The increased tameness to reduce avoidance of human in wild animals has been long proposed as the key step of animal domestication. The tameness is a complex behavior trait and largely determined by genetic factors. However, the underlying genetic mutations remain vague and how they influence the animal behaviors is yet to be explored. Behavior tests of a wild-domestic hybrid goat population indicate the locus under strongest artificial selection during domestication may exert a huge effect on the flight distance. Within this locus, only one missense mutation RRM1 ^I241V which was present in the early domestic goat ~6500 years ago. Genome editing of RRM1 ^I241V in mice showed increased tameness and sociability and reduced anxiety. These behavioral changes induced by RRM1 ^I241V were modulated by the alternation of activity of glutamatergic synapse and some other synapse-related pathways. This study established a link between RRM1 ^I241V and tameness, demonstrating that the complex behavioral change can be achieved by mutations under strong selection during animal domestication.