Evolutionary dynamics of genome-wide position effects in mammals

Alterations in genomic proximity of a gene and its regulatory elements can impact transcriptional state of the gene. Through genome-wide analysis of Conserved Noncoding Elements (CNEs) and their cognate genes from representative mammals, we show that the genes syntenic to their adjacent CNEs were associated with developmentally essential functions while the ones that had lost synteny independently in one of the non-human lineage were associated with fetal, but not post-natal, brain development in human. Accordingly, associated CNEs exhibited specific enhancer activity in fetal brain and contained SNPs associated with brain disorders. Relatively greater representation of DNA-breakpoints of germ-line origin between CNE and the gene signified the underlying developmental tolerance of CNE-gene split during loss of synteny. While between closely related species, like rat and mouse, linear split of CNE-gene synteny was compensated by their spatial proximity to maintain gene-expression, the gain and loss of genes9 proximity to CNEs between distant species strikingly correlated with the gain and loss of tissue-specific fetal gene-expression as exemplified through developing brain and heart in human and mouse. These observations highlight the nontrivial contribution of position-effect in the evolution of gene-expression pattern during development and have implications in evolutionary gain and loss of lineage-specific traits.