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. 2003 Feb 18;100(4):1896-901.
doi: 10.1073/pnas.252784499. Epub 2003 Feb 10.

Individuality and variation in gene expression patterns in human blood

Adeline R Whitney  1 , Maximilian Diehn, Stephen J Popper, Ash A Alizadeh, Jennifer C Boldrick, David A Relman, Patrick O Brown
Affiliations

Individuality and variation in gene expression patterns in human blood

Adeline R Whitney et al. Proc Natl Acad Sci U S A. .

Abstract

The nature and extent of interindividual and temporal variation in gene expression patterns in specific cells and tissues is an important and relatively unexplored issue in human biology. We surveyed variation in gene expression patterns in peripheral blood from 75 healthy volunteers by using cDNA microarrays. Characterization of the variation in gene expression in healthy tissue is an essential foundation for the recognition and interpretation of the changes in these patterns associated with infections and other diseases, and peripheral blood was selected because it is a uniquely accessible tissue in which to examine this variation in patients or healthy volunteers in a clinical setting. Specific features of interindividual variation in gene expression patterns in peripheral blood could be traced to variation in the relative proportions of specific blood cell subsets; other features were correlated with gender, age, and the time of day at which the sample was taken. An analysis of multiple sequential samples from the same individuals allowed us to discern donor-specific patterns of gene expression. These data help to define human individuality and provide a database with which disease-associated gene expression patterns can be compared.

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Figures

Figure 1
Figure 1
Variation in gene expression patterns in human blood. Whole blood was drawn from 75 healthy volunteers. Two volunteers donated samples on two occasions, resulting in a total of 77 samples. Genes with at least a 2.0-fold change in level of expression from the mean in at least five (of 77) samples are shown. The expression pattern of the corresponding ≈370 genes is displayed in hierarchical cluster format where rows represent genes (unique cDNA elements) and columns represent experimental samples. Each expression measurement represents the normalized ratio of fluorescence from the hybridized experimental sample to a reference sample (see Supporting Materials and Methods for details). Missing or excluded data are represented by gray squares. Correlation coefficients were calculated between the gene expression of every gene and each parameter (neutrophil count, lymphocyte count, time of blood draw, age, and RDW) across the 77 samples. The correlation values are plotted as moving averages of 11 genes (along the vertical axis). Gene expression data were randomly permuted 10,000 times; the correlation coefficients derived from each permutation of the data were compared with that from the actual data. The P value for each gene was calculated as the fraction of the permutations that resulted in a correlation coefficient as high as was observed in the actual data. A dashed line indicates the lowest value of correlation coefficient significant (P < 0.05) for each parameter. Supplemental data and enhanced versions of the figures, including searchable clusters and raw microarray data, can be found at http://genome-www.stanford.edu/normalblood.
Figure 2
Figure 2
Gene clusters associated with measured complete blood count parameters and time. The lymphocyte (a), neutrophil (b), reticulocyte (c), and time-correlated (d) clusters. Samples were reordered from Fig. 1 according to the scale shown across the top, and genes were hierarchically clustered. Colored text indicates the following: genes specific to B cells (orange), cytotoxic T lymphocytes or natural killer cells (light blue), T cells (dark blue), erythrocytes (blue), neutrophils (brown), myeloid cells (red), ubiquitously expressed (green), and Myc-regulated (pink).
Figure 3
Figure 3
Intrinsic interindividual differences in gene expression patterns. (a) Global gene expression was measured in PBMCs from 16 individuals who were each sampled more than once over the course of 1 month. Also included are three patients sampled only once (gray branches). Genes displayed are those with the greatest variation in intrinsic individual differences in expression, i.e., those with intrinsic scores >2 SD from the mean (see text). The expression pattern of the corresponding ≈340 genes is displayed in hierarchical cluster format. Gender is represented by colored branches: blue for male and pink for female. Blue and pink brackets represent samples from the same patient that clustered together. The other colored branches represent repeated samples from single subjects that did not cluster together. (b) DDX17 gene expression (log2) for up to six samples collected over the course of a month for 20 patients. Data are expressed as the difference from the mean expression level for the entire dataset.
Figure 4
Figure 4
Variation in gene expression in health and disease. Global gene expression was measured in 45 samples from each of five studies. See text for details on each sample set. Of the well-measured microarray elements, 3,826 were randomly selected from each group and variance was calculated for each. Variance was plotted in rank order (highest to lowest) for the genes in each of the specimen groups. DLCL, diffuse large B-cell lymphomas; CLL, chronic lymphocytic leukemia; WB, whole blood.
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