Natural variation in four human collagen genes across an ethnically diverse population
Natural variation in four human collagen genes across an ethnically diverse population
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DOI：
10.1016/j.ygeno.2007.12.008
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发表时间：
2008-04-01
期刊：
影响因子：
4.4
通讯作者：
Kwok, Pui-Yan
中科院分区：
文献类型：
--
作者：
Chan, Ting-Fung;Poon, Annie;Kwok, Pui-Yan
胶原蛋白是高等生物中最重要的结构蛋白家族之一。人类有28种类型的胶原蛋白，由43个基因编码，分为几种不同的功能蛋白质类。主要纤维胶原蛋白基因的突变导致骨生成异常（编码I型胶原蛋白链的COL 1A 1和COL 1A 2）、软骨发育不良（编码II型胶原蛋白链的COL 2A 1）和血管Ehlers-Danlos综合征（编码III型胶原蛋白链的COL 3A 1）。在过去的二十年里，这些胶原基因的突变已被编目，希望了解这些突变引起的疾病的分子病因，表征基因型-表型关系，并开发预测分子和临床结果的稳健模型。为了更好地实现这些目标，有必要了解人群中胶原蛋白基因变异的自然模式。我们在来自四个种族多样化群体的48名个体中筛选了外显子、侧翼内含子区域和保守的非编码区域，以寻找COL 1A 1、COL 1A 2、COL 2A 1和COL 3A 1的变异。我们确定了459个单核苷酸多态性（SNP），其中一半以上是新的，在公共数据库中没有发现。在编码区发现的52个SNPs中，15个引起氨基酸替换，而37个没有。虽然这四种胶原具有相似的基因和蛋白质结构，但它们具有不同的分子进化特征。例如，COL 1A 1似乎比其他基因受到了更强的负选择。系统发育分析还表明，这四个基因在不同的种族群体中具有非常不同的进化历史。我们的观察结果表明，胶原蛋白突变及其与疾病表型的关系的研究应在受试者的遗传背景的背景下进行。(c)2008年爱思唯尔公司All rights reserved.
Collagens are members of one of the most important families of structural proteins in higher organisms. There are 28 types of collagens encoded by 43 genes in humans that fall into several different functional protein classes. Mutations in the major fibrillar collagen genes lead to osteogenesis imperfecta (COL1A1 and COL1A2 encoding the chains of Type I collagen), chondrodysplasias (COL2A1 encoding the chains of Type II collagen), and vascular Ehlers - Danlos syndrome (COL3A1 encoding the chains of Type III collagen). Over the past 2 decades, mutations in these collagen genes have been catalogued, in hopes of understanding the molecular etiology of diseases caused by these mutations, characterizing the genotype - phenotype relationships, and developing robust models predicting the molecular and clinical outcomes. To achieve these goals better, it is necessary to understand the natural patterns of variation in collagen genes in human populations. We screened exons, flanking intronic regions, and conserved noncoding regions for variations in COL1A1, COL1A2, COL2A1, and COL3A1 in 48 individuals from each of four ethnically diverse populations. We identified 459 single-nucleotide polymorphisms (SNPs), more than half of which were novel and not found in public databases. Of the 52 SNPs found in coding regions, 15 caused amino acid substitutions while 37 did not. Although the four collagens have similar gene and protein structures, they have different molecular evolutionary characteristics. For example, COL1A1 appears to have been under substantially stronger negative selection than the rest. Phylogenetic analysis also suggests that the four genes have very different evolutionary histories among the different ethnic groups. Our observations suggest that the study of collagen mutations and their relationships with disease phenotypes should be performed in the context of the genetic background of the subjects. (c) 2008 Elsevier Inc. All rights reserved.