Reverse Engineering Gene Interaction Networks Using the Phi-Mixing Coefficient

TL;DR

This paper introduces a novel algorithm based on the phi-mixing coefficient to construct directed, weighted gene interaction networks with cycles, validated through experiments on lung cancer data and biological assays.

Contribution

It presents a new method for gene network inference that overcomes limitations of existing algorithms by allowing directed, weighted, cyclic networks, validated with experimental data.

Findings

Inferred networks exhibit scale-free properties.

Strong correlation between gene degree and cell survival.

Enrichment of targets in ASCL1 downstream neighborhood.

Abstract

Constructing gene interaction networks (GINs) from high-throughput gene expression data is an important and challenging problem in systems biology. Existing algorithms produce networks that either have undirected and unweighted edges, or else are constrained to contain no cycles, both of which are biologically unrealistic. In the present paper we propose a new algorithm, based on a concept from probability theory known as the phi-mixing coefficient, that produces networks whose edges are weighted and directed, and are permitted to contain cycles. Because there is no "ground truth" for genome-wide networks on a human scale, we analyzed the outcomes of several experiments on lung cancer, and matched the predictions from the inferred networks with experimental results. Specifically, we inferred three networks (NSCLC, Neuro-endocrine NSCLC plus SCLC, and normal) from the gene expression measurements of 157 lung cancer and 59 normal cell lines, compared with the outcomes of siRNA screening of 19,000+ genes on 11 NSCLC cell lines, and analyzed data from a ChIP-Seq experiment to determine putative downstream targets of the lineage specific oncogenic transcription factor ASCL1. The inferred networks displayed a scale-free or power law behavior between the degree of a node and the number of nodes with that degree. There was a strong correlation between the degree of a gene in the inferred NSCLC network and its essentiality for the survival of the cells. The inferred downstream neighborhood genes of ASCL1 in the SCLC network were significantly enriched by ChIP-Seq determined putative target genes, while no such enrichment was found in the inferred NSCLC network.