Abstract
Similarity in gene expression pattern between closely linked genes is known in several eukaryotes. Two models have been proposed to explain the presence of such coexpression patterns. The adaptive model assumes that coexpression is advantageous and is established by relocation of initially unlinked but coexpressed genes, whereas the neutral model asserts that coexpression is a type of leaky expression due to similar expressional environments of linked genes, but is neither advantageous nor detrimental. However, these models are incompatible with several empirical observations. Here, we propose that coexpression of linked genes is a form of transcriptional interference that is disadvantageous to the organism. We show that even distantly linked genes that are tens of megabases away exhibit significant coexpression in the human genome. However, the linkage is more likely to be broken during evolution between genes of high coexpression than those of low coexpression and the breakage of linkage reduces gene coexpression. These results support our hypothesis that coexpression of linked genes in mammalian genomes is generally disadvantageous, implying that many mammalian genes may never reach their optimal expression pattern due to the interference of their genomic environment and that such transcriptional interference may be a force promoting recurrent relocation of genes in the genome.
Highlights
Nonrandom distribution of genes in a genome, a widespread phenomenon in prokaryotes (Lawrence 1999), has been observed in various eukaryotes
We propose a model of the origin and evolutionary dynamics of coexpression of linked genes
We find a significant correlation between log10transformed genomic distance in nucleotides (logD) and the level of coexpression (ln[(1 þ R)/(1 À R)], see Materials and Methods) (Pearson’s correlation coefficient r 5 À0.1385, P, 10À 21; Spearman’s correlation coefficient q 5 À0.1364, P, 10À20), indicating that closer adjacent human genes have higher similarity in spatial expression profiles
Summary
Nonrandom distribution of genes in a genome, a widespread phenomenon in prokaryotes (Lawrence 1999), has been observed in various eukaryotes (reviewed in Hurst et al 2004). The observation that genes involved in the same pathway (Lee and Sonnhammer 2003) or protein complex (Teichmann and Veitia 2004) and genes having similar functions (Cohen et al 2000) tend to be linked suggests that coexpression of linked genes may be important to gene function (Hurst et al 2002; Singer et al 2005) This view, referred to as the adaptive model, assumes that it is beneficial for genes that require coexpression to be brought together via chromosomal rearrangement (Miller et al 2004; Richards et al 2005; Singer et al 2005). The model predicts that once a coexpressed gene cluster is established, the linkage of the coexpressed genes should be evolutionarily maintained by purifying selection (Hurst et al 2002; Singer et al 2005)
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