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Title: G-NEST: A gene neighborhood scoring tool to identify co-conserved, co-expressed genes

Author
item LEMAY, DANIELLE - University Of California
item MARTIN, WILLIAM - University Of California
item HINRICHS, ANGIE - University Of California
item RIJNKELS, MONIQUE - Children'S Nutrition Research Center (CNRC)
item GERMAN, J BRUCE - University Of California
item KORF, IAN - University Of California
item POLLARD, KATHERINE - University Of California

Submitted to: BMC Bioinformatics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/23/2012
Publication Date: 9/28/2012
Citation: Lemay, D.G., Martin, W.F., Hinrichs, A.S., Rijnkels, M., German, J., Korf, I., Pollard, K.S. 2012. G-NEST: A gene neighborhood scoring tool to identify co-conserved, co-expressed genes. BMC Bioinformatics. 13(253):1-17.

Interpretive Summary: To be able to better identify how the genes in the genome are regulated, a computational tool was developed that identifies gene neighborhoods, or clusters of genes that are expressed at the same time and reside in the same area of the genome. The tool uses information on the location and expression of genes as well as the evolutionary conservation of the DNA sequence to identify putative gene neighborhoods. Using the tool, it was shown that non-random gene order is primarily caused by tandem-duplication of genes, aided by certain other characteristics such as function, protein-protein interaction, and gene orientation. This information will aid researchers and the softwere tool is available for us.

Technical Abstract: In previous studies, gene neighborhoods--spatial clusters of co-expressed genes in the genome--have been defined using arbitrary rules such as requiring adjacency, a minimum number of genes, a fixed window size, or a minimum expression level. In the current study, we developed a Gene Neighborhood Scoring Tool (G-NEST) that combines genomic location, gene expression, and evolutionary sequence conservation data to score putative gene neighborhoods across all possible window sizes simultaneously. Using G-NEST on atlases of mouse and human tissue expression data, we found that large neighborhoods of ten or more genes are extremely rare in mammalian genomes. When they do occur, neighborhoods are typically composed of families of related genes. Both the highest scoring and the largest neighborhoods in mammalian genomes are formed by tandem gene duplication. Mammalian gene neighborhoods contain highly and variably expressed genes. Co-localized noisy gene pairs exhibit lower evolutionary conservation of their adjacent genome locations, suggesting that their shared transcriptional background may be disadvantageous. Genes that are essential to mammalian survival and reproduction are less likely to occur in neighborhoods, although neighborhoods are enriched with genes that function in mitosis. We also found that gene orientation and protein-protein interactions are partially responsible for maintenance of gene neighborhoods. Our experiments using G-NEST confirm that tandem gene duplication is the primary driver of non-random gene order in mammalian genomes. Non-essentiality, co-functionality, gene orientation, and protein-protein interactions are additional forces that maintain gene neighborhoods, especially those formed by tandem duplicates. We expect G-NEST to be useful for other applications such as the identification of core regulatory modules, common transcriptional backgrounds, and chromatin domains. The software is available at http://docpollard.org/software.html.