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Mitochondrial DNA genotype-phenotype interactions

A recent study has found that genetic variants in mitochondrial DNA could increase the risk of developing several common diseases, as well as influencing characteristics like height and lifespan.

Mitochondrial DNA

In humans, the mitochondrial genome is 16,569 base pairs long. It encodes 13 proteins, 22 transfer RNAs and 2 ribosomal RNAs. All of these are essential for oxidative phosphorylation and the production of cellular energy. Mitochondrial DNA (mtDNA) is inherited maternally and undergoes negligible population level intermolecular recombination. When humans migrated out of Africa, they acquired mitochondrial single-nucleotide variants (mtSNVs) which define geographical related haplotypes. Some mtSNVs directly affect mitochondrial function. Whereas others are in linkage disequilibrium (LD) with variants known to influence mitochondrial metabolism and have been associated with complex diseases, such as type 2 diabetes.

Initial studies exploring mtDNA association with complex traits were underpowered and yielded conflicting findings. In addition, the lack of genotype calling and quality-control procedures has meant that mtDNA in common diseases has been underexplored. While errors in mtDNA results in mitochondrial diseases, until now there has been little evidence suggesting these variants influence more common diseases.

Genotype-phenotype atlas

In this paper, published in Nature Genetics, researchers at the University of Cambridge developed a new technique to study mtDNA and its relation to human diseases and characteristics. The team specifically harnessed data from the UK Biobank. This included genotyping of 265 mtDNA variants from 488,377 UK Biobank participants.

The team showed that mtDNA influences the risk of a number of diseases and common characteristics. These included type 2 diabetes, multiple sclerosis, liver and kidney function, blood count parameters, life span and height. This demonstrates the role of mtDNA in a range of complex biological pathways.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit at Cambridge expressed:

“If you want a complete picture of common diseases, then clearly you’re going to need to factor in the influence of mitochondrial DNA. The ultimate aim of studies of our DNA is to understand the mechanisms that underlie these diseases and find new ways to treat them. Our work could help identify potential new drug targets.”

Nuclear and mtDNA

Interestingly the team also found correlations between nuclear and mitochondrial genomic structures within subpopulations of Great Britain. In particular, in Scotland, Wales and Northumbria. This suggests that our nuclear and mitochondrial genomes evolve together and interact with each other. One explanation for this is the need for compatibility. The respiratory chain is partly encoded for by mtDNA but also partly by nuclear DNA. Therefore, this makes it important for the genomes to be compatible so the proteins can fit together like a jigsaw. Disruption to this can subtly influence an individual’s health or physiology and thus be disadvantageous from an evolutionary perspective.

These findings have important implications for the success of mitochondrial therapy which involves replacing a mother’s defective mitochondria with those from a donor.

Chinnery explained:

“It looks like our mitochondrial DNA is matched to our nuclear DNA to some extent – in other words, you can’t just swap the mitochondria with any donor, just as you can’t take a blood transfusion from anyone.

Fortunately, this possibility has already been factored into the approach taken by the team at Newcastle who have pioneered this therapy.”

Image credit: By HeitiPaves – canva

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