Somatic Retrotransposition as a Driver of Aging

Although the pathogenesis of some aging-related diseases has been defined in terms of dynamic genome instability (e.g. cancer), the genetic basis of aging-related phenomena is widely thought of as a static process, where genes and regulatory sequences that govern health are determined at fertilization. Retrotransposition, the mechanism by which endogenous DNA elements proliferate within the genome, has long been recognized as contributing to genomic diversity and genetic disease; however, it has largely been overlooked as a driver of age-related disease. Previously, retrotransposition events were largely thought of as predominantly germ-line phenomena, whereby the presence of a novel retrotransposon insertion is propagated uniformly throughout the organism. Recent advances in genetic sequencing technology have overturned this model, providing evidence of somatic retrotransposition that occurs at a startling and previously unappreciated frequency. Using state-of-the-art sample enrichment and deep sequencing techniques, Baillie et al. (Nature 2011) identified over 20,000 individual somatic retrotransposon events in the hippocampus of three healthy human donors. The implication of this astonishing finding is that the genome is in a state of dynamic mosaicism, where the addition of retrotransposable elements occurs non-uniformly throughout life. That these findings were made in apparently healthy donor tissue suggests a profound ability of the organism to buffer against such endogenous genetic mutations. Still, the influence of somatic mutations on organismal aging and tissue function is unknown. The overall goal of this proposal is to define the extent of somatic retrotransposition in aging, and to determine the impact of these events on organismal longevity and physiology.