Evolutionary conservation of MECP2 and its relevance to neuronal stability and behavioral adaptation.

MECP2 encodes a methyl-DNA-binding chromatin protein whose dosage is critical for nervous system function: loss-of-function variants cause Rett syndrome, whereas increased dosage causes MECP2 duplication syndrome. Despite extensive research on MECP2 in neurodevelopmental diseases, its unexplored evolutionary history, which we derived from comparative genomic analysis of hundreds of species, provides a novel evolutionary framework for understanding the profound consequences of MECP2 perturbation on brain and behavior. In this review, we analyze the phylogenetic profile of MECP2 and discuss how comparative, molecular, and developmental evidence supports the idea that MECP2 gained significant importance in vertebrate nervous systems. This is because broad CpG methylation, postnatal accumulation of neuronal non-CpG methylation, and long-lived post-mitotic circuits created a growing need for stable yet flexible interpretation of methylation states. We further discuss evidence that MECP2 is functionally anchored to a conserved chromatin-repression axis, particularly the NCoR/SMRT corepressor machinery, while also showing signs of more lineage-restricted integration with mammalian dosage-sensitive regulatory networks. We propose that MECP2 is best understood as a vertebrate-specialized regulator that helps preserve transcriptional homeostasis in mature neurons while allowing experience-dependent plasticity. This framework links methylome interpretation to behavioral adaptation and may help explain why MECP2 dysregulation produces such profound and dosage-sensitive consequences for brain function and behavior.