Origin and evolution of developmental enhancers in the mammalian neocortex.
Morphological innovations such as the mammalian neocortex may involve the evolution of novel regulatory sequences. However, de novo birth of regulatory elements active during morphogenesis has not been extensively studied in mammals. Here, we use H3K27ac-defined regulatory elements active during human and mouse corticogenesis to identify enhancers that were likely active in the ancient mammalian forebrain. We infer the phylogenetic origins of these enhancers and find that ∼20% arose in the mammalian stem lineage, coincident with the emergence of the neocortex. Implementing a permutation strategy that controls for the nonrandom variation in the ages of background genomic sequences, we find that mammal-specific enhancers are overrepresented near genes involved in cell migration, cell signaling, and axon guidance. Mammal-specific enhancers are also overrepresented in modules of coexpressed genes in the cortex that are associated with these pathways, notably ephrin and semaphorin signaling. Our results also provide insight into the mechanisms of regulatory innovation in mammals. We find that most neocortical enhancers did not originate by en bloc exaptation of transposons. Young neocortical enhancers exhibit smaller H3K27ac footprints and weaker evolutionary constraint in eutherian mammals than older neocortical enhancers. Based on these observations, we present a model of the enhancer life cycle in which neocortical enhancers initially emerge from genomic background as short, weakly constrained "proto-enhancers." Many proto-enhancers are likely lost, but some may serve as nucleation points for complex enhancers to evolve.
Department of Genetics, Yale School of Medicine, New Haven, CT;
Deena
D
Emera
Department of Genetics, Yale School of Medicine, New Haven, CT;
Jun
J
Yin
Department of Genetics, Yale School of Medicine, New Haven, CT;
Steven K
SK
Reilly
Department of Genetics, Yale School of Medicine, New Haven, CT;
Jake
J
Gockley
Department of Genetics, Yale School of Medicine, New Haven, CT; Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511 james.noonan@yale.edu.
James P
JP
Noonan
D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D003198:Computer Simulation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009024:Morphogenesis / Q000235:genetics*; D019579:Neocortex / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics*
D014157:Transcription Factors
brain evolution; epigenetics; neocortical development; regulatory innovation