Steigele, Stephan;Dietzsch, Janko;Khaitovich, Philipp;Huson, Daniel;Pääbo, Svante;Nieselt-Struwe, Kay - Clustering of differentially expressed genes in the human genome

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Title: Clustering of differentially expressed genes in the human genome	P157
Steigele, Stephan; Dietzsch, Janko; Khaitovich, Philipp; Huson, Daniel; Pääbo, Svante; Nieselt-Struwe, Kay nieselt@informatik.uni-tuebingen.de Universität Tübingen, Fakultät für Informatik, Zentrum für Bioinformatik Tübingen

The difference between humans and their closest living relatives, the chimpanzees, on the genomic level is extremely small. Comparisons of the transcriptome of different tissues of humans and chimpanzees however have revealed gene expression changes specific for the human brain (Enard et al., 2002). Now the question arises how the differentially expressed genes are distributed on the human genome. Are there ``hot spots'' of human brain specific genes? In order to assess this question we combined information obtained from expression patterns of thousands of human and chimpanzee genes in 6 different brain regions with information of the genomic locations of these genes.

We applied the BLAT algorithm (Kent, 2002) to map all of the 61.648 probe sequences represented on the Affymetrix HGU95 GeneChips to the human genome, derived from the NCBI assembly (release june 2002, build 30). We were able to map 86% of these sequences uniquely.
Secondly we removed all redundant probes. A probe sequence was called redundant if it was a member of the same UniGene Cluster (according to the Affymetrix annotation table) or derived from the same "source''. In total a set of 45.999 non-redundant (nr) sequences remained. Of this nr set 38.480 (84%) could be mapped uniquely.

Gene expression data for six distinct brain regions from three adult male humans and chimpanzees using Affymetrix HGU95 arrays were collected (Khaitovich et al., 2002}. We first computed the number of ``detected'' genes, i.e. all genes that showed reliable signals in all individuals in at least one of the two species. Here we found 15.133 non-redundant present genes. Of this set a total of 13.578 genes (90%) could be mapped uniquely to the human genome. Next we computed the number of non-redundant genes that are up- or down-regulated in human, when compared to chimpanzee. Of these 2.379 genes 2.123 (90%) again were uniquely mapped to the human genome.

A viewer was developed that allows a fast scalable view of the mapping onto whole chromosomes. Different colors can be defined to annotate features of the genes, such as spotted, detected and up- or down-regulated (see figure 1 for chromosome no. 4).

Furthermore we developed statistical tests to assess the significance of the results. We compared the results against the hypergeometric distribution (figure 2) as well as against distributions from simulation tests (data not shown) (for the figures see web representation of the poster abstracts).

The mapping revealed several locations that contain higher proportion of gene expression changes than expected from the random distribution. Some of these locations show possible correlation with sequence breakpoint positions introduced by known chromosomal rearrangements between human and chimpanzee genomes.

All tools are generally expandable to other organisms and microarrays.

[1] Enard, W., Khaitovich, P., Klose, J., Zollner, S., Heissig, F., Giavalisco, P., Nieselt-Struwe, K., Muchmore, E., Varki, A., Ravid, R., Doxiadis, G.M., Bontrop, R.E., Pääbo, S., Intra- and interspecific variation in primate gene expression patterns. Science 296:340-343, 2002.
[2] Kent WJ., BLAT--the BLAST-like alignment tool. Genome Res. 12:656-64, 2002.
[3] Khaitovich, P., Arendt, T., Nieselt-Struwe, K., Steigele, S., Dietzsch, J., Pääbo, S., Regional and species-specific gene expression mapping in adult human and chimpanzee brain. Manuscript in preparation, 2002.