Mozhui Khyobeni, Ciobanu Daniel C, Schikorski Thomas, Wang Xusheng, Lu Lu, Williams Robert W
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
PLoS Genet. 2008 Nov;4(11):e1000260. doi: 10.1371/journal.pgen.1000260. Epub 2008 Nov 14.
A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21-q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of approximately 20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes.
一组非常多样的性状映射到小鼠1号染色体远端（Chr 1）上的一个区域，该区域对应于人类1q21 - q23。这个区域高度富集了控制神经和行为表型的数量性状基因座（QTL），包括运动行为、逃避潜伏期、情绪、癫痫易感性（Szs1）以及对乙醇、咖啡因、戊巴比妥和氟哌啶醇的反应。该区域还控制着大量基因的表达，包括一些与映射到1号染色体远端的经典性状相关的基因（例如，癫痫易感性）。在这里，我们探讨1号染色体上这个富含QTL的区域（Qrr1）是由单个主基因座还是由连锁但功能不相关的QTL混合物组成。为了回答这个问题并评估候选基因，我们生成并分析了几个基因表达、单倍型和序列数据集。我们利用了六个互补的小鼠杂交组合，并梳理了18个表达数据集，以确定受Qrr1调控的基因的类别归属。Qrr1大致可分为近端部分（Qrr1p）和远端部分（Qrr1d），每个部分都与不同基因子集的表达相关。Qrr1d控制RNA代谢和蛋白质合成，包括大约20种氨酰 - tRNA合成酶的表达。Qrr1d包含一个tRNA簇，这是氨酰 - tRNA合成酶的一个功能相关候选物。Rgs7和Fmn2是Qrr1d中的其他有力候选物。FMN2蛋白在神经元中，包括在树突中有明显表达，Fmn2的缺失对受Qrr1d调控的少数基因的表达有强烈影响。我们的分析揭示了Qrr1中一个高度复杂的基因表达调控区间，由多个调控功能相关基因集表达的基因座组成。
