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

Area of Science:

• Mitochondrial genetics
• Human reproduction
• Evolutionary biology

Background:

• Mitochondrial DNA (mtDNA) variation in the germline is thought to be under purifying selection in Metazoa.
• This selection acts as a filter, influencing mtDNA's evolutionary path.
• The precise location and mechanism of this germline filter remain unclear.

Purpose of the Study:

• To investigate the existence and timing of purifying selection on mtDNA mutations in human oocytes.
• To determine if selection acts on mtDNA variants during oocyte development.

Main Methods:

• Sequenced 60 mitochondrial genomes from oocytes, first and second polar bodies (PBs), and peripheral blood of nine women.
• Utilized whole genome amplification on single cells and Sanger sequencing.
• Assessed variant pathogenicity scores using MutPred, Polyphen, and SNPs&GO.

Main Results:

• No significant difference in mtDNA substitution rates was observed between first and second PBs.
• A significant difference in pathogenicity scores of protein-coding sequences was found between first and second PBs.
• Second PBs showed no significant difference in pathogenic scores compared to oocyte and blood sequences, indicating a filtering event.

Conclusions:

• Statistical evidence supports purifying selection acting on mtDNA mutations in human oocytes.
• This selection occurs between the expulsion of the first and second polar bodies.
• Findings open avenues for studying mtDNA mutations' impact on oocyte viability and mitochondrial function.