Global Properties and Functional Complexity of Human Gene Regulatory Variation

Daniel J Gaffney,Gonçalo R Abecasis

doi:10.1371/journal.pgen.1003501

Abstract

Identification and functional interpretation of gene regulatory variants is a major focus of modern genomics. The application of genetic mapping to molecular and cellular traits has enabled the detection of regulatory variation on genome-wide scales and revealed an enormous diversity of regulatory architecture in humans and other species. In this review I summarise the insights gained and questions raised by a decade of genetic mapping of gene expression variation. I discuss recent extensions of this approach using alternative molecular phenotypes that have revealed some of the biological mechanisms that drive gene expression variation between individuals. Finally, I highlight outstanding problems and future directions for development.

Highlights

Mammalian genomes harbour a diverse array of gene regulatory elements
To realise the full potential of association studies, human disease geneticists are turning their attention to the functional interpretation of regulatory variation
They estimated that up to 19% of eQTLs could be explained by variation in mRNA decay rates and the withingene distribution of associations suggests that many joint QTLs function by altering miRNA binding sites

Summary

Introduction

Mammalian genomes harbour a diverse array of gene regulatory elements. Fuelled by rapid technological advances, a decade of genomics research has begun to reveal the location, diversity, and richness of the regulatory fraction of the human genome [1]. Genetic control of transcription at most genes appears to be polygenic These effect sizes are, substantially larger than for typical whole-organism traits, and association signals in eQTL mapping studies often exceed standard genome-wide thresholds of significance, despite sample sizes as small as 50 individuals [23]. A genetic variant may influence the expression of one or both alleles of a transcript, referred to as regulation cis or trans, Citation: Gaffney DJ (2013) Global Properties and Functional Complexity of Human Gene Regulatory Variation. Genetic variation in gene expression likely results from the combined action of small numbers of relatively large effect cis-acting mutations, which are characteristically enriched near the regulated gene, and a more polygenic trans component that mostly eludes detection. The biological mechanisms that drive expression variation, remain less clear

Understanding Mechanism with Alternative Molecular Phenotypes

Findings

Incorporating Function and Progress toward Predictive Models