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The resilience of the mitochondrial genome (mtDNA) to a high mutational pressure depends, in part, on negative purifying selection in the germline. A paradigm in the field has been that such selection, at least in part, takes place in primordial germ cells (PGCs). Specifically, Floros et al. (Nature Cell Biology 20: 144–51) reported an increase in the synonymity of mtDNA mutations (a sign of purifying selection) between early-stage and late-stage PGCs. We re-analyzed Floros’ et al. data and determined that their mutational dataset was significantly contaminated with single nucleotide variants (SNVs) derived from a nuclear sequence of mtDNA origin (NUMT) located on chromosome 5. Contamination was caused by co-amplification of the NUMT sequence by cross-specific PCR primers. Importantly, when we removed NUMT-derived SNVs, the evidence of purifying selection was abolished. In addition to bulk PGCs, Floros et al. reported the analysis of single-cell late-stage PGCs, which were amplified with different sets of PCR primers that cannot amplify the NUMT sequence. Accordingly, there were no NUMT-derived SNVs among single PGC mutations. Interestingly, single PGC mutations show a decrease of synonymity with increased intracellular mutant fraction. More specifically, nonsynonymous mutations show faster intracellular genetic drift towards higher mutant fraction than synonymous ones. This pattern is incompatible with predominantly negative selection. This suggests that germline selection of mtDNA mutations is a complex phenomenon and that the part of this process that takes place in PGCs may be predominantly positive. However counterintuitive, positive germline selection of detrimental mtDNA mutations has been reported previously and potentially may be evolutionarily advantageous.
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Numbers of Mutations within Multicellular Bodies: Why It Matters
Multicellular organisms often start life as a single cell. Subsequent cell division builds the body. Each mutational event during those developmental cell divisions carries forward to all descendant cells. The overall number of mutant cells in the body follows the Luria–Delbrück process. This article first reviews the basic quantitative principles by which one can understand the likely number of mutant cells and the variation in mutational burden between individuals. A recent Fréchet distribution approximation simplifies calculation of likelihoods and intuitive understanding of process. The second part of the article highlights consequences of somatic mutational mosaicism for understanding diseases such as cancer, neurodegeneration, and atherosclerosis.
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- Award ID(s):
- 1939423
- PAR ID:
- 10417697
- Date Published:
- Journal Name:
- Axioms
- Volume:
- 12
- Issue:
- 1
- ISSN:
- 2075-1680
- Page Range / eLocation ID:
- 12
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/axioms12010012
