A common feature of domestic animals is tameness-i.e., they tolerate and are unafraid of human presence and handling. To gain insight into the genetic basis of tameness and aggression, we studied an intercross between two lines of rats (Rattus norvegicus) selected over .60 generations for increased tameness and increased aggression against humans, respectively. We measured 45 traits, including tameness and aggression, anxiety-related traits, organ weights, and levels of serum components in .700 rats from an intercross population. Using 201 genetic markers, we identified two significant quantitative trait loci (QTL) for tameness. These loci overlap with QTL for adrenal gland weight and for anxiety-related traits and are part of a five-locus epistatic network influencing tameness. An additional QTL influences the occurrence of white coat spots, but shows no significant effect on tameness. The loci described here are important starting points for finding the genes that cause tameness in these rats and potentially in domestic animals in general.

Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F 2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for .64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F 2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F 2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. B EHAVIORAL differences among members of a species are in part due to genetic variation. The identification of the genes and variants that influence behavior remains challenging. In human genome-wide association studies of psychiatric and cognitive traits, the identified loci typically explain only a small fraction of the heritability, i.e., the additive genetic contribution to the trait (Watanabe et al. 2007;Hovatta and Barlow 2008;Deary et al. 2009;Otowa et al. 2009;Calboli et al. 2010;Terracciano et al. 2010;Flint and Munafo 2013;Rietveld et al. 2013;Sokolowska and Hovatta 2013). In experimental crosses in model species, especially between inbred lines, the identified loci (termed quantitative trait loci, QTL), often explain much more of the heritability (Lynch and Walsh 1998). However, in this design the spatial resolution is limited-the QTL are wide and contain many, sometimes hundreds of genes. With the exception of a handful of identified genes with quantitative effects on behavioral traits (Yalcin et al. 2004;Watanabe et al. 2007;McGrath et al. 2009;Bendesky et al. 2012;Goodson et al. 2012), gene identification is particularly difficult for behavioral QTL that often have modest effect sizes (Flint 2003;Willis-Owen and Flint 2006;Wright et al. 2006;Hovatta and Barlow 2008).The causal variants within a QTL can alter the protein sequence encoded by a gene or affect gene expression. Such Musunuru et al. 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al. 2004;De Jong et al. 2011;Saba et al. 2011;Kelly et al. 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental...

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