The mitochondrial DNA genetic bottleneck: inheritance and beyond

Abstract

mtDNA is a multicopy genome. When mutations exist, they can affect a varying proportion of the mtDNA present within every cell (heteroplasmy). Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency seen during transmission from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be revealed. Several questions remain, including the role of selection for and against specific alleles, whether all bottlenecks are the same, and precisely how the bottleneck is controlled during development. Although originally thought to be limited to the germline, there is evidence that bottlenecks exist in other cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. Moreover, tissue-specific bottlenecks may occur throughout life in response to environmental influences, adding further complexity to the situation. Here we review key recent findings, and suggest ways forward that will hopefully advance our understanding of the role of mtDNA in human disease.