Identification of quantitative trait Loci that affect aggressive behavior in mice.

Despite the previous development of single-gene knock-out mice that exhibit alterations in aggressive behavior, very little progress has been made toward identifying the natural gene variants (alleles) that contribute to individual or strain differences in aggression. Whereas most inbred mouse strains show an intermediate level of inter-male aggression in the resident-intruder or dangler behavioral tests, NZB/B1NJ mice are extremely aggressive and A/J mice are extremely unaggressive. We took advantage of the large phenotypic difference between these strains and used an outcross-backcross breeding protocol and a genome-wide scan to identify aggression quantitative trait loci (QTLs) on distal chromosome 10 (Aggr1; p = 6 x 10(-7)) and proximal chromosome X (Aggr2; p = 2.14 x 10(-5)). Candidate genes for Aggr1 and Aggr2, respectively, include the diacylglycerol kinase alpha subunit gene (Dagk1) and the glutamate receptor subunit AMPA3 gene (Gria3). This is the first report of significant aggression QTLs established through a genome-wide scan in any mammal. The mapping of these QTLs is a step toward the definitive identification of mouse alleles that affect aggression and may lead, ultimately, to the discovery of homologous alleles that affect individual differences in aggression within other mammalian species.