Genome Evolution and Ageing

Since the 1970's the involvement of mitochondria in the ageing process has been recognized. As we age, there is clear evidence of the accumulation of a mosaic pattern of cells from different tissues that are deficient in the enzymatic capacity of the mitochondrial respiratory chain. Much of the research attention has focused on either the action of radical oxygen species, or the accumulation of somatic mutations and/or chromosomal rearrangements in mitochondrial DNA and their physiological effects. However, new hypotheses on the unusual evolutionary balance between the nuclear and mitochondrial genome are being investigated, which may have implication on the ageing process.

All aerobic eukaryotic cells maintain a distinct chromosome within the cell's mitochondria. This is the remnant chromosome of the α-proteobacterial ancestor that entered into the symbiotic relationship with the archeabacterial ancestor of our nuclear chromosomes. This association had led to our current unusual genetic system, whereby the recombining diploid genome of the nucleus must continually co-evolve with the physically isolated haploid, bacterial-like genome of the mitochondria. It has long been predicted that conflicts would arise in such a system, and indeed mito-nuclear incompatibilities have been described more extensively in Drosophila fruitfly strains, leading to accelerated ageing and other effects in the flies.

The lab focuses on two main themes:

Mito-nuclear communication, mismatch and ageing

We are studying the extent to which these incompatibilities also may play a role in ageing in mammals, using the laboratory mouse as the model organism. Divergent mouse mitochondrial DNA sequences have been bred into the common C57Bl/6N nuclear background to determine the effect on the mitochondrial function, efficiency, and the resulting effects on organismal ageing. We are also investigating intriguing differences between the closely related C57Bl/6N and C57Bl/6J strains, which seem to have profound effects on the mouse's ability to tolerate mitochondrial dysfunction.

Mitochondrial mutations and ageing

The polymorphisms in the sub-strains all had their start as spontaneous mutations along the mouse lines' ancestry. Recent research using Next Generation Sequencing platforms has revealed a previously-unacknowledged level of somatic mitochondrial mutations within healthy individuals. These mutations appear to, on a cell by cell basis, lead to mitochondrial dysfunction phenotypes during normal human ageing.  We are continuing to study the effects of the acquisition and transmission of mitochondrial DNA mutations in the mouse, and to what extent these mutations, and the resulting mitochondrial-nuclear genome interactions play in the pathophysiology and ageing process.

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