Shared regulatory sites are abundant in the human genome and shed light on genome evolution and disease pleiotropy.

Pin Tong,James G D Prendergast,Jack Monahan

doi:10.1371/journal.pgen.1006673

Abstract

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.

Highlights

It has been almost 30 years since the locus control region at the human β-globin cluster was identified [1], one of the first well-defined mammalian examples of a regulatory site linked to the regulation of multiple, nearby genes [2]
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
By first removing redundancy among eQTLs and examining their effects across tissues and how they relate to how the genome folds, we show that cis-eQTL sharing is a relatively common phenomenon

Summary

Introduction

It has been almost 30 years since the locus control region at the human β-globin cluster was identified [1], one of the first well-defined mammalian examples of a regulatory site linked to the regulation of multiple, nearby genes [2]. Subsequent studies across species have suggested that such regions may be a common feature of eukaryote gene expression [2]. Despite their potential importance, only a handful of such regions have been identified to date. How common such master cis-regulatory sites are in the human genome remains largely unclear. EQTL studies adopt a single variant to single gene testing approach; that is testing variants against genes one by one [3] These analyses provide little information on the extent to which regulatory sites are shared across genes. High levels of linkage disequilibrium between variants can confound where two eVariants are tagging distinct regulatory loci, or where multiple genes are linked to a single regulatory site

Methods

Results

Conclusion