Repeat sequences account for over half of the human genome and represent a significant source of variation that underlies physiological and pathological states. Yet, their study has been hindered due to limitations in short-reads sequencing technology and difficulties in assembly. A important category of repetitive DNA in the human genome is comprised of tandem repeats (TRs), where repetitive units are arranged in a head-to-tail pattern. Compared to other regions of the genome, TRs carry between 10 and 10,000 fold higher mutation rate. There are several mutagenic mechanisms that can give rise to this propensity toward instability, but their precise contribution remains speculative. Given the high degree of homology between these sequences and their arrangement in tandem, once damaged, TRs have an intrinsic propensity to undergo aberrant recombination with non-allelic exchange and generate harmful rearrangements that may undermine the stability of the entire genome. The dynamic mutagenesis at TRs has been found to underlie individual polymorphism associated with neurodegenerative and neuromuscular disorders, as well as complex genetic diseases like cancer and diabetes. Here, we review our current understanding of the surveillance and repair mechanisms operating within these regions, and we describe how alterations in these protective processes can readily trigger mutational signatures found at TRs, ultimately resulting in the pathological correlation between TRs instability and human diseases. Finally, we provide a viewpoint to counter the detrimental effects that TRs pose in light of their selection and conservation, as important drivers of human evolution.

重复序列占人类基因组的一半以上，是生理和病理状态的重要变异来源。然而，由于短读长测序技术的局限性和组装困难，他们的研究受到了阻碍。人类基因组中一个重要的重复 DNA 类别由串联重复 (TR) 组成，其中重复单元以头对尾的方式排列。与基因组的其他区域相比，TR 的突变率高出 10 到 10,000 倍。有几种诱变机制可以导致这种不稳定倾向，但它们的确切贡献仍然是推测性的。鉴于这些序列之间的高度同源性及其串联排列，一旦受损，TR 具有通过非等位基因交换进行异常重组并产生可能破坏整个基因组稳定性的有害重排的内在倾向。已发现 TRs 的动态诱变是与神经退行性和神经肌肉疾病以及癌症和糖尿病等复杂遗传疾病相关的个体多态性的基础。在这里，我们回顾了我们目前对在这些区域内运作的监视和修复机制的理解，并描述了这些保护过程中的改变如何容易地触发在 TRs 上发现的突变特征，最终导致 TRs 不稳定性与人类疾病之间的病理相关性。最后，我们提供了一个观点来对抗 TRs 根据它们的选择和保护而造成的不利影响，