What can a comparative genomics approach tell us about the pathogenicity of mtDNA mutations in human populations?

Hannah O'Keefe,Rachel Queen,Joanna L Elson,Phillip Lord

doi:10.1111/eva.12851

Abstract

Mitochondrial disorders are heterogeneous, showing variable presentation and penetrance. Over the last three decades, our ability to recognize mitochondrial patients and diagnose these mutations, linking genotype to phenotype, has greatly improved. However, it has become increasingly clear that these strides in diagnostics have not benefited all population groups. Recent studies have demonstrated that patients from genetically understudied populations, in particular those of black African heritage, are less likely to receive a diagnosis of mtDNA disease. It has been suggested that haplogroup context might influence the presentation and penetrance of mtDNA disease; thus, the spectrum of mutations that are associated with disease in different populations. However, to date there is only one well‐established example of such an effect: the increased penetrance of two Leber's hereditary optic neuropathy mutations on a haplogroup J background. This paper conducted the most extensive investigation to date into the importance of haplogroup context on the pathogenicity of mtDNA mutations. We searched for proven human point mutations across 726 multiple sequence alignments derived from 33 non‐human species absent of disease. A total of 58 pathogenic point mutations arise in the sequences of these species. We assessed the sequence context and found evidence of population variants that could modulate the phenotypic expression of these point mutations masking the pathogenic effects seen in humans. This supports the theory that sequence context is influential in the presentation of mtDNA disease and has implications for diagnostic practices. We have shown that our current understanding of the pathogenicity of mtDNA point mutations, primarily built on studies of individuals with haplogroups HVUKTJ, will not present a complete picture. This will have the effect of creating a diagnostic inequality, whereby individuals who do not belong to these lineages are less likely to receive a genetic diagnosis.

Highlights

Mitochondria are involved in a range of cellular functions such as apoptosis and cell death, calcium buffering and the generation of ATP by oxidative phosphorylation
It is estimated that the prevalence of mitochondrial disorders is ~1/4,300 within the adult European population and over 2/3 of these will be due to an Mitochondrial DNA (mtDNA) mutation (Gorman et al, 2015)
To expand our understanding of sequence context on the ex‐ pression and penetrance of mitochondrial mutation, this study aims to continue the work of Queen et al (2017) by identifying whether pathogenic point mutations are present in the remaining 21 tRNA genes and how the pathogenic effect seen in humans is suppressed

Summary

Introduction

Mitochondria are involved in a range of cellular functions such as apoptosis and cell death, calcium buffering and the generation of ATP by oxidative phosphorylation. It should be noted that mtDNA accumulates single nucleotide variants (SNVs) at a higher rate than nuclear DNA (Song et al, 2005) This is useful for those looking at population histories as a sufficient phylogenetic signal can accumulate to study population histories (Howell, Elson, Howell, & Turnbull, 2007). All this variation presents chal‐ lenges in the linkage of genotype to phenotype in the context of mtDNA disease. | 1913 discrepancies in the rate of diagnosis in the context of disease arising from mtDNA mutations (van der Westhuizen et al, 2015) This may be because either the pathogenic mutations or their presentation differs from those found in Caucasian Europeans. Additional evidence to support the importance of mitochondrial sequence context in the expression and penetrance of pathogenic mtDNA mutations is presented

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Conclusion