Genomics and variation of ionotropic glutamate receptors

Sequencing of the human, mouse, and rat genomes has enabled a comprehensive informatics approach to gene families. This approach is informative for identification of new members of gene families, for cross-species sequence conservation related to functional conservation, for within-species diversity related to functional variation, and for historical effects of selection. This genome informatics approach also focuses our attention on genes whose genomic locations coincide with linkages to phenotypes. We are identifying ionotropic glutamate receptor (IGR) sequence variation by resequencing technologies, including denaturing high-performance liquid chromoatography (dHPLC), for screening and direct sequencing, and by information mining of public (e.g., dbSNP and ENSEMBL) and private (i.e., Celera Discovery System) sequence databases. Each of the 16 known IGRs is represented in these databases, their positions on a canonical physical map (for example, the Celera map) are established, and comparison to mouse and rat sequences has been performed, revealing substantial conservation of these genes, which are located on different chromosomes but found within syntenic groups of genes. A collection of 38 missense variants were identified by the informatics and resequencing approaches in several of these receptor genes, including GRIN2B, GRIN3B, GRIA2, GRIA3, and GRIK1. This represents only a fraction of the sequence variation across these genes, but, in fact, these may constitute a large fraction of the common polymorphisms at these genes, and these polymorphisms are a starting point for understanding the role of these receptors in neurogenetic variation. Genetically influenced human neurobehavioral phenotypes that are likely to be linked to IGR genetic variants include addictions, anxiety/dysphoria disorders, post-brain injury behavioral disorders, schizophrenia, epilepsy, pain perception, learning, and cognition. Thus, the effects of glutamate receptor variation may be protean, and the task of relating variation to behavior difficult. However, functional variants of (1) catechol-O-methyltransferase, (2) serotonin transporter, and (3) brain-derived neurotrophic factor have recently been linked both to behavioral differences and to intermediate phenotypes, suggesting a pathway by which functional variation at IRS can be tied to an etiologically complex phenotype.