A broad comparative genomics approach to understanding the pathogenicity of Complex I mutations

Galya V Klink,Hannah O'Keefe,Georgii A Bazykin,Amrita Gogna,Joanna L Elson

doi:10.1038/s41598-021-98360-7

Abstract

Disease caused by mutations of mitochondrial DNA (mtDNA) are highly variable in both presentation and penetrance. Over the last 30 years, clinical recognition of this group of diseases has increased. It has been suggested that haplogroup background could influence the penetrance and presentation of disease-causing mutations; however, to date there is only one well-established example of such an effect: the increased penetrance of two Complex I Leber's hereditary optic neuropathy mutations on a haplogroup J background. This paper conducts the most extensive investigation to date into the importance of haplogroup context in the pathogenicity of mtDNA mutations in Complex I. We searched for proven human point mutations across more than 900 metazoans finding human disease-causing mutations and potential masking variants. We found more than a half of human pathogenic variants as compensated pathogenic deviations (CPD) in at least in one animal species from our multiple sequence alignments. Some variants were found in many species, and some were even the most prevalent amino acids across our dataset. Variants were also found in other primates, and in such cases, we looked for non-human amino acids in sites with high probability to interact with the CPD in folded protein. Using this “local interactions” approach allowed us to find potential masking substitutions in other amino acid sites. We suggest that the masking variants might arise in humans, resulting in variability of mutation effect in our species.

Highlights

Mitochondria are maternally inherited[1], which means the evolution of mitochondrial DNA is marked by the emergence of distinct lineages, called haplogroups[2,3]
If a proven point mutation associated with disease in humans is present in non-human animals but they do not have a phenotypic manifestation of disease, exploring the surrounding sequence context can give us insight into the importance of haplogroup context in the presentation and manifestation of mitochondrial DNA (mtDNA) disease
Twelve substitutions of the amino acids in ND1 that are pathogenic in humans that occurred on our phylogenetic tree were not seen in mammals, with five being seen in vertebrates and seven in invertebrates

Summary

Introduction

Mitochondria are maternally inherited[1], which means the evolution of mitochondrial DNA (mtDNA) is marked by the emergence of distinct lineages, called haplogroups[2,3]. Kern and K ondrashov[12] used single sequences from 106 species, identifying 52 ‘pathogenic mutations’ across the mt-tRNAs; [12], the existence of an accepted methodology to link genotype to phenotype had not yet become available at the time of publication of either of these studies. These prior studies looked at purported disease-causing mutations with weak evidence to support a link between the mtDNA variants and disease in humans, many of their examples were later demonstrated to be population variants

Methods

Results

Conclusion