Combined application of behavior genetics and microarray analysis to identify regional expression themes and gene-behavior associations.
In this report we link candidate genes to complex behavioral phenotypes by using a behavior genetics approach. Gene expression signatures were generated for the prefrontal cortex, ventral striatum, temporal lobe, periaqueductal gray, and cerebellum in eight inbred strains from priority group A of the Mouse Phenome Project. Bioinformatic analysis of regionally enriched genes that were conserved across all strains revealed both functional and structural specialization of particular brain regions. For example, genes encoding proteins with demonstrated anti-apoptotic function were over-represented in the cerebellum, whereas genes coding for proteins associated with learning and memory were enriched in the ventral striatum, as defined by the Expression Analysis Systematic Explorer (EASE) application. Association of regional gene expression with behavioral phenotypes was exploited to identify candidate behavioral genes. Phenotypes that were investigated included anxiety, drug-naive and ethanol-induced distance traveled across a grid floor, and seizure susceptibility. Several genes within the glutamatergic signaling pathway (i.e., NMDA/glutamate receptor subunit 2C, calmodulin, solute carrier family 1 member 2, and glutamine synthetase) were identified in a phenotype-dependent and region-specific manner. In addition to supporting evidence in the literature, many of the genes that were identified could be mapped in silico to surrogate behavior-related quantitative trait loci. The approaches and data set described herein serve as a valuable resource to investigate the genetic underpinning of complex behaviors.
Letwin
Noah E
NE
Department of Functional Genomics, The Institute for Genomic Research, Rockville, Maryland 20850, USA.
Kafkafi
Neri
N
Benjamini
Yoav
Y
Mayo
Cheryl
C
Frank
Bryan C
BC
Luu
Troung
T
Lee
Norman H
NH
Elmer
Greg I
GI
D000437:Alcoholism / Q000235:genetics; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D001923:Brain Chemistry / Q000235:genetics; D001931:Brain Mapping / Q000379:methods; D002874:Chromosome Mapping / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000502:physiology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005824:Genetics, Behavioral / Q000379:methods*; D023281:Genomics / Q000379:methods*; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity
D018698:Glutamic Acid