Meredith M. Course et al.
Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, researchers use long-read sequencing to characterize a human-specific 69 base pair variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition. In addition, the authors used NINDS Repository samples in combination with other cohort samples to demonstrate that greater repeat copy number is significantly enriched in individuals with sporadic amyotrophic lateral sclerosis (ALS). The repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. The study additionally leveraged 288 samples to uncover the mechanism of WDR7 VNTR expansion. The observed expansion patterns were consistent with a combination of duplication events and a replication error called template switching. It was 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. This work provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.
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