AbstractConserved noncoding elements (CNEs) have significant regulatory influence on their neighbouring genes. Loss of synteny to CNEs through genomic rearrangements can, therefore, impact the transcriptional states of the cognate genes. Yet, the evolutionary implications of such chromosomal position effects have not been studied. Through genome-wide analysis of CNEs and the cognate genes of representative species from 5 different mammalian orders, we observed significant loss of synteny to CNEs in rat lineage. The CNEs and genes losing synteny had significant association with the fetal, but not the post-natal, brain development as assessed through ontology terms, developmental gene expression, chromatin marks and genetic mutations. The loss of synteny correlated with the independent evolutionary loss of fetus-specific upregulation of genes in rat brain. DNA-breakpoints implicated in brain abnormalities of germ-line origin had significant representation between CNE and the gene that exhibited loss of synteny, signifying the underlying developmental tolerance of genomic rearrangements that had allowed the evolutionary splits of CNEs and the cognate genes in rodent lineage. These observations highlighted the non-trivial impact of chromosomal position-effect in shaping the evolutionary dynamics of mammalian brain development and might explain loss of brain traits, like cerebral folding of cortex, in rodent lineage.Author SummaryExpression of genes is regulated by proximally located non-coding regulatory elements. Loss of linear proximity between gene and its regulatory element thus can alter the expression of gene. Such a phenomenon can be tested at whole genome scale using evolutionary methods. We compared the positions of genes and regulatory elements in 5 different mammals and identified the significant loss of proximities between gene and their regulatory elements in rat during evolution. Brain development related function was selectively enriched among the genes and regulatory elements that had lost the proximity in rat. The observed separation of genes and their regulatory elements was strongly associated with the evolutionary loss of developmental gene expression pattern in rat brain, which coincided with the loss of brain traits in rodents. The study highlighted the importance of relative chromosomal positioning of genes and their gene regulatory elements in the evolution of phenotypes.
Thyroid hormone up-regulates NGFI-A gene expression in rat brain during development.