Cis - and Trans -Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics

Abstract

<p class="first" id="P1">Over thirty hereditary diseases are caused by the expansion of microsatellite repeats. The length of the expandable repeat is the main hereditary determinant of these disorders. They are also affected by numerous genomic variants that are nearby ( <i>cis</i>) and physically separated from ( <i>trans</i>) the repetitive locus, which we review here. These genetic variants have largely been elucidated in model systems using gene knockouts, while a few have been directly observed as single nucleotide polymorphisms (SNPs) in patients. There is a notable disconnect between these two bodies of knowledge: knockouts poorly approximate the SNP-level variation in human populations that gives rise to medically-relevant <i>cis</i>- and <i>trans</i>-modifiers, while the rarity of these diseases limits the statistical power of SNP-based analysis in humans. We propose that high-throughput SNP-based screening in model systems could become a useful approach to quickly identify and characterize modifiers with clinical relevance for patients. </p>