The unorthodox genetics of the mtDNA is providing new perspectives on the etiology of the common "complex" diseases. The maternally inherited mtDNA codes for essential energy genes, is present in thousands of copies per cell, and has a very high mutation rate. New mtDNA mutations arise among thousands of other mtDNAs. The mechanisms by which these "heteroplasmic" mtDNA mutations come to predominate in the female germline and somatic tissues is poorly understood, but essential for understanding the clinical variability of a range of diseases. Maternal inheritance and heteroplasmy also pose major challengers for the diagnosis and prevention of mtDNA disease. THE GENETIC CHALLENGES OF mtDNA DISEASES

The Mitomap database of human mitochondrial DNA (mtDNA) information has been an important compilation of mtDNA variation for researchers, clinicians, and genetic counselors for the past 25 years. The Mitomap protocol shows how users may look up human mitochondrial gene loci, search for public mitochondrial sequences, and browse or search for reported general population nucleotide variants as well as those reported in clinical disease. Within Mitomap is the powerful sequence analysis tool for human mitochondrial DNA, Mitomaster. The Mitomaster protocol gives step‐by‐step instructions showing how to submit sequences to identify nucleotide variants relative to the rCRS, determine the haplogroup, and view species conservation. User‐supplied sequences, GenBank identifiers, and single‐nucleotide variants may be analyzed. Curr. Protoc. Bioinform. 44:1.23.1‐1.23.26. © 2013 by John Wiley & Sons, Inc.

SUMMARY Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homo-plasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA.