The identification of the causative genetic variants in quantitative trait loci (QTL) influencing phenotypic traits is challenging, especially in crosses between outbred strains. We have previously identified several QTL influencing tameness and aggression in a cross between two lines of wild-derived, outbred rats (Rattus norvegicus) selected for their behavior towards humans. Here, we use targeted sequence capture and massively parallel sequencing of all genes in the strongest QTL in the founder animals of the cross. We identify many novel sequence variants, several of which are potentially functionally relevant. The QTL contains several regions where either the tame or the aggressive founders contain no sequence variation, and two regions where alternative haplotypes are fixed between the founders. A re-analysis of the QTL signal showed that the causative site is likely to be fixed among the tame founder animals, but that several causative alleles may segregate among the aggressive founder animals. Using a formal test for the detection of positive selection, we find 10 putative positively selected regions, some of which are close to genes known to influence behavior. Together, these results show that the QTL is probably not caused by a single selected site, but may instead represent the joint effects of several sites that were targets of polygenic selection.
Bibliographical noteFunding Information:
We are grateful to Lars Rönnegard and Elizabeth Blankenhorn for insightful discussions, and to Martin Kircher for help with sequence analysis, and to the reviewers for constructive comments on the manuscript. This work was supported by funds from the Max Planck Society, the Swedish Foundation for Strategic Research the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, a EURYI Award to ÖC, and HHMI and NIH grant #P01 CA013106-39.
- High-throughput sequencing
- Positive selection
- QTL mapping
- Sequence capture