Linking dopamine neurotransmission and neurogenesis: The evolutionary history of the NTAD (NCAM1-TTC12-ANKK1-DRD2) gene cluster

Genetic studies have long suggested the important role of the DRD2 gene in psychiatric disorders and behavior. Further research has shown a conjoined effect of genes in the Chr11q22–23 region, which includes the NCAM1, TTC12, ANKK1 and DRD2 genes, or NTAD cluster. Despite a growing need to unravel the role of this cluster, few studies have taken into account interspecies and evolutionary approaches. This study shows that behaviorally relevant SNPs from the NTAD cluster, such as rs1800497 (Taq1A) and rs6277, are ancient polymorphisms that date back to the common ancestor between modern humans and Neanderthals/Denisovans. Conserved synteny and neighborhood indicate the NTAD cluster seems to have been established at least 400 million years ago, when the first Sarcopterygians emerged. The NTAD genes are apparently co-regulated and this could be attributed to adaptive functional properties, including those that emerged when the central nervous system became more complex. Finally, our findings indicate that NTAD genes, which are related to neurogenesis and dopaminergic neurotransmission, should be approached as a unit in behavioral and psychiatric genetic studies.