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A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21–q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility ( Szs1 ), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 ( Qrr1 ) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by  Qrr1 .  Qrr1  can be broadly divided into a proximal part ( Qrr1p ) and a distal part ( Qrr1d ), each associated with the expression of distinct subsets of genes.  Qrr1d  controls RNA metabolism and protein synthesis, including the expression of ∼20 aminoacyl-tRNA synthetases.  Qrr1d  contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases.  Rgs7  and  Fmn2  are other strong candidates in  Qrr1d . FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of  Fmn2  had a strong effect on the expression of few genes modulated by  Qrr1d . Our analysis revealed a highly complex gene expression regulatory interval in  Qrr1 , composed of multiple loci modulating the expression of functionally cognate sets of genes.

Dissection of a QTL Hotspot on Mouse Distal Chromosome 1 that Modulates Neurobehavioral Phenotypes and Gene Expression