Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors).
Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors).
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DOI：
10.1186/1478-1336-3-2
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发表时间：
2005-09-30
期刊：
影响因子：
--
通讯作者：
Schuetz EG
中科院分区：
文献类型：
--
作者：
Krasowski MD;Yasuda K;Hagey LR;Schuetz EG
人类核激素受体（NR）超家族补体由48个基因组成，在代谢稳态，发育和解毒中具有不同的作用。一般来说，NR在脊椎动物物种之间是高度保守的，并且已经证明了在这个超家族内的分子适应（正选择）的一些例子。利用两种比较的先前研究揭示了大多数NR基因的强纯化（阴性）选择，两个可能的例外是双烷X受体（PXR，NR 1 I2）和组成型雄烷受体（CAR，NR 1 I3）的配体结合结构域（LBD），这两种蛋白质参与毒性化合物代谢和消除的调节。本研究的目的是应用最大似然法对脊椎动物NR超家族的全部基因进行详细的系统发育分析。在所有脊椎动物和仅限于哺乳动物中进行分析，并且除了全长序列之外，还分别针对NR的两个主要结构域，DNA结合结构域（DBD）和LBD进行分析。还报告了PXR和维生素D受体（VDR; NR 1 I1）激活的其他功能数据，以进一步了解NR 1 I亚家族的演变。NR基因似乎受到强烈的纯化选择，特别是在DBD中。对非同义核苷酸与同义核苷酸取代率的比率（ω比率）的估计揭示，仅PXR LBD具有估计的ω比率大于1的密码子亚群。CAR在DBD和LBD中显示出高的相对ω比率也是不寻常的，这一发现可能与CAR基因的最近出现有关（推测是通过复制前哺乳动物PXR基因），就在哺乳动物进化之前。NR 1 I亚家族的功能分析表明，人类和斑马鱼的PXR显示出类似的激活类固醇激素和早期胆汁盐，属性不共享的海七鳃鳗，小鼠，或人类的VDRs，或非洲爪蟾PXR。NR基因通常表现出很强的序列保守性，很少有正选择的证据。主要的例外是PXR和CAR，这些基因可能适应了有毒化合物暴露的跨物种差异。
The nuclear hormone receptor (NR) superfamily complement in humans is composed of 48 genes with diverse roles in metabolic homeostasis, development, and detoxification. In general, NRs are strongly conserved between vertebrate species, and few examples of molecular adaptation (positive selection) within this superfamily have been demonstrated. Previous studies utilizing two-species comparisons reveal strong purifying (negative) selection of most NR genes, with two possible exceptions being the ligand-binding domains (LBDs) of the pregnane X receptor (PXR, NR1I2) and the constitutive androstane receptor (CAR, NR1I3), two proteins involved in the regulation of toxic compound metabolism and elimination. The aim of this study was to apply detailed phylogenetic analysis using maximum likelihood methods to the entire complement of genes in the vertebrate NR superfamily. Analyses were carried out both across all vertebrates and limited to mammals and also separately for the two major domains of NRs, the DNA-binding domain (DBD) and LBD, in addition to the full-length sequences. Additional functional data is also reported for activation of PXR and the vitamin D receptor (VDR; NR1I1) to gain further insight into the evolution of the NR1I subfamily. The NR genes appear to be subject to strong purifying selection, particularly in the DBDs. Estimates of the ratio of the non-synonymous to synonymous nucleotide substitution rates (the ω ratio) revealed that only the PXR LBD had a sub-population of codons with an estimated ω ratio greater than 1. CAR was also unusual in showing high relative ω ratios in both the DBD and LBD, a finding that may relate to the recent appearance of the CAR gene (presumably by duplication of a pre-mammalian PXR gene) just prior to the evolution of mammals. Functional analyses of the NR1I subfamily show that human and zebrafish PXRs show similar activation by steroid hormones and early bile salts, properties not shared by sea lamprey, mouse, or human VDRs, or by Xenopus laevis PXRs. NR genes generally show strong sequence conservation and little evidence for positive selection. The main exceptions are PXR and CAR, genes that may have adapted to cross-species differences in toxic compound exposure.