Centre de Recherche du CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.
PLoS One. 2012;7(6):e38667. doi: 10.1371/journal.pone.0038667. Epub 2012 Jun 7.
Identifying and understanding the impact of gene regulatory variation is of considerable importance in evolutionary and medical genetics; such variants are thought to be responsible for human-specific adaptation and to have an important role in genetic disease. Regulatory variation in cis is readily detected in individuals showing uneven expression of a transcript from its two allelic copies, an observation referred to as allelic imbalance (AI). Identifying individuals exhibiting AI allows mapping of regulatory DNA regions and the potential to identify the underlying causal genetic variant(s). However, existing mapping methods require knowledge of the haplotypes, which make them sensitive to phasing errors. In this study, we introduce a genotype-based mapping test that does not require haplotype-phase inference to locate regulatory regions. The test relies on partitioning genotypes of individuals exhibiting AI and those not expressing AI in a 2×3 contingency table. The performance of this test to detect linkage disequilibrium (LD) between a potential regulatory site and a SNP located in this region was examined by analyzing the simulated and the empirical AI datasets. In simulation experiments, the genotype-based test outperforms the haplotype-based tests with the increasing distance separating the regulatory region from its regulated transcript. The genotype-based test performed equally well with the experimental AI datasets, either from genome-wide cDNA hybridization arrays or from RNA sequencing. By avoiding the need of haplotype inference, the genotype-based test will suit AI analyses in population samples of unknown haplotype structure and will additionally facilitate the identification of cis-regulatory variants that are located far away from the regulated transcript.
鉴定和理解基因调控变异在进化和医学遗传学中具有重要意义;这些变异被认为是人类特有的适应的原因,并在遗传疾病中起着重要作用。在个体中,当一个转录本的两个等位基因拷贝表现出不均匀表达时,顺式调控变异很容易被检测到,这种观察结果被称为等位基因不平衡(AI)。鉴定表现出 AI 的个体可以对调控 DNA 区域进行映射,并有可能识别潜在的因果遗传变异。然而,现有的映射方法需要了解单倍型,这使得它们容易受到相位误差的影响。在这项研究中,我们引入了一种基于基因型的映射测试方法,该方法不需要单倍型相位推断来定位调控区域。该测试依赖于将表现出 AI 和不表达 AI 的个体的基因型划分为 2×3 列联表。通过分析模拟和经验 AI 数据集,检验了该测试在检测潜在调控位点与位于该区域的 SNP 之间的连锁不平衡(LD)的性能。在模拟实验中,随着调控区域与其调控转录本之间的距离增加,基于基因型的测试比基于单倍型的测试表现更好。基于基因型的测试与全基因组 cDNA 杂交阵列或 RNA 测序的实验 AI 数据集的表现同样出色。通过避免单倍型推断的需要,基于基因型的测试将适合未知单倍型结构的群体样本中的 AI 分析,并有助于识别远离受调控转录本的顺式调控变异。