Monday, 16 November 2015

Single Nucleotides in the mtDNA Sequence Modify Mitochondrial Molecular Function and Are Associated with Sex-Specific Effects on Fertility and Aging

M. Florencia Camus, Jochen B.W. Wolf, Edward H. Morrow, Damian K. Dowling 

In this study, the authors bred flies containing the same nuclear genome, but different mitochondrial genomes, corresponding to different mitochondrial haplotypes from across the world. In doing this, the authors were able to demonstrate how the mitochondrial genotype can affect the phenotype of the fly, without considering the effect of nuclear DNA.

In 7 of the 13 haplotypes considered, the authors found that mtDNA copy number was increased in females above males, with the effect becoming stronger with age. Conversely (and strikingly), across 9 of the 13 mitochondrial genes tested, mitochondrial gene expression was higher in males, in all 9 genes, across all 13 haplotypes.

The authors found that mean longevity was higher in female flies. This intriguing finding, although only correlative, suggests that differences in the expression of the mitochondrial genome between males and females, may result in increased female longevity, as this may provide a selective advantage for such haplotypes (as mtDNA is maternally inherited). As an additional curiosity, the authors found that the Brownsville haplotype in this nuclear background induces cytoplasmic male sterility (male infertility, due to an interaction between mtDNA and nucleus). This is the only known case in metazoans.

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

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.