Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3′-5′ direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.

提出串联重复序列有助于人类特有的性状，并且已知超过40个串联重复序列扩增会引起神经系统疾病。在这里，我们在WDR7的最后一个内含子中鉴定了人类特异性的69 bp可变数串联重复序列（VNTR）如长期阅读测序所揭示的，其在拷贝数和核苷酸组成上均表现出惊人的可变性。另外，在散发性肌萎缩性侧索硬化症（ALS）的三个独立队列中，更大的重复拷贝数显着丰富。重复序列的每个单元形成一个具有产生微小RNA潜力的茎环结构，并且重复序列RNA在细胞中表达时可以聚集。我们利用其显着的序列变异性来比对288个样品中的重复序列，并揭示其扩增机制。我们发现，重复序列在3'-5'方向上扩展，并被重复单元组除以2。我们观察到的扩展模式与复制事件和称为模板切换的复制错误一致。我们还观察到，VNTR在Denisovan和尼安德特人的基因组中均得到扩展，但在非人灵长类动物中固定为一个拷贝或更少。对1000个基因组计划样本中的重复序列进行评估后发现，在某些地理种群中，某些重复序列片段仅存在或不存在。该VNTR中较大的重复单元，再加上我们的多重测序策略，为研究重复扩增机制提供了前所未有的机会，并为评估VNTR在人类进化和疾病中的作用提供了框架。