Trends in Genetics
Volume 16, Issue 11, 1 November 2000, Pages 500-505
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Perspectives
The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both?

https://doi.org/10.1016/S0168-9525(00)02120-XGet rights and content

Abstract

The mammalian mitochondrial genome (mtDNA) is a small double-stranded DNA molecule that is exclusively transmitted down the maternal line. Pathogenic mtDNA mutations are usually heteroplasmic, with a mixture of mutant and wild-type mtDNA within the same organism. A woman harbouring one of these mutations transmits a variable amount of mutant mtDNA to each offspring. This can result in a healthy child or an infant with a devastating and fatal neurological disorder. Understanding the biological basis of this uncertainty is one of the principal challenges facing scientists and clinicians in the field of mitochondrial genetics.

Section snippets

The inheritance of heteroplasmic polymorphisms in mice

To advance our understanding of the mechanisms of transmission of mtDNA heteroplasmy, a number of groups have developed heteroplasmic mice by karyoplast (cytoplast) transfer (White et al., unpublished; Refs 17., 18., 19., 20.). Extensive studies have been carried out on large pedigrees of these mice that transmit heteroplasmic and apparently neutral mtDNA polymorphisms. The offspring of a single heteroplasmic mouse can have dramatically different levels of heteroplasmy, but the mean level of

Differences between mice and humans

Mature human and mouse oocytes contain approximately 100 000 mtDNA molecules22., 23.. After fertilization of the mouse oocyte, there is no measurable mtDNA turnover until the embryo implants, so that the amount of mtDNA in the embryo remains constant until the blastocyst stage24. During this period, the embryo (and mtDNA) is constrained within the zona pellucida, where it is compartmentalized into a large number of cells (Fig. 2). Following implantation, there is massive cellular proliferation,

Selection for and against mutant mtDNA occurs in humans

For some mtDNA mutations, particularly those with severe phenotypic effects, selection might operate during the life span of the individual. In some tissues and organs, selection may lead to a decrease in the amount of mutant mtDNA, whereas the level of mutant mtDNA can increase in others. In rapidly dividing stem cell populations, mutant mtDNA can be removed by selection operating at the level of the cell. Vegetative segregation could lead to high levels of mutant mtDNA in some stem cells, and

The inheritance of mtDNA heteroplasmy in humans

It is generally assumed that mtDNA deletions are not transmitted from mother to offspring, since the vast majority of patients who have a single mtDNA deletion do not have any relevant family history. There have been a handful of reports describing the transmission of mtDNA rearrangements, but it has often been unclear whether the rearranged molecules were actually duplications or deletions. We therefore restricted our analysis to human pedigrees transmitting pathogenic mtDNA point mutations.

Conclusions and future prospects

How can we resolve whether selection or pure random drift is the predominant factor in human mtDNA transmission? So far it has not been possible to generate a female mouse that transmits a heteroplasmic pathogenic mtDNA mutation. This is an area of intense interest3, and when a murine model for heteroplasmic mtDNA disease does become available, it might help us considerably to address these issues. Unfortunately, there remain important anatomical and physiological differences between mice and

Acknowledgements

This work was supported by a Wellcome Trust collaborative grant and an Australian NHMRC Centre Grant. P.F. Chinnery is a Wellcome Advanced Clinical Research Fellow. H.H.M. Dahl is an NHMRC Principal Research Fellow. N. H. is supported by a grant from the National Sciences Foundation.

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