An integrative functional genomics approach towards quantitative trait gene nomination in existing and emerging mouse genetic reference populations

An approach that has been widely applied for the genetic dissection of complex traits is Quantitative Trait Locus (QTL) mapping. QTL mapping identifies genomic regions that harbor polymorphisms, responsible for the observed variation in a complex trait. If these polymorphisms are located within a gene, then these genes are called Quantitative Trait Genes (QTG). Prior to advancements in QTL mapping populations, QTL mapping resolution was often poor, resulting in large QTL intervals. Therefore, after mapping a QTL, fine mapping was initiated to further reduce the QTL interval and to identify the QTG. While successful, fine mapping using genetic approaches have been extremely time and resource intensive, making it the rate-limiting step in QTG discovery. Thus far, only a few QTGs have been successfully identified and validated. The disproportionate ratio of QTLs mapped to QTGs identified has been a cause of concern. Successful QTG discovery relies on the power and resolution with which QTLs are mapped and the genetic architecture of the underlying QTL mapping population. Here, QTL mapping performance in two recently developed QTL mapping populations, namely the expanded BXD Recombinant Inbred (RI) strain panel and the collaborative cross (CC) are assessed. Results indicate that while both the expanded BXD RI strain panel and the CC improve QTL mapping resolution, the CC is able to achieve greater precision and resolution in QTL v mapping. However, neither the BXD RI nor the CC facilitates gene level resolution in QTL mapping. Recent studies have used the integration and convergence of evidence among functional genomics studies as a successful strategy towards the efficient and rapid nomination of QTG. Here, the complementary in silico approach of integrative functional genomics, using GeneWeaver (www.geneweaver.org), is applied towards the reduction of two cocaine-induced locomotor activation QTLs, mapped in the expanded BXD RI strain panel. Integrative functional genomic analyses of these QTLs led to the nomination of Rab3b as a putative QTG. Functional assessment of Rab3b using Rab3bcd knockout mice reveals its role in acute habituation mediated cocaine response, serving as evidence of the efficiency and utility of integrative functional genomics for the identification of highly relevant QTG.