Genetic Correlates of Gene Expression in Recombinant Inbred Strains: A Relational Model System to Explore Neurobehavioral Phenotypes

Abstract

Full genome sequencing, high-density genotyping, expanding sets of microarray assays, and systematic phenotyping of neuroanatomical and behavioral traits are producing a wealth of data on the mouse central nervous system (CNS). These disparate resources are still poorly integrated. One solution is to acquire these data using a common reference population of isogenic lines of mice, providing a point of integration between the data types. Recombinant inbred (RI) mice, derived through inbreeding of progeny from an inbred cross, are a powerful tool for complex trait mapping and analysis of the challenging phenotypes of neuroscientific interest. These isogenic RI lines are a retrievable genetic resource that can be repeatedly studied using a wide variety of assays. Diverse data sets can be related through fixed and known genomes, using tools such as the interactive web-based system for complex trait analysis, www.WebQTL.org. In this report, we demonstrate the use of WebQTL to explore complex interactions among a wide variety of traits--from mRNA transcripts to the impressive behavioral and pharmacological variation among RI strains. The relational approach exploiting a common set of strains facilitates study of multiple effects of single genes (pleiotropy) without a priori hypotheses required. Here we demonstrate the power of this technique through genetic correlation of gene expression with a database of neurobehavioral phenotypes collected in these strains of mice through more than 20 years of experimentation. By repeatedly studying the same panel of mice, early data can be re-examined in light of technological advances unforeseen at the time of their initial collection.

Correlation analysis between genome-wide expression profiles and cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

“…29,30 We employed the approach to identify genes and biological processes that are associated with cytoarchitectural abnormalities found in the PFC of major psychiatric disorders. Our functional annotation analysis revealed that multiple biological processes including cell metabolism, neurodevelopment, cell motility and programmed cell death were commonly associated with the prefrontal cytoarchitectural deficits of perineuronal oligodendrocytes (Table 4) and calbindin-positive GABAergic neurons (Table 5).…”

The methylated-DNA binding protein MBD2 enhances NGFI-A (egr-1)-mediated transcriptional activation of the glucocorticoid receptor

“…We then performed an in silico analysis of the relation between MBD2 expression and that of the GR gene using data hippocampal expression analyses with recombinant mouse strains available through the NIH-supported project (http://www.genenet work.org) [29]. The GeneNetwork database contains data …”

The Collaborative Cross, a community resource for the genetic analysis of complex traits

“…genetic structure of the RI strains will enable us to establish networks of functionally important relationships within and among diverse sets of physiological and behavioral phenotypes 13,14 . Gene-environment interaction is a crucial problem in genetics, and a key contributor to most common diseases, which has been difficult to study in any mammalian population.…”