ABSTRACT
The MITOMAP database of mitochondrial mutations has extensive data tables showing just how great is the challenge of relating mutations to phenotypes. Many mitochondrial functions are encoded by nuclear genes, so that nuclear variation can be an important cause or modifier of mitochondrial phenotypes. For most genetic diseases, the clinical features are the end result of a long chain of causation, and the holy grail of molecular pathology, genotype-phenotype correlation, will always be elusive. A number of other studies have sought rare "resilient" individuals who seem perfectly healthy despite apparently having genotypes normally considered pathogenic. Most genotype-phenotype correlations describe phenotypes in terms of entries in the OMIM database. Molecular pathology seeks to explain why a certain genetic change causes a particular phenotype. Traditional phenotype-centric views of genotype–phenotype relationships are being challenged by data from large-scale sequencing projects. This chapter focuses on the mechanisms by which a genotype can lead to a phenotype.
