Hundreds to thousands of independently replicating copies of the mitochondrial genome (mtDNA) are present in each cell. Therefore, mutations in mtDNA can be present at varying heteroplasmic frequencies and can be pathogenic at high levels. How mutant mtDNA can rise in frequency despite being deleterious to the host is a fundamental question in the field of mitochondrial genetics. We reasoned that study of mutant mtDNA as evolutionarily 'selfish' elements might provide insights into this question. Towards this end, we have developed C. elegans as a model system to study transmission dynamics of mutant mtDNA. Specifically, we have characterized a mutant mtDNA that is heteroplasmically inherited along with wildtype mtDNA. Our data reveal existence of a homeostatic mtDNA copy number control mechanism in the C. elegans germline, which the mutant mtDNA evades in order to replicate uncontrollably. In fact, our results suggest a model in which the mutant mtDNA takes advantage of the germline's copy number control mechanism to 'hitchhike' to high frequency. We are currently analyzing whole genome sequencing data from dozens of additional heteroplasmies to determine whether escape from germline copy number control is a common mechanism that mutant mtDNA employ to ensure their faithful inheritance. In summary, our results provide novel mechanistic insights into the transmission dynamics of selfish mutant mtDNA.
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