The variable ELF3 polyglutamine tract mediates complex epistatic interactions in Arabidopsis thaliana

ABSTRACT Short tandem repeats 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 recently proposed that short tandem repeats are likely to engage in epistasis because they are well-positioned to compensate for genetic variation arising at other loci due to their high mutation rate. We previously reported that natural ELF3 polyglutamine variants cause reciprocal genetic incompatibilities in two divergent Arabidopsis thaliana backgrounds. Here, we dissected the genetic architecture of this incompatibility and used a yeast two-hybrid strategy to identify proteins whose physical interactions with ELF3 were modulated by polyglutamine tract length. Using these two orthogonal 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 short tandem repeat 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 disproportionately to the epistatic component of heritability.