Is there a functional link between gene interdigitation and multi-species conservation of synteny blocks?

It is often overlooked that, in addition to the integrity of protein-coding sequences (PCSs), human health is crucially linked to the normal expression of genes by cis-regulatory sequences (CRSs). These CRSs often lie at some considerable distance from the PCSs whose expression they control and often within other genes. The resulting gene interdigitation can make long-range CRS identification and characterisation difficult. We propose that the need to conserve long-range CRSs in cis with their target PCSs through evolution, in combination with gene interdigitation and co-regulation of many genes by individual CRSs has contributed to the persistence of conserved synteny blocks between diverse species. We further hypothesise that examination of the varying extents of synteny blocks between multiple species in combination with phylogenetic footprinting to find CRSs might provide important clues to the existence of crucial functional CRS-PCS linkages. Identifying CRS-PCS linkages crucial to human health will lead to a better understanding of how their disruption by CRS mutation or chromosome translocation might contribute to many distressing human diseases. (C) 2004 Wiley Periodicals, Inc.