Systematic analysis of head-to-head gene organization: evolutionary conservation and potential biological relevance

Abstract

Several "head-to-head" (or "bidirectional") gene pairs have been studied in individual experiments, but genome-wide analysis of this gene organization, especially in terms of transcriptional correlation and functional association, is still insufficient. We conducted a systematic investigation of head-to-head gene organization focusing on structural features, evolutionary conservation, expression correlation and functional association. Of the present 1,262, 1,071, and 491 head-to-head pairs identified in human, mouse, and rat genomes, respectively, pairs with 1- to 400-base pair distance between transcription start sites form the majority (62.36%, 64.15%, and 55.19% for human, mouse, and rat,respectively) of each dataset, and the largest group is always the one with a transcription start site distance of 101 to 200 base pairs. The phylogenetic analysis among Fugu, chicken, and human indicates a negative selection on the separation of head-to-head genes across vertebrate evolution, and thus the ancestral existence of this gene organization. The expression analysis shows that most of the human head-to-head genes are significantly correlated,and the correlation could be positive, negative, or alternative depending on the experimental conditions. Finally, head to-head genes statistically tend to perform similar functions, and gene pairs associated with the significant cofunctions seem to have stronger expression correlations. The findings indicate that the head-to-head gene organization is ancient and conserved, which subjects functionally related genes to correlated transcriptional regulation and thus provides an exquisite mechanism of transcriptional regulation based on gene organization. These results have significantly expanded the knowledge about head-to-head gene organization. Supplementary materials for this study are available at http://www.scbit.org/h2h.

Figure 1. A Schematic Illustration of Head-to-Head Gene Organization

(A and B) Nonoverlapping and overlapping head-to-head gene pairs, respectively.

Figure 2. Distribution of TSS Distance of Head-to-Head Genes

Figure 3. Relationship between Head-to-Head Gene Pair Ratio and Gene Density

Figure 4. The Bimodal Distribution of the Expression Correlation between Head-to-Head Genes

h2h, correlation distribution for head-to-head gene pairs, averaged over three distributions derived from three microarray datasets separately; random, correlation distribution for random pairs, also averaged over three random distributions from three microarray datasets.

Figure 5. The Distribution of Functional Similarities for Head-to-Head Gene Pairs

(A−C) GO subsystems “biological process,” “molecular function,” and “cellular component,” respectively.