Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways.

Background: The cohesin complex plays an essential role in genome organisation and cell division. A full complement of the cohesin complex and its regulators is important for normal development, since heterozygous mutations in genes encoding these components can be sufficient to produce a disease phenotype. The implication that genes encoding the cohesin subunits or cohesin regulators must be tightly controlled and resistant to variability in expression has not yet been formally tested.

Methods: Here, we identify spatial-regulatory connections with potential to regulate expression of cohesin loci (Mitotic: , , , , /; Meiotic: , , , ), cohesin-ring support genes (, , , , ) and , including linking their expression to that of other genes. We searched the genome-wide association studies (GWAS) catalogue for SNPs mapped or attributed to cohesin genes by GWAS (GWAS-attributed) and the GTEx catalogue for SNPs mapped to cohesin genes by -regulatory variants in one or more of 44 tissues across the human body (expression quantitative trail locus-attributed).

Results: Connections that centre on the cohesin ring subunits provide evidence of coordinated regulation that has little tolerance for perturbation. We used the CoDeS3D SNP-gene attribution methodology to identify transcriptional changes across a set of genes coregulated with the cohesin loci that include biological pathways such as extracellular matrix production and proteasome-mediated protein degradation. Remarkably, many of the genes that are coregulated with cohesin loci are themselves intolerant to loss-of-function.

Conclusions: The results highlight the importance of robust regulation of cohesin genes and implicate novel pathways that may be important in the human cohesinopathy disorders.