Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.
PLoS Comput Biol. 2012;8(9):e1002663. doi: 10.1371/journal.pcbi.1002663. Epub 2012 Sep 6.
The serotonin 2C receptor (5-HT(2C)R)-a key regulator of diverse neurological processes-exhibits functional variability derived from editing of its pre-mRNA by site-specific adenosine deamination (A-to-I pre-mRNA editing) in five distinct sites. Here we describe a statistical technique that was developed for analysis of the dependencies among the editing states of the five sites. The statistical significance of the observed correlations was estimated by comparing editing patterns in multiple individuals. For both human and rat 5-HT(2C)R, the editing states of the physically proximal sites A and B were found to be strongly dependent. In contrast, the editing states of sites C and D, which are also physically close, seem not to be directly dependent but instead are linked through the dependencies on sites A and B, respectively. We observed pronounced differences between the editing patterns in humans and rats: in humans site A is the key determinant of the editing state of the other sites, whereas in rats this role belongs to site B. The structure of the dependencies among the editing sites is notably simpler in rats than it is in humans implying more complex regulation of 5-HT(2C)R editing and, by inference, function in the human brain. Thus, exhaustive statistical analysis of the 5-HT(2C)R editing patterns indicates that the editing state of sites A and B is the primary determinant of the editing states of the other three sites, and hence the overall editing pattern. Taken together, these findings allow us to propose a mechanistic model of concerted action of ADAR1 and ADAR2 in 5-HT(2C)R editing. Statistical approach developed here can be applied to other cases of interdependencies among modification sites in RNA and proteins.
5-羟色胺 2C 受体（5-HT(2C)R）是调节多种神经过程的关键受体，其前体 mRNA 通过腺苷脱氨酶（A-to-I 前体 mRNA 编辑）在五个不同的位点进行特异性编辑，从而产生功能多样性。在这里，我们描述了一种统计方法，该方法用于分析五个位点的编辑状态之间的相关性。通过比较多个个体的编辑模式，估计了观察到的相关性的统计显著性。对于人和大鼠的 5-HT(2C)R，发现物理上接近的位点 A 和 B 的编辑状态具有很强的依赖性。相比之下，物理上接近的位点 C 和 D 的编辑状态似乎不是直接依赖的，而是分别通过对位点 A 和 B 的依赖性来联系的。我们观察到人类和大鼠之间的编辑模式存在显著差异：在人类中，位点 A 是其他位点编辑状态的关键决定因素，而在大鼠中，这种作用属于位点 B。编辑位点之间的依赖性结构在大鼠中明显比在人类中简单，这意味着 5-HT(2C)R 编辑的调节更为复杂，并且可以推断出人类大脑中的功能更为复杂。因此，对 5-HT(2C)R 编辑模式的详尽统计分析表明，位点 A 和 B 的编辑状态是其他三个位点的编辑状态以及整体编辑模式的主要决定因素。总之，这些发现使我们能够提出 ADAR1 和 ADAR2 在 5-HT(2C)R 编辑中协同作用的机制模型。这里开发的统计方法可以应用于 RNA 和蛋白质中修饰位点之间相互依赖的其他情况。
