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Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease

Nature Reviews Genetics volume 9, pages 657–662 (2008)Cite this article

Abstract

Mutations of mitochondrial DNA (mtDNA) are frequent in humans and are implicated in many different types of pathology. The high substitution rate and the maternal, asexual mode of transmission of mtDNA make it more likely to accumulate deleterious mutations. Here, we discuss recent evidence that mtDNA transmission is subject to strong purifying selection in the mammalian female germ line, limiting the accumulation of such mutations. This process shapes mitochondrial sequence diversity and is therefore probably of fundamental importance for animal evolution and in human mitochondrial disease.

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Figure 1: Mammalian germline development and the mtDNA bottleneck.
Figure 2: The signature of purifying selection in the female germ line.
Figure 3: Potential levels of mitochondrial DNA (mtDNA) selection in the mammalian female germ line.

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Acknowledgements

We wish to acknowledge the support of the Swedish Research Council, Torsten and Ragnar Söderbergs Stiftelse, the Swedish Heart and Lung Foundation, the Knut and Alice Wallenberg Foundation and EUMITOCOMBAT. J.B.S was supported by a postdoctoral fellowship from the Wenner-Gren Stiftelserna. J.L.E is supported by a Research Council UK RCUK Academic fellowship.

Author information

Authors and Affiliations

  1. Christoph Freyer and Nils-Göran Larsson are at the Department of Laboratory Medicine, Division of Metabolic Diseases, James Bruce Stewart, Karolinska Institutet, SE-171 77 Stockholm, Sweden.,

    James Bruce Stewart, Christoph Freyer & Nils-Göran Larsson

  2. Joanna L. Elson is at the Mitochondrial Research Group, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.,

    Joanna L. Elson

  3. Nils-Göran Larsson is also at the Max Planck Institute for Biology of Ageing, Gleueler Str 50a, D-50931 Cologne, Germany.,

    Nils-Göran Larsson

Authors
  1. James Bruce Stewart
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  2. Christoph Freyer
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  4. Nils-Göran Larsson
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Corresponding author

Correspondence to Nils-Göran Larsson.

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FURTHER INFORMATION

The Edinburgh Mouse Atlas Project (emap)

The Human Mitochondrial Genome Database (mtDB)

MITOMAP: a database of human mtDNA variation and disease

Glossary

Muller's ratchet

The irreversible accumulation of deleterious mutations in asexual populations of finite size. The average load of mutations increases over generations because the class of individuals that carry the smallest number of mutant alleles is occasionally lost by genetic drift. In the absence of recombination, this class can never be re-created. The process is named after H. J. Muller, who described it in 1964.

Purifying selection

The form of natural selection by which alleles with reduced fitness or viability are lost in a population.

Genetic bottleneck for mtDNA transmission

A sampling-effect phenomenon, whereby a small number of mtDNA molecules are the progenitors of all of the copies present in the mature animal. If the bottleneck is sufficiently small, this could result in rapid segregation of new variants by stochastic sampling.

Homoplasmy

The existence of only one mtDNA allele in a cell.

Heteroplasmy

The existence of two or more alleles of mtDNA in a mixed proportion within the cell.

Mitotic segregation

A process by which mitochondrial mutation loads can be randomly skewed owing to the unequal portioning of more mutant mitochondria into one of the daughter cells of a cell division.

McDonald–Kreitman test

A comparison of between-species divergence and within-species polymorphism at replacement and synonymous sites to infer adaptive protein evolution.

Synonymous mutation

A mutation that does not alter the gene product, such as silent changes at third codon positions of protein-coding genes.

Non-synonymous mutation

A mutation that alters the gene product, typically an amino-acid substitution.

Primordial germ cell

(PGC). An undifferentiated diploid cell identifiable in the early embryo. PGCs are the cells from which the mature germ cells develop.

Oogonia

Diploid, differentiated germ cells that give rise to the oocytes.

Balbiani Body

A congregation in the cytoplasm of female germ cells consisting of mitochondria, endoplasmic reticulum and granulofibrillar material. These bodies have been reported in many divergent animal species.

Relaxed replication

Non-stringent control of mtDNA replication during the cell cycle, which might lead to different molecules within the same cell replicating at different rates.

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Stewart, J., Freyer, C., Elson, J. et al. Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease. Nat Rev Genet 9, 657–662 (2008). https://doi.org/10.1038/nrg2396

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