美国麻省理工学院 (MIT) 和哈佛大学布罗德研究所Po-Ru Loh、Steven A. McCarroll、Ronen E. Mukamel和Robert E. Handsaker研究团队合作发现蛋白质编码重复多态性明显塑造不同人类表型。这一研究成果于2021年9月24日发表在国际顶尖学术期刊《科学》上。

他们开发了从全外显子组测序数据估计串联重复序列 (VNTR)长度，并将 VNTR 等位基因归入单核苷酸多态性单倍型的方法。分析 415,280 名英国生物银行参与者的 118 个蛋白质改变 VNTR 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 进一步实现了与相同基因中更多蛋白质编码突变的关联的精细定位。 这些结果指出了迄今为止尚未进行分子分析的高度多态性常见结构变体的神秘影响。

据了解，由于蛋白质编码外显子中VNTR的数量可变，许多人类蛋白质包含大小或拷贝数不同的结构域。然而，由于难以测量此类重复元素，因此 VNTR 与大多数表型的关系尚不清楚。

附：英文原文

Title: Protein-coding repeat polymorphisms strongly shape diverse human phenotypes

Author: Ronen E. Mukamel, Robert E. Handsaker, Maxwell A. Sherman, Alison R. Barton, Yiming Zheng, Steven A. McCarroll, Po-Ru Loh

Issue&Volume: 2021-09-24

Abstract: 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.

DOI: abg8289

Source: https://www.science.org/doi/10.1126/science.abg8289