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Hum Reprod. 2017 May 1;32(5):1100-1107. doi: 10.1093/humrep/dex051.

Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis.

Author information

1
Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna 40126, Italy.
2
Institute of Atmospheric Pollution Research, National Research Council, C/O Physics Department, University of Bari 'Aldo Moro', Bari 70132, Italy.
3
Medical Genetics Unit, S. Orsola Hospital, University of Bologna, Bologna 40126, Italy.
4
Current address: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
5
Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari 'Aldo Moro',Bari70132, Italy.
6
Reproductive Medicine Unit, S.I.S.Me.R., Bologna 40138, Italy.

Abstract

STUDY QUESTION:

Does selection for mtDNA mutations occur in human oocytes?

SUMMARY ANSWER:

We provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs).

WHAT IS KNOWN ALREADY:

Several lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature.

STUDY DESIGN, SIZE, DURATION:

In this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Whole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO).

MAIN RESULTS AND THE ROLE OF CHANCE:

Unlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB.

LARGE SCALE DATA:

N/A.

LIMITATIONS, REASONS FOR CAUTION:

The sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased.

WIDER IMPLICATIONS OF THE FINDINGS:

This work opens the way to the study of the correlation between mtDNA mutations, mitochondrial capacity and viability of oocytes.

STUDY FUNDING/COMPETING INTEREST(S):

This work was supported by a SISMER grant. Laboratory facilities and skills were freely provided by SISMER, and by the Alma Mater Studiorum, University of Bologna. The authors have no conflict of interest to disclose.

KEYWORDS:

first and second polar body; heteroplasmy; human oocytes; mtDNA variants; purifying selection

PMID:
28333293
PMCID:
PMC5850138
DOI:
10.1093/humrep/dex051
[Indexed for MEDLINE]
Free PMC Article

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