Fig. 3: Cryptic mtDNA mutations, unlike other types, can expand neutrally. | Nature Communications

Fig. 3: Cryptic mtDNA mutations, unlike other types, can expand neutrally.

From: Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species

Fig. 3

We show the SFS for mutations classified by their potential pathology, as well as the RBC-difference (see ‘Methods’ section) which shows the magnitude of difference between these SFSs (for a breakdown of the number of cells and mutations represented in each SFS, see Table S5). a All cryptic mutations taken from healthy human pancreas tissue30 show no significant evidence of selection in either the non-synonymous/synonymous ratio or in the RBC-difference between cSFSs, indicating these mutations are not under selective pressure. b When we consider all non-cryptic mutations, we see a non-synonymous/synonymous ratio significantly < 1 (two-sided Fisher’s exact test p < 10−8) as well as a significant shift of the SFS of high pathogenicity mutations as compared to synonymous and low pathogenicity mutations (two-sided Mann–Whitney U test p < 10−6, 10−3, respectively), though we do not see evidence for selection against low pathogenicity mutations compared to synonymous, suggesting that mutations occurring on the germline or during development experience selective pressure based on the level of dysfunction they cause. c The SFS for all mutations found in cells from culture43 show a similar selection pattern to non-cryptic mutations taken from tissue samples. They have a non-synonymous/synonymous ratio significantly < 1 (two-sided Fisher’s exact test p < 10−3) and the spectra of high pathogenicity mutations show a significant shift towards lower heteroplasmies when compared to synonymous and low pathogenicity mutations (two-sided Mann–Whitney U test p < 10−4, 0.05, respectively). d Though we cannot score the potential pathogenicity of non-synonymous mutations in mice, we look at the difference in the cSFS of synonymous and non-synonymous mutations finding no evidence of selection (two-sided Mann–Whitney U test p > 0.05). We do, however, find a significant lack of non-synonymous mutations at heteroplasmies h > 10% (two-sided Fisher’s exact test p < 10−4).

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