Boettger Linda M, Salem Rany M, Handsaker Robert E, Peloso Gina M, Kathiresan Sekar, Hirschhorn Joel N, McCarroll Steven A
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Nat Genet. 2016 Apr;48(4):359-66. doi: 10.1038/ng.3510. Epub 2016 Feb 22.
One of the first protein polymorphisms identified in humans involves the abundant blood protein haptoglobin. Two exons of the HP gene (encoding haptoglobin) exhibit copy number variation that affects HP protein structure and multimerization. The evolutionary origins and medical relevance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from many recurring deletions, more specifically, reversions of an ancient hominin-specific duplication of these exons. Although this polymorphism has been largely invisible to genome-wide genetic studies thus far, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We further show that these deletions, and a SNP that affects HP expression, appear to drive the strong association of cholesterol levels with SNPs near HP. Recurring exonic deletions in HP likely enhance human health by lowering cholesterol levels in the blood.
人类中最早发现的蛋白质多态性之一涉及丰富的血液蛋白触珠蛋白。触珠蛋白（HP）基因的两个外显子表现出拷贝数变异，这会影响HP蛋白的结构和多聚化。这种多态性的进化起源和医学相关性一直不明确。在这里，我们表明这种变异可能源于许多反复出现的缺失，更具体地说，是这些外显子古老的人亚科特异性重复的回复突变。尽管到目前为止这种多态性在全基因组遗传研究中基本未被发现，但我们描述了一种通过从单核苷酸多态性（SNP）单倍型进行推断来分析它的方法，并在22288名个体中发现这些HP外显子缺失与低密度脂蛋白（LDL）和总胆固醇水平降低有关。我们进一步表明，这些缺失以及一个影响HP表达的SNP，似乎驱动了胆固醇水平与HP附近SNP的强关联。HP中反复出现的外显子缺失可能通过降低血液中的胆固醇水平来增强人类健康。
