Comparing Phylogeny and the Predicted Pathogenicity of Protein Variations Reveals Equal Purifying Selection across the Global Human mtDNA Diversity

Abstract

We used detailed phylogenetic trees for human mtDNA, combined with pathogenicity predictions for each amino acid change, to evaluate selection on mtDNA-encoded protein variants. Protein variants with high pathogenicity scores were significantly rarer in the older branches of the tree. Variants that have formed and survived multiple times in the human phylogenetics tree had significantly lower pathogenicity scores than those that only appear once in the tree. We compared the distribution of pathogenicity scores observed on the human phylogenetic tree to the distribution of all possible protein variations to define a measure of the effect of selection on these protein variations. The measured effect of selection increased exponentially with increasing pathogenicity score. We found no measurable difference in this measure of purifying selection in mtDNA across the global population, represented by the macrohaplogroups L, M, and N. We provide a list of all possible single amino acid variations for the human mtDNA-encoded proteins with their predicted pathogenicity scores and our measured selection effect as a tool for assessing novel protein variations that are often reported in patients with mitochondrial disease of unknown origin or for assessing somatic mutations acquired through aging or detected in tumors.

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

“…4B). The parameterizations in our data are similar to the previous study (28). We also confirmed that the observed value for polymorphisms with very high pathogenicity scores (>0.9) deviates from the exponential fit, indicating that forces other than purifying selection might have acted on these variants (28).…”

“…In the absence of natural selection, mutations are similar to random draws from all possible changes in the genome, so the selection function is expected to be equal to a constant, 1. Consistent with previous study (28), the selection function of polymorphism can be modeled by a simple function of exponential decay (R 2 = 0.9758, P = 4.71e-06; Fig. 4B).…”

“…To further quantitatively compare the effect of natural selection on these two types of mtDNA variants, we defined a selection function by dividing the observed distribution of pathogenicity scores for all NS heteroplasmies (or polymorphisms) by the expected distribution of pathogenicity scores from all possible NS variants. This quantitative method has been previously applied to mitochondrial polymorphisms (28). In the absence of natural selection, mutations are similar to random draws from all possible changes in the genome, so the selection function is expected to be equal to a constant, 1.…”

“…Interestingly, in contrast to polymorphism, it has an additional constant very close to 1, indicating that purifying selection is too weak to effectively remove pathogenic heteroplasmies, likely due to their low frequency inside the cells. Using the selection functions for both polymorphisms and heteroplasmies, the relative effect of selection on two different amino acid variations could be assessed by a ratio of the exponential functions for the two pathogenicity scores (28). For example, a population polymorphic variant with a pathogenicity score of 0.8 is subject to ∼2× stronger purifying selection than a polymorphic variant with a score of 0.6.…”

“…To explore the pathogenicity of mitochondrial heteroplasmy on a broader basis, we applied computational methods to predict the deleterious effect of nonsynonymous (NS) and tRNA mutations. For NS heteroplasmy, we first defined pathogenicity scores for all possible NS changes in the mtDNA with the MutPred algorithm (27,28). The pathogenicity score ranges from 0 to 1 with a higher pathogenicity score indicating greater likelihood of being pathogenic.…”