The human genome contains more than one million short tandem repeats, and expansion of a subset of these repeat tracts underlies more than 50 human disorders. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides. Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features. We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis. We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated. Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.

人类基因组包含超过一百万个短串联重复序列，这些重复序列的子集的扩展是 50 多种人类疾病的基础。在这篇综述中，我们讨论了短串联重复序列的扩增导致疾病的四种主要机制：通过转录抑制而丧失功能、通过RNA结合蛋白的凝胶化和隔离而获得RNA介导的功能获得、规范翻译重复序列的功能获得-含有蛋白质，以及有毒重复肽的重复相关非AUG翻译。体细胞重复不稳定性放大了这些机制并影响疾病的发病年龄和致病特征的组织特异性。我们关注这些疾病机制之间的串扰，并认为它们经常协同作用来驱动发病机制。我们还讨论了重复元件的新兴天然功能以及它们的动态如何可能比目前认识的更大规模地导致疾病。最后，我们提出将这些疾病机制和天然功能联系在一起的关键提供了有希望的治疗靶点，并在此类人类疾病中具有潜在的共同应用。