Cellular Heterogeneity in the Level of mtDNA Heteroplasmy in Mouse Embryonic Stem Cells

http://www.sciencedirect.com/science/article/pii/S2211124715011730


Jitesh Neupane, Sabitri Ghimire, Mado Vandewoestyne, Yuechao Lu, Jan Gerris, Rudy Van Coster, Tom Deroo, Dieter Deforce, Stijn Vansteelandt, Petra De Sutter, Björn Heindryckx

Recent work has shown that non-pathological mtDNA variants (haplotypes) can show preferential expansion, in vivo. This is contrary to the common belief that nonpathological mutations exhibit neutral genetic drift. The authors of this study sought to study this phenomenon at the single-cell level using Mouse Embryonic Stem Cells (ESCs).

The authors established sets of cell lines, with differing proportions of two mtDNA haplotypes (NZB and BALB). The parental mice were themselves heteroplasmic in these two mtDNA haplotypes. By successive passage of the cells, the authors measure the ratio of the two haplotypes (heteroplasmy) with time. They find that, regardless of the initial ratio, the NZB haplotype tends to dominate over BALB with time (~12% over 30 passages), in this system. Furthermore, upon differentiation, cells tended to become more heterogeneous in heteroplasmy, and tended to shift back in heteroplasmy towards BALB (~8% reduction).

The results are significant, as they show that apparently neutral haplotypes have some kind of selective pressure. These dynamics are not necessarily straightforward, and seem to have some dependence on the system under study.