AbstractNeurons have become highly diverse in cell size, morphology, phenotype and function in mammalian evolution, whereas glial cells are much less varied in size and types across species. This difference in diversity suggests that neuron-specific protein-coding gene sequences have admitted more variation in evolution, that is, are less evolutionarily conserved than those expressed in glial cells. We calculated values of dN/dS from Ensembl98 for coding sequences expressed specifically in neurons, astrocytes, oligodendrocytes, microglia and endothelial cells in the brain across 92 mammalian species with reference to either mouse or human. Surprisingly, we find that protein-coding sequences that are specifically expressed in neurons are far less variable than those specific to other cell types in the brain. We next analyzed phastCons values for the same genes and found that neuron-specific promoter sequences are at least as conserved as other cell type-specific promoter sequences. Moreover, neuron-specific coding sequences are as highly conserved across mammalian species as ATPase coding sequences, the benchmark of evolutionary conservation, followed by heart and skeletal muscle-specific sequences. Neuronal diversity in mammalian evolution thus arises despite high levels of negative selection on neuron-specific protein-coding sequences. We propose that such strong evolutionary conservation is imposed by excitability, which continually exposes cells to the risk of excitotoxic death, and speculate that variability of neuronal cell sizes arises as a consequence of variability in levels of activity, possibly constrained by energy supply to the developing brain.Significance StatementThe majority of cells in the mammalian body, including glial cells in the brain, maintain a constant size across species from mice to elephants. The exception is neurons, whose size varies over 100- fold both within each brain and across species, often becoming larger in larger brains. What evolutionary mechanism allows neurons to be so exceptionally diverse in size? We show that neuron-specific genes are some of the most highly conserved in mammalian evolution, which implicates alternate causes of diversity in neuronal cell size beyond heritable genetics. We propose a novel direction of research into how neuronal cell size diversity might be a self-organized response to variations in levels of activity, which are an exclusive property of excitable cells like neurons.
Neuron-specific coding sequences are the most highly conserved in the mammalian brain