The human genome contains dozens of genes that encode for proteins containing long poly-glutamine repeats – 10Qs or more called polyQ. However, only nine of these genes have been reported to expand beyond the healthy variation and cause diseases. Utilizing a web-based tool which was previously developed in our lab (“BindDB”: Livyatan et al., Cell Stem Cell, 2015), we analyzed the chromatin structure of all repeat containing genes in the human and mouse genomes. Intriguingly, we found that the 9 rogue polyQ-related genes are characterized by an open chromatin profile in pluripotent stem cells. In contrast to all other repeat-containing genes in both human and mouse, which are epigenetically suppressed, the 9 polyQ-related genes are enriched for active chromatin marks and depleted for suppressive chromatin marks, in pluripotent cells. This surprising finding raises the idea that this active epigenetic landscape may support decreased stability and susceptibility for expansion mutations during human evolution.