Wei Wei, Salih Tuna, Michael J. Keogh, Katherine R. Smith, Timothy J. Aitman, F. Lucy Raymond, Mark Caulfield, Ernest Turro, Patrick F. Chinnery and others
- The authors analyse 1526 mother-offspring pairs from rare-disease patients in the 100,000 genomes project, to show that 45% of individuals display heteroplasmy at >1% variant allele frequency (VAF).
- The authors define 3 kinds of variant: transmitted/inherited (present in both mother and offspring and heteroplasmic in at least one; transmitted = mother, inherited = offspring), lost (present in mother, absent in offspring) and de novo (present in offspring, absent in mother). Absence is defined as VAF < 1%.
- Transmitted variants had a much larger heteroplasmic fraction than lost and de novo variants.
- Transmitted VAF correlates with inherited VAF (in logit-transformed space).
- Heteroplasmy transmission/inheritance did not display a significantly skewed distribution in the inter-generational VAF shift, which is compatible with this set of mutations undergoing neutral drift.
- The D-loop had an approximately 4 times higher inter-generational mutation rate per base pair than the rest of the mitochondrial genome, suggesting the existence of stronger selective pressures against mutation on the reset of the genome, or potentially an intrinsically lower de novo mutation rate.
- tRNA, rRNA, and non-synonymous mutations tended to have a lower VAF than D-loop and synonymous mutations, suggesting the existence of selection.
- The authors identified haplogroup-matched (92%) and haplogroup-mismatched (2.3%) groups within their dataset (6% could not be identified). Haplogroup mismatching arises from mixed-race ancestry. The heteroplasmic variants in the mismatched group were significantly more likely to match the ancestry of the nuclear genetic background than the mtDNA background on which the heteroplasmy occurred.
Nice summary!
ReplyDeleteWhat is the difference between "stronger selective pressures against mutation on the rest of the genome" and "potentially an intrinsically lower de novo mutation rate"?
(I suppose reset is a typo).
Hi Ferdinando, I guess my point is simply that if one observes variability in the number of mutations per base-pair in different regions of the mitochondrial genome, that may be because 1) mutations at certain positions of the genome have stronger functional effects, and such mutations may be selectively removed through quality-control pathways (so you see fewer of them); or 2) certain positions, for whatever reason, are more or less susceptible to mutation. (2) could be because there might be e.g. sequences or positions in the genome which are more prone to copying errors, or perhaps are more prone to e.g. oxidative damage. Both of the hypotheses potentially explain differences in the mutational load per bp.
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