Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Henrike O. Heyne, Susann Lautenschläger, Ronald Nelson, François Besnier, Maxime Rotival, Alexander Cagan, Rimma Kozhemyakina, Irina Z. Plyusnina, Lyudmila Trut, Örjan Carlborg, Enrico Petretto, Leonid Kruglyak, Svante Pääbo, Torsten Schöneberg, Frank W. Albert
(Submitted on 14 Apr 2014)

Inter-individual 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 F2 intercross of two outbred lines of rats selected for tame and aggressive behavior towards humans for more than 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 F2 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 F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40 and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals.

One thought on “Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

  1. Nice paper. We discussed it at our lab journal club last week. Here were a comments that came up:

    -Richer use of RNAseq. Can the RNAseq be used to identify loss of function variants or mono allelic expression that might arise from a deletion? Given the large number of eQTLs at the largest tameness loci, I wonder if allele specific expression (using coding SNPs identified by RNAseq) could be used to either improve mapping resolution or clarify the causal role of local genetic variation.

    -tame-1. Is there any evidence that the tame-1 locus has a reduced recombination rate? Ie is there an inversion or something else suppressing recombination? Or is the size of the critical interval about what one should expect given the effect size and number of observed meioses? Conversely, is there any evidence that the locus harbors multiple linked, functional variants? Are the effects in the same direction for the eqtl and tame-1 correlations? Are closely linked genes enriched for effects in the same direction, which might suggest a shared causal variant?

    -Replication. Given the hypothesis that selection acted on standing variation, could the authors use data from a more heterogeneous cross to map the basis of tameness related traits or brain eQTLs in unselected individuals? Perhaps this could provide replication and improved resolution.

    -Figure 1. Probably because of our lack of experience with linkage analysis, we found the allele effect plots difficult to interpret.

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