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Elucidating the Role of Gonadal Hormones in Sexually Dimorphic Gene Coexpression Networks

Departments of Human Genetics (A.v.N., S.S.W., N.Y., S.H., L.I.-D., A.J.L.), Microbiology, Immunology, and Molecular Genetics (A.J.L.), Pathology and Laboratory Medicine (T.A.D.), Medicine (A.J.L.), and Obstetrics and Gynecology and Molecular and Medical Pharmacology (G.C.) and Molecular Biology Institute (A.J.L.), David Geffen School of Medicine; Department of Biostatistics (S.H.), School of Public Health; and Department of Physiological Science and Laboratory of Neuroendocrinology of the Brain Research Institute (A.P.A.), University of California, Los Angeles, California 90095; and Department of Genetics (D.G., B.Z., E.E.S.), Rosetta Inpharmatics, a wholly owned subsidiary of Merck & Co. Inc., Seattle, Washington 98109

Address all correspondence and requests for reprints to: Aldons J. Lusis, University of California, Los Angeles, Med-Cardio/Microbio, Box 951679, 3730 MRL, Los Angeles, California 90095-1679. E-mail: jlusis{at}mednet.ucla.edu.

We previously used high-density expression arrays to interrogate a genetic cross between strains C3H/HeJ and C57BL/6J and observed thousands of differences in gene expression between sexes. We now report analyses of the molecular basis of these sex differences and of the effects of sex on gene expression networks. We analyzed liver gene expression of hormone-treated gonadectomized mice as well as XX male and XY female mice. Differences in gene expression resulted in large part from acute effects of gonadal hormones acting in adulthood, and the effects of sex chromosomes, apart from hormones, were modest. We also determined whether there are sex differences in the organization of gene expression networks in adipose, liver, skeletal muscle, and brain tissue. Although coexpression networks of highly correlated genes were largely conserved between sexes, some exhibited striking sex dependence. We observed strong body fat and lipid correlations with sex-specific modules in adipose and liver as well as a sexually dimorphic network enriched for genes affected by gonadal hormones. Finally, our analyses identified chromosomal loci regulating sexually dimorphic networks. This study indicates that gonadal hormones play a strong role in sex differences in gene expression. In addition, it results in the identification of sex-specific gene coexpression networks related to genetic and metabolic traits.

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