Addendum to stress and the dynamic genome: Steroids, epigenetics, and the transposome

In a recent paper, Hunter at al. propose a functional role for retrotransposons in the brain and mammalian stress response. In contrast to the predominant paradigm of “junk” DNA or parasitic leftovers, they hypothesize that these mobile genetic elements have been co-opted by cells to regulate the expression of proteinencoding genes in response to environmental insults. Retrotransposons were thought to be “controlling elements” of gene expression by their discoverer, but this view was not widely shared until recently and remains controversial. Due to the advent of next-generation sequencing, it is now possible to answer questions about their evolutionary role and effects on complex behaviors, such as psychological stress, that had been impossible to address even a few years ago. The prevailing assumption is that retrotransposons are leftover from viral inserts, duplication errors, or runaway transposition—and functionally useless. This negative hypothesis is difficult to demonstrate, and also hard to accept based on the principal of parsimony: biological systems do not waste energy needlessly, or are replaced by others that can do the same thing more efficiently. Because of the unbalanced ratio of retrotransposons to protein-encoding genes, if the “junk” hypothesis was correct, the trillions of cells present in a single organism would be spending 10 times the energy needed to replicate. The cost is even higher when the negative effects of errant retrotransposon transcription are taken into account. In the long evolution of eukaryotes, it is unlikely that this would not have been selected against. Thus, the simplest solution is that the vast regions of non-protein coding DNA, including retrotransposons, do something biologically relevant, even if the purpose is poorly understood at present. Just as many genes were discovered through malfunctions leading to disease, several disorders show some level of transposon dysregulation. Retrotransposons have been implicated in schizophrenia, addiction, and post-traumatic stress disorder, among others. Their unwanted overexpression can even lead to physical degeneration of the nervous system. It is possible that loss of control of retrotransposon expression could be either a cause or a predictive biomarker of other psychological disorders. The brain must be malleable in order to adapt to environmental stresses, including psychological stress. Because a large number of brain cells are post-mitotic, and persist from birth until death, finetuned control of the genome is paramount if the organism is to survive. The dynamic nature of neuronal DNA has been the target of intense research into how neuronal structure and function are affected by varying the likelihood that certain genes will be expressed through changes in histone and DNA marks. The portion of the genome consisting of retrotransposons appears to be inversely correlated with the