Chesler EJ, Lu L, Shou SM, Qu YH, Gu J, Wang JT et al. Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37: 233-242

University of Alabama at Birmingham, Birmingham, Alabama, United States
Nature Genetics (Impact Factor: 29.35). 04/2005; 37(3):233-42. DOI: 10.1038/ng1518
Source: PubMed


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.

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    • "We converted permutationderived P-values to q-values with the QVALUE software, using the bootstrap method to estimate p 0 and the default l tuning parameters (Storey et al. 2004). We set the significance threshold for declaring an eQTL at a false discovery rate of 1% (Chesler et al. 2005). "
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    • "In eQTL mapping, two types of eQTLs are analyzed: cis-eQTLs that are in close proximity to the gene locus and trans-eQTLs that occur at greater distances from the gene locus [10]. Previous eQTL studies for multiple organisms [2-4,6] have shown that many genes are trans-regulated by a small number of genomic regions, known as ‘regulatory hotspots’. Although several eQTL studies have successfully identified regulatory hotspots [11-13], it has been reported in studies of recombinant inbred mice that regulatory hotspots replicate poorly [14]. "
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    • "In this study, we focus on sex-specific genetic effects on immune response phenotypes to T. muris in a population of BXD recombinant inbred (RI) mice. This reference panel consists of experimentally tractable mouse lines capturing a large amount of naturally occurring genetic variation and is ideally suited to integrate and analyse massive phenotypic data sets [21,22] thus providing a valuable tool to identify loci that contribute to immune phenotypes in T. muris infection. To determine the heritable differences in immune phenotypes to T. muris, we profiled parasite burden and infection-induced cytokine responses in peripheral blood in 20 BXD lines and both parental strains, C57Bl/6J and DBA/2J. "
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