BACKGROUND: The neuronal synapse is a fundamental functional unit in the central 
nervous system of animals. Because synaptic function is evolutionarily 
conserved, we reasoned that functional sequences of genes and related genomic 
elements known to play important roles in neurotransmitter release would also be 
conserved.
RESULTS: Evolutionary rate analysis revealed that presynaptic proteins evolve 
slowly, although some members of large gene families exhibit accelerated 
evolutionary rates relative to other family members. Comparative sequence 
analysis of 46 megabases spanning 150 presynaptic genes identified more than 
26,000 elements that are highly conserved in eight vertebrate species, as well 
as a small subset of sequences (6%) that are shared among unrelated presynaptic 
genes. Analysis of large gene families revealed that upstream and intronic 
regions of closely related family members are extremely divergent. We also 
identified 504 exceptionally long conserved elements (> or =360 base pairs, > or 
=80% pair-wise identity between human and other mammals) in intergenic and 
intronic regions of presynaptic genes. Many of these elements form a highly 
stable stem-loop RNA structure and consequently are candidates for novel 
regulatory elements, whereas some conserved noncoding elements are shown to 
correlate with specific gene expression profiles. The SynapseDB online database 
integrates these findings and other functional genomic resources for synaptic 
genes.
CONCLUSION: Highly conserved elements in nonprotein coding regions of 150 
presynaptic genes represent sequences that may be involved in the 
transcriptional or post-transcriptional regulation of these genes. Furthermore, 
comparative sequence analysis will facilitate selection of genes and noncoding 
sequences for future functional studies and analysis of variation studies in 
neurodevelopmental and psychiatric disorders.