Title:
Genetics of Mitochondrial Genome ： Maternal Inheritance and Rapid Segregation

Hiromichi Yonekawa, Ph.D.
Fundamental Technology Center , The Tokyo Metropolitan Institute of Medical Science

Abstract:
Although the mutation rate of mitochondrial genome (mtDNA) is high, almost all of the mtDNA molecules in a normal individual is identical. This phenomenon is called homoplasmy. Homoplasmy of mtDNA is maintained by two genetic events unique to mtDNA: maternal inheritance and rapid segregation. It had been believed that mtDNA is maternally transmitted. In early 1990s, however, considerable discussion on this issue had arisen, since Gyllensten et al. (1991) reported that paternal mtDNA is also inherited in interspecific hybrids between Mus musculus and Mus spretus . To address this issue, we developed an assay that can detect sperm mtDNA in a single mouse embryo. In intraspecific hybrids of Mus musculus , paternal mtDNA was detected only by the early pronucleus stage, showing that maternal inheritance is strictly maintained in the intraspecific hybrids. By contrast, in interspecific hybrids between M. musculus and Mus spretus , paternal mtDNA was detected throughout development from pronucleus stage to adulthood. We conclude that cytoplasmic genomes are transmitted uniparentally in intraspecific crosses in mammals as in Chlamydomonas and that the leakage of parental mtDNA is limited to interspecific crosses, which rarely occur in nature (Kaneda et al., 1995). Next, we traced the fate of paternal mtDNA retained in the interspecific hybrids. In the next generation, we could not find any paternal mtDNA in the N 2 hybrids. This showed that maternal inheritance is strict even in interspecific hybrids, when at least two generations are passed (Shitara et al., 1998, 2000).
The next issue to address is rapid segregation of mtDNA variants between generations. Observations of rapid shifts in mtDNA variants between generations prompted the creation of the bottleneck theory. A prevalent hypothesis is that a massive reduction in mtDNA content during early oogenesis leads to the bottleneck. To test this, we estimated the mtDNA copy number in single germline cells and in single somatic cells of early embryos in mice. Primordial germ cells (PGCs) show consistent, moderate mtDNA copy numbers across developmental stages, whereas primary oocytes demonstrate substantial mtDNA expansion during early oocyte maturation. We conclude that the mitochondrial bottleneck is not due to a drastic decline in mtDNA copy number in early oogenesis but rather to a small effective number of segregation units for mtDNA in mouse germ cells. These results provide new information for mtDNA segregation models and for understanding the recurrence risks for mtDNA diseases (Cao et al., 2007; Cao et al., 2009).

References:
Gyllensten, U. et al. , Nature 352, 255-257, 1991.

Kaneda, H. et al. , Proc. Natl. Acad. Sci. USA, 92, 4542-4546, 1995

Shitara, H. et al. , Genetics, 148, 851-858, 1998

Shitara, H. et al. , Genetics, 156, 1277-1284, 2000

Cao, L. et al. , Nature Genetics 39, 386 ? 390, 2007

Cao, L. et al . PLoS Genet. 5: e1000756, 2009