Differences in Strength and Timing of the mtDNA Bottleneck between Zebrafish Germline and Non-germline Cells

• The zebrafish model is highly suitable to study the mtDNA bottleneck mechanism
• Zebrafish oocytes have a high mtDNA number with large intra-individual variation
• Size and timing of the bottleneck differ between germline and non-germline cells
• Low mtDNA amounts in germ cells can explain the occurrence of de novo mutations

SummaryWe studied the mtDNA bottleneck in zebrafish to elucidate size, timing, and variation in germline and non-germline cells. Mature zebrafish oocytes contain, on average, 19.0 × 106 mtDNA molecules with high variation between oocytes. During embryogenesis, the mtDNA copy number decreases to ∼170 mtDNA molecules per primordial germ cell (PGC), a number similar to that in mammals, and to ∼50 per non-PGC. These occur at the same developmental stage, implying considerable variation in mtDNA copy number in (non-)PGCs of the same female, dictated by variation in the mature oocyte. The presence of oocytes with low mtDNA numbers, if similar in humans, could explain how (de novo) mutations can reach high mutation loads within a single generation. High mtDNA copy numbers in mature oocytes are established by mtDNA replication during oocyte development. Bottleneck differences between germline and non-germline cells, due to early differentiation of PGCs, may account for different distribution patterns of familial mutations.

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