Abstract

Hannah O’Keefe1,2 , Rachel Queen3, Phillip Lord2, Joanna L. Elson1,4*

1. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ ,

United Kingdom

2. School of Computing, Newcastle University, Newcastle-upon-Tyne, NE4 5TG , United Kingdom

3. Bioinformatics Core Facility, Newcastle University, United Kingdom

4. Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa

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 under-studied 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. 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.