Chen Jian-Min, Férec Claude, Cooper David N
INSERM, U613, 29220, Brest, France.
Hum Genet. 2006 Oct;120(3):301-33. doi: 10.1007/s00439-006-0218-x. Epub 2006 Jun 29.
In an attempt both to catalogue 3' regulatory region (3' RR)-mediated disease and to improve our understanding of the structure and function of the 3' RR, we have performed a systematic analysis of disease-associated variants in the 3' RRs of human protein-coding genes. We have previously analysed the variants that have occurred in two specific domains/motifs of the 3' untranslated region (3' UTR) as well as in the 3' flanking region. Here we have focused upon 83 known variants within the upstream sequence (USS; between the translational termination codon and the upstream core polyadenylation signal sequence) of the 3' UTR. To place these variants in their proper context, we first performed a comprehensive survey of known cis-regulatory elements within the USS and the mechanisms by which they effect post-transcriptional gene regulation. Although this survey supports the view that RNA regulatory elements function within the context of specific secondary structures, there are no general rules governing how secondary structure might exert its influence. We have therefore addressed this question by systematically evaluating both functional and non-functional (based upon in vitro reporter gene and/or electrophoretic mobility shift assay data) USS variant-containing sequences against known cis-regulatory motifs within the context of predicted RNA secondary structures. This has allowed us not only to establish a reliable and objective means to perform secondary structure prediction but also to identify consistent patterns of secondary structural change that could potentiate the discrimination of functional USS variants from their non-functional counterparts. The resulting rules were then used to infer potential functionality in the case of some of the remaining functionally uncharacterized USS variants, from their predicted secondary structures. This not only led us to identify further patterns of secondary structural change but also several potential novel cis-regulatory motifs within the 3' UTRs studied.
为了对3'调控区（3'RR）介导的疾病进行编目，并增进我们对3'RR结构和功能的理解，我们对人类蛋白质编码基因3'RR中的疾病相关变异进行了系统分析。我们之前分析了3'非翻译区（3'UTR）两个特定结构域/基序以及3'侧翼区域中出现的变异。在这里，我们聚焦于3'UTR上游序列（USS；翻译终止密码子与上游核心聚腺苷酸化信号序列之间）内的83个已知变异。为了将这些变异置于适当的背景中，我们首先对USS内已知的顺式调控元件及其影响转录后基因调控的机制进行了全面调查。尽管这项调查支持RNA调控元件在特定二级结构背景下起作用的观点，但对于二级结构如何发挥其影响并没有普遍规律。因此，我们通过在预测的RNA二级结构背景下，针对已知的顺式调控基序，系统地评估包含功能性和非功能性（基于体外报告基因和/或电泳迁移率变动分析数据）USS变异的序列，来解决这个问题。这不仅使我们能够建立一种可靠且客观的方法来进行二级结构预测，还能识别出一致的二级结构变化模式，从而有可能区分功能性USS变异与其非功能性对应物。然后，利用所得规则，根据一些剩余功能未明确的USS变异的预测二级结构推断其潜在功能。这不仅使我们识别出更多二级结构变化模式，还在研究的3'UTR内发现了几个潜在的新型顺式调控基序。
