Evolutionary and topological properties of gene modules and driver mutations in a leukemia gene regulatory network

TL;DR

This study reveals how the topology of a leukemia gene regulatory network correlates with gene evolutionary age, identifying a core enriched with cancer mutations that could inform targeted therapies.

Contribution

It introduces new measures of network efficiency and demonstrates the link between gene evolution, network position, and cancer mutations in leukemia.

Findings

Old, cold genes tend to interact with each other.

Young, hot genes are located on the network periphery.

The cancer network core is highly enriched for driver mutations.

Abstract

The diverse, specialized genes in today's lifeforms evolved from a common core of ancient, elementary genes. However, these genes did not evolve individually: gene expression is controlled by a complex network of interactions, and alterations in one gene may drive reciprocal changes in its proteins' binding partners. We show that the topology of a leukemia gene regulatory network is strongly coupled with evolutionary properties. Slowly-evolving ("cold"), old genes tend to interact with each other, as do rapidly-evolving ("hot"), young genes, causing genes to evolve in clusters. We argue that gene duplication placed old, cold genes at the center of the network, and young, hot genes on the periphery, and demonstrate this with single-node centrality measures and two new measures of efficiency. Integrating centrality measures with evolutionary information, we define a medically-relevant "cancer network core," strongly enriched for common cancer mutations ($p=2\times 10^{-14}$). This could aid in identifying driver mutations and therapeutic targets.