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Patterns of sequence conservation in presynaptic neural genes

Dexter Hadley12, Tara Murphy34, Otto Valladares3, Sridhar Hannenhalli12, Lyle Ungar15, Junhyong Kim156 and Maja Bućan13*

Author Affiliations

1 Penn Center for Bioinformatics, 423 Guardian Drive, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

2 Genomics and Computational Biology Graduate Group, 423 Guardian Drive, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

3 Department of Genetics in the School of Medicine, University of Pennsylvania, 415 Curie Boulevard Philadelphia, Pennsylvania 19104, USA

4 UCLA Neuroscience Graduate Office, 695 Young Drive South, Los Angeles, California 90095, USA

5 Department of Computer & Information Sciences in School of Engineering and Applied Sciences, 3330 Walnut Street, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

6 Department of Biology in the School of Arts and Sciences, 433 S University Avenue, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

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Genome Biology 2006, 7:R105  doi:10.1186/gb-2006-7-11-r105

Published: 10 November 2006

Abstract

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 (≥360 base pairs, ≥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.