Neuron-specific homologous coding genes and non-coding regulatory regions are the most conserved amongst amniotes despite neuron-specific cell size diversity.

Neurons are unique in that they are the only cell type in the body to display massive diversity in cell size, morphology, phenotype, and function both within individuals and across species. Previous studies comparing human to mouse and chimpanzee genomes reported that neuron-specific sequences are more conserved than nonneuronal-specific sequences, which is seemingly at odds with the enormous variation that we have documented in neuronal, but not nonneuronal, cell densities across individuals and hundreds of species. Here we use datasets encompassing up to 92 mammalian and 31 sauropsidian species to examine whether neuron-specific diversity occurs with higher evolutionary variation of homologous neuron-specific coding genes and regulatory regions compared to non-neuronal counterparts across the entirety of amniotes. We find that neuronal diversity in mammalian and sauropsidian evolution arose despite extreme levels of average negative selection on homologous neuron-specific protein-coding sequences which we show to be on par with ATPase coding sequences, the benchmark of evolutionary conservation. Further, we show that the high conservation of homologous neuron-specific sequences is not simply attributable to high expression levels. We argue that such strong evolutionary conservation may be imposed by excitability, which continually exposes neurons to the risk of excitotoxic death.