Ancient cis-regulatory constraints and the evolution of genome architecture

•Conserved gene order reveals constraints on cis-regulation and genome architecture.•Hundreds of local gene associations have been conserved since the origin of animals.•Constraints include coregulation and the formation of multigenic regulatory blocks.•Establishment and disruption of regulatory blocks are highly dynamic in evolution.•No conserved regulatory blocks have been found so far in non-animal eukaryotes.

The order of genes along metazoan chromosomes has generally been thought to be largely random, with few implications for organismal function. However, two recent studies, reporting hundreds of pairs of genes that have remained linked in diverse metazoan species over hundreds of millions of years of evolution, suggest widespread functional implications for gene order. These associations appear to largely reflect cis-regulatory constraints, with either (i) multiple genes sharing transcriptional regulatory elements, or (ii) regulatory elements for a developmental gene being found within a neighboring ‘bystander’ gene (known as a genomic regulatory block). We discuss implications, questions raised, and new research directions arising from these studies, as well as evidence for similar phenomena in other eukaryotic groups.