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

• DOI: 10.1016/j.celrep.2016.06.023
• Publication Date: 2016-07-02T14:49:43Z
• Authors: Auke B.C. Otten; Tom E.J. Theunissen; Josien G. Derhaag; Ellen H. Lambrichs; Iris B.W. Boesten; Marie Winandy; Aafke P.A. van Mo...; Katsiaryna Tarbas...; Erez Raz; Mike Gerards; Jo M. Vanoevelen; Bianca J.C. van d...; Marc Muller; Hubert J.M. Smeets
• Keywords: DNA Replication; 0301 basic medicine; TRANSMISSION; QH301-705.5; Gene Dosage; HUMAN OOCYTES; Embryonic Development; MAMMALIAN MITOCHONDRIAL-DNA; DNA, Mitochondrial; 03 medical and health sciences; Oogenesis; RAPID SEGREGATION; Animals; Biology (General); Zebrafish; Cell Differentiation; DNA COPY NUMBER; OOGENESIS; RANDOM GENETIC DRIFT; Mitochondria; Germ Cells; REPLICATION; Mutation; Oocytes; HETEROPLASMY; MATERNAL AGE; Female

We 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 × 10(6) 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.