If “junk” DNA goes toxic, does that suggest it had an original normal function? See the conclusion of this new paper, “Native functions of short tandem repeats” (emphasis added):
Historically, repetitive elements within human genomes have been viewed as mostly unregulated ‘junk DNA’ that is not under selective evolutionary pressure. As such expansions of these repetitive elements are unfortunate accidents which become apparent and important only when they elicit highly penetrant and syndromic human diseases. Consistent with this line of reasoning, the field of REDs [Repetitive Element Diseases] has largely focused on emergent toxic mechanisms as drivers of disease only in the setting of large STR [Short Tandem Repeats] expansions rather than considering their pathology as alterations in the native functions played by these repeats in their normal genomic contexts. Here, we propose re-framing the discussion around repetitive elements in general — and STRs in particular — within human genomes. For each STR, we suggest first considering whether the STRs associated with a human disease have any native functions at their ‘normal’ size. If a native function exists, then expansion of these STRs can be viewed primarily as an aberrancy of that native function with coincident predictable impacts on gene expression dysregulation above certain repeat lengths. This reframing aligns with the approach typically taken in studying gain-of-function and loss-of-function mutations in disease associated single amino acid mutations and better ties the native functions of STRs to their pathology. It also suggests that shared regulatory rules will likely apply across REDs.
The article by Shannon E. Wright and Peter K. Todd is open access at eLife. Of course, lots of so-called “junk” has turned out to be functional. For another recent example, see here.