Housekeeping (HK) genes fulfill the basic needs for a cell to survive and function properly. Their ubiquitous expression, originally thought to be constant, can vary from tissue to tissue, but this variation remains largely uncharacterized and it could not be explained by previously identified properties of HK genes such as short gene length and high GC content. By analyzing microarray expression data for human genes, we uncovered a previously unnoted characteristic of HK gene expression, namely that the ranking order of their expression levels tends to be preserved from one tissue to another. Further analysis by tensor product decomposition and pathway stratification identified three main factors of the observed ranking preservation, namely that, compared to those of non-HK (NHK) genes, the expression levels of HK genes show a greater degree of dispersion (less overlap), stableness (a smaller variation in expression between tissues), and correlation of expression. Our results shed light on regulatory mechanisms of HK gene expression that are probably different for different HK genes or pathways, but are consistent and coordinated in different tissues.

High-throughput transcriptomic experiments have made it possible to classify genes that are ubiquitously expressed as housekeeping (HK) genes and those expressed only in selective tissues as tissue-specific (TS) genes. Although partitioning a transcriptome into HK and TS genes is conceptually problematic owing to the lack of precise definitions and gene expression profile criteria for the two, information whether a gene is an HK or a TS gene can provide an initial clue to its cellular and/or functional role. Consequently, the development of new and novel HK (TS) classification methods has been a topic of considerable interest in post-genomics research. Here, we report such a development. Our method, called HKera, differs from the others by utilizing a novel property of HK genes that we have previously uncovered, namely that the ranking order of their expression levels, as opposed to the expression levels themselves, tends to be preserved from one tissue to another. Evaluated against multiple benchmark sets of human HK genes, including one recently derived from second generation sequencing data, HKera was shown to perform significantly better than five other classifiers that use different methodologies. An enrichment analysis of pathway and gene ontology annotations showed that HKera-predicted HK and TS genes have distinct functional roles and, together, cover most of the ontology categories. These results show that HKera is a good transcriptome partitioner that can be used to search for, and obtain useful expression and functional information for, novel HK (TS) genes.