Positional cloning of the mouse saccharin preference (Sac) locus

Differences in sweetener intake among inbred strains of mice are partially determined by allelic variation of the saccharin preference (Sac) locus. Ge netic and physical mapping limited a critical genomic interval containing S ac to a 194 kb DNA fragment. Sequencing and annotation of this region ident ified a gene (Tas1r3) encoding the third member of the T1R family of putati ve taste receptors, T1R3. Introgression by serial backcrossing of the 194 k b chromosomal fragment containing the Tas1r3 allele from the high-sweetener -preferring C57BL/6ByJ strain onto the genetic background of the low-sweete ner-preferring 129P3/J strain rescued its low-sweetener-preference phenotyp e. Polymorphisms of Tas1r3 that are likely to have functional significance were identified using analysis of genomic sequences and sweetener-p referen ce phenotypes of genealogically distant mouse strains. Tas1r3 has two commo n haplotypes, consisting of six single nucleotide polymorphisms: one haplot ype was found in mouse strains with elevated sweetener preference and the o ther in strains relatively indifferent to sweeteners. This study provides c ompelling evidence that Tas1r3 is equivalent to the Sac locus and that the T1R3 receptor responds to sweeteners.