G-NEST: a gene neighborhood scoring tool to identify co-conserved, co-expressed genes
1 Genome Center, University of California Davis, 451 Health Science Dr, Davis, CA, 95616, United States of America
2 Department of Food Science and Technology, University of California Davis, One Shields Avenue, Davis, CA, 95616, United States of America
3 Center for Biomolecular Science and Engineering, University of California Santa Cruz, 1156 High St, Santa Cruz, CA, 95064, United States of America
4 Department of Pediatrics, Children’s Nutrition Research Center, Baylor College of Medicine, 1100 Bates Street, Houston, TX, 77030, United States of America
5 Gladstone Institutes, Division of Biostatistics and Institute for Human Genetics, University of California San Francisco, 1650 Owens St, San Francisco, CA, 94158, United States of America
BMC Bioinformatics 2012, 13:253 doi:10.1186/1471-2105-13-253Published: 28 September 2012
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) which 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 webcite