Tas2r alleles at this locus, and RI lines containing C57BL/6J Tas2r alleles are more sensitive to QHCl than are lines containing DBA/2J alleles. Thus, the entire Tas2r cluster comprises a large haplotype that correlates with quinine taster status. Conclusion These studies, the first using a taste-salient assay to map the major QTL for quinine taste, indicate that a T2R-dependent transduction cascade is responsible for the majority of strain variance in quinine taste sensitivity. Furthermore, the large number of polymorphisms within coding exons of the Tas2r cluster, coupled with evidence that inbred strains exhibit largely similar bitter taste phenotypes, suggest that T2R receptors are quite tolerant to variation. Background Animals use the gustatory system to provide information about food quality. For example, sweet-tasting foods may have a high caloric content and are preferred, while bitter-tasting foods often contain toxic substances, and are generally avoided. Two families of G protein-coupled receptors (GPCRs) expressed in subpopulations of taste receptor cells (TRCs) of the gustatory epithelium have been implicated in the detection and transduction of sweet, bitter and umami (i.e., glutamate) taste: T1Rs for sweet-and umami-tasting stimuli [1-8], and T2Rs for bitter-tasting compounds [9-11]. The genes that encode T2Rs, the Tas2rs, were first identified by database mining of mammalian genomes near chromosomal markers previously linked to differences in bitter taste sensitivity [9,11-18]. In mice, the majority of Tas2rs lie within a single cluster on distal chromosome 6. Thirty-three human Tas2rs (including 8 pseudogenes) and thirty-six mouse Tas2rs (including 3 pseudogenes in C57BL/6J mice) have been identified [9,11,19], and several of these respond to particular bitter stimuli in heterologous expression assays [10,20-23], or represent a strong candidate gene for a specific bitter taste quantitative trait [18,24,25]. Several quantitative trait loci (QTL) have been identified that influence two-bottle intake of bitter stimuli in the mouse, including loci for quinine (Qui) [12,16,26], cyclohexamide (Cyx) [13] and sucrose octaacetate (Soa) [14,15,17] sensitivity. Each of these QTL map to mouse distal chromosome 6 and are linked to the marker D6Mit13, which lies within a cluster of 24 intact Tas2rs in the C57BL/6 genome (e.g., [16,27,28]). However, the interpretation of these studies remains problematic for two reasons. First, the density of chromosomal markers and number of recombinant inbred (RI) strains used in these earlier studies did not permit the physical definition of the intervals containing each QTL. Second, these previous attempts to map bitter taste QTLs relied on behavioral assays that measured consumption, and were thus susceptible to contributions of post-ingestive eff