The laboratory rat, widely used in biomedical research, is domesticated from wild brown rat. The origin and genetic mechanism underlying domestication of the laboratory rat remain largely elusive. In the present study, large scale genomes supported a single origin for the laboratory rat, possibly from a sister group to wild rats from Europe/Africa/Middle East. Genomic and transcriptomic analyses uncovered many artificially selected genes (e.g. FOXP2, B3GAT1, and CLOCK) involved in the nervous system. These genes associate with learning ability and regulation of circadian rhythm, which likely enabled the successful domestication of the laboratory rat. Particularly, many genes, including mitochondrial genes responsible for energy metabolism, displayed a substantially increased expression in the brain of laboratory rats compared to wild rats. Our findings demystify the origin and evolution of this model animal, and provide insight into the process of its domestication