Abstract

Variable number tandem repeat (VNTR) is a pervasive and highly mutable genetic feature that varies in both length and repeat sequence. Despite the well-studied copy-number variants, the functional impacts of repeat motif polymorphisms remain unknown. Here, we present the largest genome-wide VNTR polymorphism map to date, with over 2.5 million VNTR length polymorphisms (VNTR-LPs) and over 11 million VNTR motif polymorphisms (VNTR-MPs) detected in 8,222 high-coverage genomes. Leveraging the large-scale NyuWa cohort, we identified 2,982,456 (31.8%) NyuWa-specific VNTR-MPs, of which 95.3% were rare. Moreover, we found 1,937 out of 38,685 VNTRs that were associated with gene expression through VNTR-MPs in lymphoblastoid cell lines. Specifically, we clarified that the expansion of a likely causal motif could upregulate gene expression by improving the binding concentration of PU.1. We also explored the potential impacts of VNTR polymorphisms on phenotypic differentiation and disease susceptibility. This study expands our knowledge of VNTR-MPs and their functional implications.