Pervasive coexpression of spatially proximal genes is buffered at the protein level

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.