Learning Gene Networks under SNP Perturbations Using eQTL Datasets

Abstract

The standard approach for identifying gene networks is based on experimental perturbations of gene regulatory systems such as gene knock-out experiments, followed by a genome-wide profiling of differential gene expressions. However, this approach is significantly limited in that it is not possible to perturb more than one or two genes simultaneously to discover complex gene interactions or to distinguish between direct and indirect downstream regulations of the differentially-expressed genes. As an alternative, genetical genomics study has been proposed to treat naturally-occurring genetic variants as potential perturbants of gene regulatory system and to recover gene networks via analysis of population gene-expression and genotype data. Despite many advantages of genetical genomics data analysis, the computational challenge that the effects of multifactorial genetic perturbations should be decoded simultaneously from data has prevented a widespread application of genetical genomics analysis. In this article, we propose a statistical framework for learning gene networks that overcomes the limitations of experimental perturbation methods and addresses the challenges of genetical genomics analysis. We introduce a new statistical model, called a sparse conditional Gaussian graphical model, and describe an efficient learning algorithm that simultaneously decodes the perturbations of gene regulatory system by a large number of SNPs to identify a gene network along with expression quantitative trait loci (eQTLs) that perturb this network. While our statistical model captures direct genetic perturbations of gene network, by performing inference on the probabilistic graphical model, we obtain detailed characterizations of how the direct SNP perturbation effects propagate through the gene network to perturb other genes indirectly. We demonstrate our statistical method using HapMap-simulated and yeast eQTL datasets. In particular, the yeast gene network identified computationally by our method under SNP perturbations is well supported by the results from experimental perturbation studies related to DNA replication stress response.

Author Summary

A complete understanding of how gene regulatory networks are wired in a biological system is important in many areas of biology and medicine. The most popular method for investigating a gene network has been based on experimental perturbation studies, where the expression of a gene is experimentally manipulated to observe how this perturbation affects the expressions of other genes. Such experimental methods are costly, laborious, and do not scale to a perturbation of more than two genes at a time. As an alternative, genetical genomics approach uses genetic variants as naturally-occurring perturbations of gene regulatory system and learns gene networks by decoding the perturbation effects by genetic variants, given population gene-expression and genotype data. However, since there exist millions of genetic variants in genomes that simultaneously perturb a gene network, it is not obvious how to decode the effects of such multifactorial perturbations from data. Our statistical approach overcomes this computational challenge and recovers gene networks under SNP perturbations using probabilistic graphical models. As population gene-expression and genotype datasets are routinely collected to study genetic architectures of complex diseases and phenotypes, our approach can directly leverage these existing datasets to provide a more effective way of identifying gene networks.