Clustering of housekeeping genes provides a unified model of gene order in the human genome

Abstract

It is often supposed that, except for tandem duplicates, genes are randomly distributed throughout the human genome. However, recent analyses suggest that when all the genes expressed in a given tissue (notably placenta and skeletal muscle) are examined, these genes do not map to random locations but instead resolve to clusters. We have asked three questions: (i) is this clustering true for most tissues, or are these the exceptions; (ii) is any clustering simply the result of the expression of tandem duplicates and (iii) how, if at all, does this relate to the observed clustering of genes with high expression rates? We provide a unified model of gene clustering that explains the previous observations. We examined Serial Analysis of Gene Expression (SAGE) data for 14 tissues and found significant clustering, in each tissue, that persists even after the removal of tandem duplicates. We confirmed clustering by analysis of independent expressed-sequence tag (EST) data. We then tested the possibility that the human genome is organized into subregions, each specializing in genes needed in a given tissue. By comparing genes expressed in different tissues, we show that this is not the case: those genes that seem to be tissue-specific in their expression do not, as a rule, cluster. We report that genes that are expressed in most tissues (housekeeping genes) show strong clustering. In addition, we show that the apparent clustering of genes with high expression rates is a consequence of the clustering of housekeeping genes.

Repetitive sequence environment distinguishes housekeeping genes

“…1a), in accordance with previously published reports (Bird, 1986;Lercher et al, 2002). HK genes were also flanked by significantly higher concentrations of Alu elements (Fig.…”

“…Housekeeping genes also typically have small introns (Eisenberg and Levanon, 2003) that lack repetitive sequences (Han et al, 2004). Housekeeping genes have been found to cluster together on the genome to some degree (Lercher et al, 2002), and to preferentially localize to GC-rich fractions of genomic DNA known as isochores on cesium sulfate gradients (Lercher et al, 2003).…”

Is optimal gene order impossible?

“…This idea is supported by the finding that genes that are similarly expressed are found in clusters (e.g. genes that are co-expressed [5][6][7] and/or broadly expressed [8,9] and/or highly expressed [10,11]). Second, genome proximity might evolve to reduce the recombination rate between specific genes [12,13].…”

Function prediction and protein networks

“…Also in Homo sapiens highly expressed genes are clustered in the genome [49]. This pattern, however, appears to be caused by the clustering of housekeeping genes [50 ], and therewith to give only a very weak signal for function prediction.…”