When man got his mtDNA deletions?

Abstract

Somatic mtDNA mutations and deletions in particular are known to clonally expand within cells, eventually reaching detrimental intracellular concentrations. The possibility that clonal expansion is a slow process taking a lifetime had prompted an idea that founder mutations of mutant clones that cause mitochondrial dysfunction in the aged tissue might have originated early in life. If, conversely, expansion was fast, founder mutations should predominantly originate later in life. This distinction is important: indeed, from which mutations should we protect ourselves - those of early development/childhood or those happening at old age? Recently, high-resolution data describing the distribution of mtDNA deletions have been obtained using a novel, highly efficient method (Taylor et al., ). These data have been interpreted as supporting predominantly early origin of founder mutations. Re-analysis of the data implies that the data actually better fit mostly late origin of founders, although more research is clearly needed to resolve the controversy.

Figure 1

The ‘slow’ and the ‘fast’ expansion scenarios and the predicted changes in the diversity and extent of expansion of mtDNA mutations with age. Diversity and extent of expansion can be directly measured and used to distinguish between the two scenarios. mtDNA molecules with different deletions are depicted by small circles of different bright colors. Wild-type mtDNA molecules and cells that never get mutations are not shown for simplicity. Of course in a real tissue, mutant cells are surrounded by a great majority of nonmutant cells.

Figure 2

The observed changes in diversity and extent of expansion of mtDNA mutations in brain with age in Taylor et al. data. (A) Diversity of mtDNA deletions (number of deletion types per 10¹⁰ mtDNA) shows strong increase with age (P < 0.0003), corroborating the ‘fast’ expansion scenario (Fig. 1B). (B) The extent of expansion shows excessive variance and does not seem to support any of the two scenarios (neither ‘fast’ nor ‘slow’) to any significant extent. Interpretation of these data requires more detailed analysis.