A 2007 paper in the journal Genomics Proteomics & Bioinformatics, “A Brief Review of Short Tandem Repeat Mutation,” notes that “Short tandem repeats (STRs) are short tandemly repeated DNA sequences that involve a repetitive unit of 1–6 bp [base pairs].” STRs make up about 5 percent of the human genome. Yet the paper notes that “Although STRs widely exist in organisms, most of them are thought to have no biological uses at all and are regarded as ‘junk DNA’.” That was 16 years ago, during which the “Junk DNA” concept has taken a battering overall. Now a new paper in Science reports, “Short tandem repeats bind transcription factors to tune eukaryotic gene expression.” It finds that STRs have important functions related to gene regulation.

How It Works

The Editor’s Summary provides a nice explanation of how this works:

Short tandem repeats (STRs) are common within regulatory elements in eukaryotic genomes. Although changes in STR lengths often correlate with altered transcription, the mechanism by which they tune gene expression has remained mysterious. Horton et al. show that many transcription factor (TF) proteins directly bind STRs and that TF-preferred STRs need not resemble known binding sites (see the Perspective by Kuhlman). This binding can be explained and predicted by simple additive models in which repeated instances of low-affinity binding sites sum to have large effects. These findings suggest that STRs provide a regulatory mechanism to tune levels of TF binding and downstream gene expression.

The abstract elaborates on how important STRs seem to be:

Short tandem repeats (STRs, consecutively repeated units of one to six nucleotides) provide a good example of these sequence contexts. STRs comprise ~5% of the human genome (compared with 1.5% for all protein-coding genes) and are enriched in enhancers. Variations in STR length have been associated with changes in gene expression and implicated in several complex phenotypes, such as schizophrenia, cancer, autism, and Crohn’s disease.

[…]

Analysis of previously published protein-binding microarray and SELEX data suggests that ~90% of eukaryotic TFs preferentially bind at least one type of STR (see the figure, panel E). Because STRs are highly mutable, we propose that they should be considered an easily evolvable class of cis-regulatory elements. Preferred STRs need not resemble known motifs, suggesting a mechanism by which TF paralogs can be recruited to different regulatory regions and regulate distinct target genes. Although STRs maximize the number of potential weak binding sites, we anticipate that nonrepetitive sequence contexts containing many low-affinity binding sites should similarly increase binding. Thus, we propose that STRs function as “rheostats” to tune local TF concentration and binding responses to regulate gene expression in disease, development, and homeostasis.

What’s a Rheostat?

If you don’t know what a rheostat is, it’s an engineering component that is described as a “variable resistor which is used to control current.” In other words, it can precisely control some function. Rheostats are “often used as power control devices, for example to control light intensity (dimmer), speed of motors, heaters, and ovens.”

Rheostat is a good description for how STRs regulate gene expression by providing additional DNA loci where transcription factors can (or cannot) potentially bind. These TFs don’t necessarily bind as strongly to STRs as they do to the “core gene regulatory sequences” but the binding is still much stronger than with random sequences. This allows STRs to function as a mechanism for fine-tuning gene expression, precisely controlling how strongly TFs bind to DNA and foster transcription of a gene. As an accompanying commentary in Science puts it: “STRs tune transcription factor binding to precisely regulate gene expression.” This fine-tuning is important because “STRs also affect binding kinetics, thereby playing a role in enhancing the speed at which organisms can respond to changing environments.” 

Not Just Wrong

Or as the technical paper puts it, “mutations in STRs occur several orders of magnitude more frequently than short insertions and deletions (indels, 1 to 3 bp) and base substitutions, suggesting that STRs can provide an easily evolvable mechanism to tune transcription.” In other words, STRs seem to be a pre-programmed mechanism to rapidly allow for needed microevolutionary fine-tuning of gene expression. 

A 2023 paper in eLife states:

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.

It now seems that this historical evolutionary view of STRs was not just wrong, but certainly did not anticipate such important functions for STRs.