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Human Molecular Genetics Advance Access originally published online on December 21, 2005
Human Molecular Genetics 2006 15(3):481-492; doi:10.1093/hmg/ddi462
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© The Author 2005. Published by Oxford University Press. All rights reserved.
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Integrative genetic analysis of transcription modules: towards filling the gap between genetic loci and inherited traits

Hongqiang Li1,2,{dagger}, Hao Chen3,{dagger}, Lei Bao1,2, Kenneth F. Manly2,4,5, Elissa J. Chesler4, Lu Lu2,4, Jintao Wang2, Mi Zhou1,2, Robert W. Williams2,4,6 and Yan Cui1,2,*

1Department of Molecular Sciences, 2Center of Genomics and Bioinformatics, 3Department of Pharmacology, 4Department of Anatomy and Neurobiology, 5Department of Pathology and Laboratory Medicine and 6Department of Pediatrics, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163, USA

* To whom correspondence should be addressed. Tel: +1 9014483240; Fax: +1 9014487360; Email: ycui2{at}utmem.edu

Received June 9, 2005; Revised September 1, 2005; Accepted November 2, 2005

Genetic loci that regulate inherited traits are routinely identified using quantitative trait locus (QTL) mapping methods. However, the genotype–phenotype associations do not provide information on the gene expression program through which the genetic loci regulate the traits. Transcription modules are ‘self-consistent regulatory units’ and are closely related to the modular components of gene regulatory network [Ihmels, J., Friedlander, G., Bergmann, S., Sarig, O., Ziv, Y. and Barkai, N. (2002) Revealing modular organization in the yeast transcriptional network. Nat. Genet., 31, 370–377; Segal, E., Shapira, M., Regev, A., Pe'er, D., Botstein, D., Koller, D. and Friedman, N. (2003) Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat. Genet., 34, 166–176]. We used genome-wide genotype and gene expression data of a genetic reference population that consists of mice of 32 recombinant inbred strains to identify the transcription modules and the genetic loci regulating them. Twenty-nine transcription modules defined by genetic variations were identified. Statistically significant associations between the transcription modules and 18 classical physiological and behavioral traits were found. Genome-wide interval mapping showed that major QTLs regulating the transcription modules are often co-localized with the QTLs regulating the associated classical traits. The association and the possible co-regulation of the classical trait and transcription module indicate that the transcription module may be involved in the gene pathways connecting the QTL and the classical trait. Our results show that a transcription module may associate with multiple seemingly unrelated classical traits and a classical trait may associate with different modules. Literature mining results provided strong independent evidences for the relations among genes of the transcription modules, genes in the regions of the QTLs regulating the transcription modules and the keywords representing the classical traits.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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