Variability in a Short Tandem Repeat Mediates Complex Epistatic Interactions in Arabidopsis thaliana

Short tandem repeats (STRs) are hypervariable genetic elements that occur frequently in coding regions. Their high mutation rate readily generates genetic variation, contributing to adaptive evolution and human diseases. We previously reported that natural ELF3 polyglutamine variants cause reciprocal genetic incompatibilities in two divergent Arabidopsis thaliana backgrounds. Here, we dissect the genetic architecture of this incompatibility, revealing as many as four loci putatively interacting with ELF3. We were able to specifically identify one such ELF3-interacting gene, LSH9. We further used a yeast two-hybrid strategy to identify proteins whose physical interactions with ELF3 were affected by polyglutamine tract length. We found two proteins for which this was the case, ELF4 and AtGLDP1. Using these two approaches, we identify specific genetic interactions and physical mechanisms by which the ELF3 polyglutamine tract may mediate the observed genetic incompatibilities. Our work elucidates how STR variation, which is generally underascertained in population-scale sequencing, can contribute to phenotypic variation. Furthermore, our results support our proposal that highly variable STR loci can contribute to the epistatic component of heritability.