Accurate measurement of gene copy number for human alpha-defensin DEFA1A3.
Accurate measurement of gene copy number for human alpha-defensin DEFA1A3.
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DOI：
10.1186/1471-2164-14-719
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发表时间：
2013-10-20
期刊：
影响因子：
4.4
通讯作者：
Armour JA
中科院分区：
文献类型：
--
作者：
Khan FF;Carpenter D;Mitchell L;Mansouri O;Black HA;Tyson J;Armour JA
多等位基因拷贝数变异包括个体之间重要基因拷贝数广泛变异的例子，最显着的是涉及免疫功能的基因。这种变异的定义及其对功能影响的分析一直受到大规模但准确的基因组拷贝数分型的技术难度的阻碍。人类 8 号染色体上的拷贝变异 α 防御素基因座 DEFA1A3 通常每个二倍体基因组有 4 到 10 个拷贝，这对准确的高通量分型提出了相当大的挑战。在本研究中，我们开发了两种旁系同源物比率测试和三种等位基因比率测量，它们相结合，为测量 DEFA1A3 基因数量提供了准确且可扩展的方法。我们将来自不同测量的信息组合在最大似然框架中，这表明大多数样本可以高置信度地分配给整数拷贝数，并将其应用于 589 个不相关的欧洲 DNA 样本的分型。输入三代谱系的成员可以进一步确保已分配了正确的整数拷贝数。我们的结果使我们发现，SNP rs4300027 与欧洲样本中的 DEFA1A3 基因拷贝数密切相关。我们开发了一种准确且稳健的方法来测量 DEFA1A3 拷贝数。全基因组关联研究中对 rs4300027 和相关 SNP 的询问 SNP 数据没有证据表明 α-防御素拷贝数是克罗恩病、I 型糖尿病、HIV 进展和多发性硬化症等表型的强危险因素。本文的在线版本 (doi:10.1186/1471-2164-14-719) 包含补充材料，可供授权用户使用。
Multi-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing. In this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples. We have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn’s disease, type I diabetes, HIV progression and multiple sclerosis. The online version of this article (doi:10.1186/1471-2164-14-719) contains supplementary material, which is available to authorized users.
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