美国哈佛医学院Po-Ru Loh等研究人员合作发现，拷贝数可变区的蛋白质改变变体影响人类的各种表型。相关论文于2024年3月28日在线发表在《自然—遗传学》杂志上。

研究人员利用能检测亚外显子拷贝数变异（CNV）和节段重复内变异的单倍型知情方法，从英国生物库全外显子测序数据（n=468570）中确定了改变蛋白质的CNV。将CNV纳入预测会导致基因功能缺失（LOF）的罕见变异的分析中，研究人员发现了100个预测LOF变异与41个数量性状的关联。RGL3第6外显子的低频部分缺失赋予了基因LOF对高血压风险最强的保护作用之一（比值比=0.86 (0.82-0.90)）。

在节段性重复中快速演化的基因家族中的蛋白质编码变异（以前大多数分析方法都无法发现这种变异），产生了人类基因组中对2型糖尿病风险、时间型和血细胞性状变异贡献最大的一些基因。这些结果表明，迄今为止尚未进行大规模分析的基因组变异有可能带来新的遗传学见解。

据了解，CNV是最大的遗传变异之一，但大多数遗传关联研究尚未有效确定CNV。

附：英文原文

Title: Protein-altering variants at copy number-variable regions influence diverse human phenotypes

Author: Hujoel, Margaux L. A., Handsaker, Robert E., Sherman, Maxwell A., Kamitaki, Nolan, Barton, Alison R., Mukamel, Ronen E., Terao, Chikashi, McCarroll, Steven A., Loh, Po-Ru

Issue&Volume: 2024-03-28

Abstract: Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not been effectively ascertained in most genetic association studies. Here we ascertained protein-altering CNVs from UK Biobank whole-exome sequencing data (n=468,570) using haplotype-informed methods capable of detecting subexonic CNVs and variation within segmental duplications. Incorporating CNVs into analyses of rare variants predicted to cause gene loss of function (LOF) identified 100 associations of predicted LOF variants with 41 quantitative traits. A low-frequency partial deletion of RGL3 exon 6 conferred one of the strongest protective effects of gene LOF on hypertension risk (odds ratio=0.86 (0.82–0.90)). Protein-coding variation in rapidly evolving gene families within segmental duplications—previously invisible to most analysis methods—generated some of the human genome’s largest contributions to variation in type 2 diabetes risk, chronotype and blood cell traits. These results illustrate the potential for new genetic insights from genomic variation that has escaped large-scale analysis to date.

DOI: 10.1038/s41588-024-01684-z

Source: https://www.nature.com/articles/s41588-024-01684-z