Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function
Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function
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DOI：
10.1038/ng1518
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发表时间：
2005-03-01
期刊：
影响因子：
30.8
通讯作者：
Williams, RW
中科院分区：
文献类型：
--
作者：
Chesler, EJ;Lu, L;Williams, RW
中枢神经系统的基因表达模式是高度可变和可遗传的。正常人之间的这种基因变异导致了相当大的结构、功能和行为差异。我们设计了一个通用的方法来解剖遗传网络系统跨越生物尺度，从碱基对到行为，使用一个参考群体的重组近交系。我们使用Affymetrix寡核苷酸阵列分析了BXD重组自交系的基因表达，我们有广泛的SNP和单倍型数据。我们整合了一个包含这些菌株25年遗留表型数据的补充数据库。基因表达与药理学和行为性状之间的协方差通常非常显著，证实了已知的功能关系，并且通常由共同的数量性状位点产生。我们发现，少数主要效应的数量性状位点以特定于每个组织的模式共同调节大量转录本和经典神经表型。我们以参与神经突触功能的基因集为例，开发了新的分析和图理论方法来研究性状网络的共享遗传调节。我们将这些工具构建到一个名为WebQTL的开放网络资源中，可以用来测试一系列广泛的假设。
Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred strains, for which we have extensive SNP and haplotype data. We integrated a complementary database comprising 25 years of legacy phenotypic data on these strains. Covariance among gene expression and pharmacological and behavioral traits is often highly significant, corroborates known functional relations and is often generated by common quantitative trait loci. We found that a small number of major-effect quantitative trait loci jointly modulated large sets of transcripts and classical neural phenotypes in patterns specific to each tissue. We developed new analytic and graph theoretical approaches to study shared genetic modulation of networks of traits using gene sets involved in neural synapse function as an example. We built these tools into an open web resource called WebQTL that can be used to test a broad array of hypotheses.