Thursday, 12 June 2014

Mitochondrial genomes: anything goes

Mitochondrial genomes: anything goes

This is a really nice review of the crazy diversity in physical and genetic structure of mitochondrial genomes throughout eukaryotes. Because, in the early days, research focussed on animals, it was a while before this diversity became apparent. For example, it was thought that all mtDNA molecules were circular, and mapped circularly; there's now evidence for mtDNAs that map circularly but consist of many linearly concatenated sections, and mtDNAs that map linearly, and even some with multiple "chromosomes".

There's great diversity in mtDNA length and gene content, and not an obvious correlation between the two. Plasmodium parasites have mtDNA about 6 kbp long; rice's is 490 kbp (plant mtDNA in general is a bit crazy). Individual mitochondrial genes are often highly noncontiguous, broken up into many pieces that are jumbled and may lie on either strand of the mtDNA. Some interesting hypotheses are raised as to the reasons for this diversity, including horizontal transfer of mitochondrial genes, the special case of parasitism, and "competence" of plant mtDNA whereby genetic information from chloroplasts, nuclear, viral, and as-yet-unknown sources has been assimilated. Well worth a read!

mtDNA Segregation in Heteroplasmic Tissues Is Common In Vivo and Modulated by Haplotype Differences and Developmental Stage

mtDNA Segregation in Heteroplasmic Tissues Is Common In Vivo and Modulated by Haplotype Differences and Developmental Stage

Different mtDNA haplotypes can coexist inside the same cell, as a result of mutation, or as a consequence of recently-proposed medical therapies. Several studies have shown that haplotypes involving harmful mutations experience segregation -- they are outcompeted in cells over time, perhaps due to mitochondrial quality control. But little evidence exists exploring segregation between two natural and functional haplotypes, except in one model case. In medical applications, such a mixture of natural, functional haplotypes may be expected to arise, as cells will contain haplotype pairs sampled from a diverse population.

This research constructed new model mice, with their cells containing (a) mtDNA from mice captured from wild populations in Europe paired with (b) mtDNA from lab mice. This wild mtDNA was sequenced, and four different samples were chosen (a1), (a2), (a3), (a4), so that the genetic differences in the pairs (a1)-(b) ... (a4)-(b) represented the expected differences in samples from a human population. Measurements of the proportion of (a) in many different cell types was measured, and new mathematical modelling and statistics were used to powerfully compare results from across many different mice.

Segregation, surprisingly, was very common, across a wide range of tissues, including post-mitotic tissues like heart and muscle, of particular relevance for mitochondrial disease. It was often observed that (a) came to dominate over (b) (though sometimes (b) won), and the rms speed at which this domination occurred was proportional to the genetic distance between (a) and (b). Furthermore, new dynamic regimes of segregation were found, including a constant rate of proliferation of one haplotype over another, a constant proliferation during early development then stabilisation, and a constant proliferation during much of life then stabilisation in old age.