Abstract
Genes are not randomly distributed in the genome. In humans, 10% of protein‐coding genes are transcribed from bidirectional promoters and many more are organised in larger clusters. Intriguingly, neighbouring genes are frequently coexpressed but rarely functionally related. Here we show that coexpression of bidirectional gene pairs, and closeby genes in general, is buffered at the protein level. Taking into account the 3D architecture of the genome, we find that co‐regulation of spatially close, functionally unrelated genes is pervasive at the transcriptome level, but does not extend to the proteome. We present evidence that non‐functional mRNA coexpression in human cells arises from stochastic chromatin fluctuations and direct regulatory interference between spatially close genes. Protein‐level buffering likely reflects a lack of coordination of post‐transcriptional regulation of functionally unrelated genes. Grouping human genes together along the genome sequence, or through long‐range chromosome folding, is associated with reduced expression noise. Our results support the hypothesis that the selection for noise reduction is a major driver of the evolution of genome organisation.
Highlights
The position of genes in the human genome is not random (Hurst et al, 2004)
These pairs do not share a promoter region, we find that 22% have co-regulated mRNA abundances (PCC > 0.5, BHadjusted P < 0.001)
We find that genes which are coexpressed with their neighbours are more often flanked by heterochromatin, upstream of their transcription start site (Fig 3B)
Summary
Genes are often found in pairs or larger clusters that tend to be coexpressed (Caron et al, 2001; Lercher et al, 2002; Trinklein et al, 2004). Some of these coordinate transcription of genes with related functions, for example histone genes and other clusters resulting from gene duplication. 35 DNA repair genes are transcribed from bidirectional promoters, but none of their paired genes is involved in DNA repair (Xu et al, 2012). This raises intriguing questions: Why are functionally unrelated genes clustered in the genome and how can the cell tolerate their coexpression?
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