Inferring mechanisms of copy number change from haplotype structures at the human DEFA1A3 locus.
Inferring mechanisms of copy number change from haplotype structures at the human DEFA1A3 locus.
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DOI：
10.1186/1471-2164-15-614
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发表时间：
2014-07-21
期刊：
影响因子：
4.4
通讯作者：
Al Armour J
中科院分区：
文献类型：
--
作者：
Black HA;Khan FF;Tyson J;Al Armour J
确定基因拷贝数可变区的结构单倍型可以揭示基因拷贝数变化的机制，并解释基因拷贝数与表达之间的关系。然而，在显示广泛拷贝数变异的区域（如DEFA 1A 3基因座）获得空间信息是复杂的，因为这些区域的定相和组装是困难的。DEFA 1A 3基因座的有趣之处在于，尽管其拷贝数具有高变异性（n = 3-16），但其福尔斯落在高连锁不平衡区域内;因此，负责该基因座拷贝数变化的机制尚不清楚。在这项研究中，DEFA 1A 3基因座侧翼的区域在120个独立的欧洲血统单倍型中进行测序，确定了5种常见的DEFA 1A 3单倍型。在1000个基因组项目中，DEFA 1A 3类与单倍型的比较突出了不同祖先人群之间DEFA 1A 3类频率的显著差异。每个DEFA 1A 3类别的特征，例如，相关的DEFA 1A 3拷贝数，最初在欧洲队列（n = 599）中进行评估，并在1000个基因组样本中进行复制，显示DEFA 1A 3基因座特征的类内相似性，但类间和人群间差异。使用乳液单倍型融合PCR在DEFA 1A 3位点产生61个结构单倍型，显示出高的类内结构相似性。DEFA 1A 3基因座的结构单倍型表明等位基因内重排是DEFA 1A 3拷贝数变化的主要机制，解释了该基因座连锁不平衡的保守性。在DEFA 1A 3基因座的常见结构单倍型的鉴定可以帮助研究DEFA 1A 3拷贝数如何影响表达，这是目前尚不清楚的。本文的在线版本（doi：10.1186/1471-2164-15-614）包含补充材料，可供授权用户使用。
The determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression. However, obtaining spatial information at regions displaying extensive copy number variation, such as the DEFA1A3 locus, is complex, because of the difficulty in the phasing and assembly of these regions. The DEFA1A3 locus is intriguing in that it falls within a region of high linkage disequilibrium, despite its high variability in copy number (n = 3–16); hence, the mechanisms responsible for changes in copy number at this locus are unclear. In this study, a region flanking the DEFA1A3 locus was sequenced across 120 independent haplotypes with European ancestry, identifying five common classes of DEFA1A3 haplotype. Assigning DEFA1A3 class to haplotypes within the 1000 Genomes project highlights a significant difference in DEFA1A3 class frequencies between populations with different ancestry. The features of each DEFA1A3 class, for example, the associated DEFA1A3 copy numbers, were initially assessed in a European cohort (n = 599) and replicated in the 1000 Genomes samples, showing within-class similarity, but between-class and between-population differences in the features of the DEFA1A3 locus. Emulsion haplotype fusion-PCR was used to generate 61 structural haplotypes at the DEFA1A3 locus, showing a high within-class similarity in structure. Structural haplotypes across the DEFA1A3 locus indicate that intra-allelic rearrangement is the predominant mechanism responsible for changes in DEFA1A3 copy number, explaining the conservation of linkage disequilibrium across the locus. The identification of common structural haplotypes at the DEFA1A3 locus could aid studies into how DEFA1A3 copy number influences expression, which is currently unclear. The online version of this article (doi:10.1186/1471-2164-15-614) contains supplementary material, which is available to authorized users.
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