This study creates a compendium of gene expression in normal human tissues suitable as a reference for defining basic organ systems biology. Using oligonucleotide microarrays, we analyze 59 samples representing 19 distinct tissue types. Of ∼7,000 genes analyzed, 451 genes are expressed in all tissue types and designated as housekeeping genes. These genes display significant variation in expression levels among tissues and are sufficient for discerning tissue-specific expression signatures, indicative of fundamental differences in biochemical processes. In addition, subsets of tissue-selective genes are identified that define key biological processes characterizing each organ. This compendium highlights similarities and differences among organ systems and different individuals and also provides a publicly available resource (Human Gene Expression Index, the HuGE Index, http://www.hugeindex.org ) for future studies of pathophysiology.

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The very high dimensional space of gene expression measurements obtained by DNA microarrays impedes the detection of underlying patterns in gene expression data and the identification of discriminatory genes. In this paper we show the use of projection methods such as principal components analysis (PCA) to obtain a direct link between patterns in the genes and patterns in samples. This feature is useful in the initial interactive pattern exploration of gene expression data and data-driven learning of the nature and types of samples. Using oligonucleotide microarray measurements of 40 samples from different normal human tissues, we show that distinct patterns are obtained when the genes are projected on a two-dimensional plane spanned by the loadings of the two major principal components. These patterns define the particular genes associated with a sample class (i.e., tissue). When used separately from the other genes, these class-specific (i.e., tissue-specific) genes in turn define distinct tissue patterns in the projection space spanned by the scores of the two major principal components. In this study, PCA projection facilitated discriminatory gene selection for different tissues and identified tissue-specific gene expression signatures for liver, skeletal muscle, and brain samples. Furthermore, it allowed the classification of nine new samples belonging to these three types using the linear combination of the expression levels of the tissue-specific genes determined from the first set of samples. The application of the technique to other published data sets is also discussed

We propose a method for the mapping of the physiological state of cells and tissues from multidimensional expression data such as those obtained with DNA microarrays. The method uses Fisher discriminant analysis to create a linear projection of gene expression measurements that maximizes the separation of different sample classes. Relative to other typical classification methods, this method provides insights into the discriminating characteristics of expression measurements in terms of the contribution of individual genes to the definition of distinct physiological states. This projection method also facilitates visualization of classification results in a reduced dimensional space. Examples from four different cases demonstrate the ability of the method to produce well-separated groups in the projection space and to identify important genes for defining physiological states. The method can be augmented to also include data from the proteomic and metabolic phenotypes and can be useful in disease diagnosis, drug screening and bioprocessing applications.

. Shortterm resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides. Am J Physiol Endocrinol Metab 287: E662-E670, 2004; 10.1152/ajpendo.00114.2004.-To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. Despite increased caloric intake after 2 days of high-fat feeding, body weights of A/J mice remained stable. On and after 1 wk of high-fat feeding, A/J mice adjusted their food intake to consume the same amount of calories as mice fed a low-fat diet; thus their body weight and insulin, corticosterone, free fatty acid, and glucose levels remained unchanged for 4 wk. We found no changes in hypothalamic expression of several orexigenic and/or anorexigenic neuropeptides known to play an important role in energy homeostasis for the duration of the study. Uncoupling protein-2 mRNA expression in brown adipose tissue, however, was significantly upregulated after 2 days of high-fat feeding and tended to remain elevated for the duration of the 4-wk study. Gene array analysis revealed that several genes are up-or downregulated in response to 2 days and 1 wk of high-fat feeding. Real-time PCR analysis confirmed that expression of the hypothalamic IL-1 pathway (IL-1␤, IL-1 type 1 and 2 receptors, and PPM1b/PP2C-␤, a molecule that has been implicated in the inhibition of transforming growth factor-␤-activated kinase-1-mediated IL-1 action) is altered after 2 days, but not 1 wk, of high-fat feeding. The role of additional molecules discovered by microarray analysis needs to be further explored in the future. neuropeptides; energy homeostasis; uncoupling protein-2; interleukin-1; microarray THE EPIDEMIC OF OBESITY in Western populations is associated with overconsumption of high-fat diets. The exact mechanism by which certain people (34) and certain strains of rodents (44) are susceptible to high-fat diet-induced obesity (DIO), whereas others are relatively resistant to its effects, is the subject of intensive investigation.The most thoroughly studied experimental model of DIO is the C57Bl/6J mouse strain, whereas one of the most commonly studied DIO-resistant models is the A/J mouse strain (33, 38 -40). Investigation of the physiological responses of neuroendocrine factors, hypothalamic neuropeptides, and uncoupling proteins (UCPs) to high-fat feeding in these strains of mice could extend our understanding of the pathogenesis of DIO in humans, leading to potentially important therapeutic advances. Although several studies have used the DIO-sensitive C57Bl/6J strain to examine the effect of diet composition on hypothalamic neuropeptides and/or neuroendocrine factors important in energy homeostasis, only one study has focused on the hypothalami...