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About the Authors:
Pin Tong
Affiliation: Wellcome Trust Centre for Cell Biology and Institute of Cell Biology, School of Biological Sciences, The University of Edinburgh, Max Born Crescent, Edinburgh, Scotland, United Kingdom
Jack Monahan
Affiliation: The European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
ORCID http://orcid.org/0000-0002-0635-0015
James G. D. Prendergast
* E-mail: [email protected]
Affiliation: The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Scotland, United Kingdom
ORCID http://orcid.org/0000-0001-8916-018XAbstract
Large-scale gene expression datasets are providing an increasing understanding of the location of cis-eQTLs in the human genome and their role in disease. However, little is currently known regarding the extent of regulatory site-sharing between genes. This is despite it having potentially wide-ranging implications, from the determination of the way in which genetic variants may shape multiple phenotypes to the understanding of the evolution of human gene order. By first identifying the location of non-redundant cis-eQTLs, we show that regulatory site-sharing is a relatively common phenomenon in the human genome, with over 10% of non-redundant regulatory variants linked to the expression of multiple nearby genes. We show that these shared, local regulatory sites are linked to high levels of chromatin looping between the regulatory sites and their associated genes. In addition, these co-regulated gene modules are found to be strongly conserved across mammalian species, suggesting that shared regulatory sites have played an important role in shaping human gene order. The association of these shared cis-eQTLs with multiple genes means they also appear to be unusually important in understanding the genetics of human phenotypes and pleiotropy, with shared regulatory sites more often linked to multiple human phenotypes than other regulatory variants. This study shows that regulatory site-sharing is likely an underappreciated aspect of gene regulation and has important implications for the understanding of various biological phenomena, including how the two and three dimensional structures of the genome have been shaped and the potential causes of disease pleiotropy outside coding regions.
Author summary
Where a gene’s regulatory site is disrupted by a genetic variant, its expression levels will vary between individuals depending on the version of the variant they carry. Such genetic loci, termed eQTLs, have been found to be disproportionately associated with disease and have proven to be a powerful tool for identifying the...