Institute for Genome Sciences & Policy, Duke University, USA.
Mol Biol Evol. 2010 Feb;27(2):465-79. doi: 10.1093/molbev/msp276. Epub 2009 Nov 12.
Understanding genetic variation and its functional consequences within cis-regulatory regions remains an important challenge in human genetics and evolution. Here, we present a fine-scale functional analysis of segregating variation within the cis-regulatory region of prodynorphin, a gene that encodes an endogenous opioid precursor with roles in cognition and disease. In order to characterize the functional consequences of segregating variation in cis in a region under balancing selection in different human populations, we examined associations between specific polymorphisms and gene expression in vivo and in vitro. We identified five polymorphisms within the 5' flanking region that affect transcript abundance: a 68-bp repeat recognized in prior studies, as well as two microsatellites and two single nucleotide polymorphisms not previously implicated as functional variants. The impact of these variants on transcription differs by brain region, sex, and cell type, implying interactions between cis genotype and the differentiated state of cells. The effects of individual variants on expression level are not additive in some combinations, implying epistatic interactions between nearby variants. These data reveal an unexpectedly complex relationship between segregating genetic variation and its expression-trait consequences and highlights the importance of close functional scrutiny of natural genetic variation within even relatively well-studied cis-regulatory regions.
理解基因变异及其在顺式调控区域内的功能后果仍然是人类遗传学和进化中的一个重要挑战。在这里，我们对前脑啡肽原顺式调控区域内的分离变异进行了精细的功能分析，该基因编码一种内源性阿片前体，在认知和疾病中发挥作用。为了描述在不同人群中处于平衡选择的顺式区域内分离变异的功能后果，我们检查了特定多态性与体内和体外基因表达之间的关联。我们在 5'侧翼区鉴定出五个影响转录丰度的多态性：一个先前研究中识别的 68 碱基对重复，以及两个微卫星和两个先前未被认为是功能变体的单核苷酸多态性。这些变体对转录的影响因脑区、性别和细胞类型而异，暗示了顺式基因型与细胞分化状态之间的相互作用。在某些组合中，个体变体对表达水平的影响不是加性的，暗示了附近变体之间的上位性相互作用。这些数据揭示了分离遗传变异与其表达性状后果之间出乎意料的复杂关系，并强调了即使在研究相对较好的顺式调控区域内，对自然遗传变异进行密切功能研究的重要性。
