Evidence for Transposons to be Important in Differences in Dog Longevity by Breed
Inadvertent and deliberate breeding programs in domesticated animals have engineered great diversity into single species. Different breeds of dogs exhibit radically different life spans, for example, and this natural experiment may allow some insight into the relative importance of various mechanisms of aging. Research suggests that transposon activity is an important factor in determining the longevity of a dog breed, as outlined here. Transposons are relics of ancient viral infections, DNA sequences capable of hijacking cell machinery to copy themselves across the genome. In youth, transposon activity is suppressed, but with advancing age their activity increases as a consequence of epigenetic changes, acting as a source of mutational damage and disruption of cell activities.
Within a species, larger individuals often have shorter lives and higher rates of age-related disease. Despite this well-known link, we still know little about underlying age-related epigenetic differences, which could help us better understand inter-individual variation in aging and the etiology, onset, and progression of age-associated disease. Dogs exhibit this negative correlation between size, health, and longevity and thus represent an excellent system in which to test the underlying mechanisms. Here, we quantified genome-wide DNA methylation in a cohort of 864 dogs in the Dog Aging Project.
Age strongly patterned the dog epigenome, with the majority (66% of age-associated loci) of regions associating age-related loss of methylation. These age effects were non-randomly distributed in the genome and differed depending on genomic context. We found the LINE1 (long interspersed elements) class of TEs (transposable elements) were the most frequently hypomethylated with age. This LINE1 pattern differed in magnitude across breeds of different sizes - the largest dogs lost 0.26% more LINE1 methylation per year than the smallest dogs. This suggests that epigenetic regulation of TEs, particularly LINE1s, may contribute to accelerated age and disease phenotypes within a species.
Since our study focused on the methylome of immune cells, we looked at LINE1 methylation changes in golden retrievers, a breed highly susceptible to hematopoietic cancers, and found they have accelerated age-related LINE1 hypomethylation compared to other breeds. We also found many of the LINE1s hypomethylated with age are located on the X chromosome and are, when considering X chromosome inactivation, counter-intuitively more methylated in males. These results have revealed the demethylation of LINE1 transposons as a potential driver of inter-species, demographic-dependent aging variation.