Many human proteins contain domains that vary in size or copy number because of variable numbers of tandem repeats (VNTRs) in protein-coding exons. However, the relationships of VNTRs to most phenotypes are unknown because of difficulties in measuring such repetitive elements. We developed methods to estimate VNTR lengths from whole-exome sequencing data and impute VNTR alleles into single-nucleotide polymorphism haplotypes. Analyzing 118 protein-altering VNTRs in 415,280 UK Biobank participants for association with 786 phenotypes identified some of the strongest associations of common variants with human phenotypes, including height, hair morphology, and biomarkers of health. Accounting for large-effect VNTRs further enabled fine-mapping of associations to many more protein-coding mutations in the same genes. These results point to cryptic effects of highly polymorphic common structural variants that have eluded molecular analyses to date.

中文翻译：

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蛋白质编码重复多态性强烈塑造了不同的人类表型


由于蛋白质编码外显子中串联重复序列 (VNTR) 的数量不同，许多人类蛋白质含有大小或拷贝数不同的结构域。然而，由于测量此类重复元件存在困难，VNTR 与大多数表型的关系尚不清楚。我们开发了从全外显子组测序数据估计 VNTR 长度的方法，并将 VNTR 等位基因归入单核苷酸多态性单倍型。对 415,280 名英国生物银行参与者中的 118 个蛋白质改变 VNTR 进行分析，确定其与 786 种表型的关联，确定了常见变异与人类表型的一些最强关联，包括身高、头发形态和健康生物标志物。考虑到大效应 VNTR，进一步能够对同一基因中更多蛋白质编码突变的关联进行精细绘制。这些结果指出了高度多态性的常见结构变体的神秘效应，迄今为止尚未进行分子分析。