Rufy1 or Hnrnph1 is a likely quantitative trait gene for methamphetamine sensitivity

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Sensitivity to the locomotor stimulant properties of drugs of abuse is a heritable trait and its genetic basis may be shared with alleles that modulate activation of the mesolimbic reward pathway. We previously used mouse lines derived from C57BL/6J and DBA/2J alleles that were selected for high and low methamphetamine (MA) sensitivity and identified a genome‐wide significant quantitative trait locus (QTL) on chromosome 11. In order to further pursue this QTL, we utilized the power of an F2 cross and the iterative nature of interval‐specific congenic lines in an effort to identify the causal gene(s) underlying this QTL. The results of F2 mice and the larger congenic lines revealed two large‐effect QTLs for MA‐induced locomotor activity; however, the phenotypic results of the smaller subcongenic lines revealed additional smaller effect QTLs with different modes of inheritance. One subcongenic locus converged remarkably well with the QTL peak in the F2 cross and altered methamphetamine sensitivity in a time‐dependent manner. We generated eight sub‐subcongenic lines derived from this subcongenic line (17 congenic lines total). Owing to a fortuitous recombination event, we identified and replicated a 0.23 Mb region spanning 50.17–50.40 Mb that was critical for MA sensitivity. This region contains only three genes (Rufy1, Hnrnph1, and Cby3) and only two of these genes are expressed in the brain (Rufy1 and Hnrnph1). This study exemplifies how a careful and detailed use of congenic lines can yield narrow QTL intervals and a tractable number of genes for quantitative trait gene identification.