Population stratification of a common APOBEC gene deletion polymorphism.
Population stratification of a common APOBEC gene deletion polymorphism.
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普通APOBEC基因缺失多态性的种群分层。
DOI：
10.1371/journal.pgen.0030063
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发表时间：
2007-04-20
期刊：
影响因子：
4.5
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
--
作者：
Kidd, Jeffrey M.;Newman, Tera L.;Tuzun, Eray;Kaul, Rajinder;Eichler, Evan E.
APOBEC3基因家族在先天细胞免疫中发挥作用，抑制逆转录病毒感染、乙肝病毒繁殖和内源性成分的逆转录转位。我们给出了一个29.5kb的人类常见缺失多态的详细序列和群体遗传学分析，该多态移除了APOBEC3B基因。我们开发了一种基于聚合酶链式反应的基因分型方法，对1,277个人类多样性样本进行了鉴定，发现缺失等位基因的频率在主要大陆群体之间存在显著差异(全球F-ST=0.2843)。缺失在非洲人和欧洲人中很少见(0.9%和6%)，在东亚人和美洲印第安人中更常见(36.9%和57.7%)，在大洋洲人群中几乎固定(92.9%)。尽管全球频率为22.5%，但国际HapMap项目的数据分析显示，现有的任何单一标签单核苷酸多态都不能作为缺失变体的替代，强调如果不仔细分析，其表型影响可能会在关联研究中被忽视。应用基于单倍型的测试进行选择，揭示了直接应用现有方法分析基因组结构变异的潜在陷阱。这些数据强调了在关联研究中直接对结构变异进行基因分型的重要性，以及在进行更详细的群体遗传分析之前准确解决变异断裂点的重要性。最近的几项研究表明，缺失、重复和倒置在人类基因组中占总变异量的很大一部分。在这项研究中，我们对先前通过将单个个体的基因组与人类基因组参考序列进行比较而确定的单个缺失进行了全面的群体遗传学分析。获得了跨越缺失区域的完整基因组序列，使我们能够定义缺失断裂点，并建立直接的基因分型方法。分析表明，该缺失移除了参与针对病毒病原体的先天免疫反应的基因家族的一个成员。我们对来自人类多样性小组的样本进行了基因分型，发现世界各地的缺失频率存在巨大差异。使用来自HapMap项目的数据和现有分析技术的应用，我们说明了直接对这种类型的变异进行基因分型和明确界定其边界的重要性。如果没有这种详细程度，可能会错过这种变异的潜在功能重要性。
The APOBEC3 gene family plays a role in innate cellular immunity inhibiting retroviral infection, hepatitis B virus propagation, and the retrotransposition of endogenous elements. We present a detailed sequence and population genetic analysis of a 29.5-kb common human deletion polymorphism that removes the APOBEC3B gene. We developed a PCR-based genotyping assay, characterized 1,277 human diversity samples, and found that the frequency of the deletion allele varies significantly among major continental groups (global F ST = 0.2843). The deletion is rare in Africans and Europeans (frequency of 0.9% and 6%), more common in East Asians and Amerindians (36.9% and 57.7%), and almost fixed in Oceanic populations (92.9%). Despite a worldwide frequency of 22.5%, analysis of data from the International HapMap Project reveals that no single existing tag single nucleotide polymorphism may serve as a surrogate for the deletion variant, emphasizing that without careful analysis its phenotypic impact may be overlooked in association studies. Application of haplotype-based tests for selection revealed potential pitfalls in the direct application of existing methods to the analysis of genomic structural variation. These data emphasize the importance of directly genotyping structural variation in association studies and of accurately resolving variant breakpoints before proceeding with more detailed population-genetic analysis. Several recent studies have demonstrated that deletions, duplications, and inversions contribute a substantial fraction of the total amount of variation present in the human genome. In this study, we provide a comprehensive population-genetic analysis of a single deletion previously identified by comparing the genome of a single individual against the human genome reference sequence. Complete genomic sequence spanning the deleted region was obtained, allowing us to define the deletion breakpoints and develop a direct genotyping assay. Analysis showed that the deletion removes a member of a gene family involved in the innate immune response against viral pathogens. We genotyped samples from a human diversity panel and found drastic differences in the frequency of the deletion around the world. Using data from the HapMap project and the application of existing analysis techniques, we illustrate the importance of directly genotyping this type of variation and of clearly defining its boundaries. Without this level of detail the potential functional importance of such variation may be missed.
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