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Extreme heterogeneity of human mitochondrial DNA from organelles to populations

Nature Reviews Genetics volume 22, pages 106–118 (2021)Cite this article

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Abstract

Contrary to the long-held view that most humans harbour only identical mitochondrial genomes, deep resequencing has uncovered unanticipated extreme genetic variation within mitochondrial DNA (mtDNA). Most, if not all, humans contain multiple mtDNA genotypes (heteroplasmy); specific patterns of variants accumulate in different tissues, including cancers, over time; and some variants are preferentially passed down or suppressed in the maternal germ line. These findings cast light on the origin and spread of mtDNA mutations at multiple scales, from the organelle to the human population, and challenge the conventional view that high percentages of a mutation are required before a new variant has functional consequences.

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Fig. 1: Human mitochondrial DNA.
Fig. 2: Nuclear–mitochondrial sequences and the paternal inheritance of mtDNA.
Fig. 3: How mitochondrial DNA heteroplasmy levels change.
Fig. 4: The role of mtDNA in human diseases.

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Acknowledgements

J.B.S. is supported by the Max Planck Society and a project grant from the United Mitochondrial Disease Foundation. P.F.C. is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK National Institute for Health Research (NIHR) Senior Investigator, who receives support from the UK Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease, the Leverhulme Trust (RPG-2018-408) and the NIHR Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health and Social Care.

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Authors and Affiliations

  1. Max Planck Institute for Biology of Ageing, Cologne, Germany

    James B. Stewart

  2. Wellcome Centre for Mitochondrial Research, Newcastle University Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    James B. Stewart

  3. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Patrick F. Chinnery

  4. Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK

    Patrick F. Chinnery

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Glossary

Heteroplasmy

A mixture of wild-type and mutant mitochondrial DNA. The proportion of mutant and wild-type molecules is often referred to as the heteroplasmy percentage, heteroplasmy frequency or heteroplasmy burden (see the glossary description for ‘allele frequency’).

Nuclear–mitochondrial sequences

Segments of mitochondrial DNA that have translocated into nuclear chromosomes of the cell.

Relaxed replication

Replication of mitochondrial DNA throughout the cell cycle and is independent of nuclear division.

D-loop

Approximately 1.1 kb of non-coding mitochondrial DNA in humans involved in the initiation of transcription and mitochondrial DNA replication. The D stands for ‘displacement’.

Selfish replication

When a genotype is preferentially propagated despite have a deleterious effect on the organism or population.

Allele frequency

Also known as variant allele frequency. The proportion of alleles carrying a specific variant. This term can be used to describe the proportion of individuals with a homoplasmic mitochondrial DNA variant in a population group, or the proportion of mitochondrial DNA molecules within an individual person, organ, cell or mitochondrion. The latter is the same as the heteroplasmy fraction, or heteroplasmy burden.

Vegetative segregation

Changes in heteroplasmy that occur through the unequal partitioning of different mitochondrial genotypes during cell division.

Homoplasmy

When all mitochondrial DNA molecules are identical.

Cybrid

A cellular model system usually used to study the effects of mitochondrial DNA variants or mutations on the same nuclear genetic background.

Mitophagy

A specific form of autophagy in which mitochondria are engulfed by a lysosome and destroyed.

Clonal expansion

When a mitochondrial DNA molecule containing a specific variant or haplotype increases in allele frequency.

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Stewart, J.B., Chinnery, P.F. Extreme heterogeneity of human mitochondrial DNA from organelles to populations. Nat Rev Genet 22, 106–118 (2021). https://doi.org/10.1038/s41576-020-00284-x

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