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  4. Reanalysis of mtDNA mutations of human primordial germ cells (PGCs) reveals NUMT contamination and suggests that selection in PGCs may be positive
 
research article

Reanalysis of mtDNA mutations of human primordial germ cells (PGCs) reveals NUMT contamination and suggests that selection in PGCs may be positive

Fleischmann, Zoe
•
'Heureux, Auden Cote-L
•
Franco, Melissa
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December 16, 2023
Mitochondrion

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 crossspecific 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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Type
research article
DOI
10.1016/j.mito.2023.10.005
Web of Science ID

WOS:001138874400001

Author(s)
Fleischmann, Zoe
'Heureux, Auden Cote-L
Franco, Melissa
Oreshkov, Sergey
Annis, Sofia
Khrapko, Mark
Aidlen, Dylan
Popadin, Konstantin  
Woods, Dori C.
Tilly, Jonathan L.
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Date Issued

2023-12-16

Publisher

Elsevier Sci Ltd

Published in
Mitochondrion
Volume

74

Article Number

101817

Subjects

Life Sciences & Biomedicine

•

Mtdna

•

Numt Contamination

•

Positive Selection

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPFELLAY  
FunderGrant Number

U.S. National Institutes of Health

R01-HD091439

National Science Foundation

NSF 1750996

Russian Science Foundation

21-75-20143

Available on Infoscience
February 21, 2024
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/205019
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