct, then the organelle sequences should be most similar to homologous sequences found in eubacteria.

The New Genetics

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