Academic journal article Genetics

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

Academic journal article Genetics

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

Article excerpt

BEHAVIORAL 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, Le., 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 ex- plain 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 se- quence encoded by a gene or affect gene expression. Such regulatory variants can be identified as "expression QTE' (eQTL). An attractive approach for nominating candidate genes underlying QTL is therefore to identify genes within the QTL regions whose expression is influenced by an eQTL in a tissue of relevance to the phenotype (Hubner et al. 2005; Petretto et al. 2006b; Mackay et al. 2009). This ap- proach has been successfully applied to quantitative traits in different species, e.g., yeast (Perlstein et al. 2007), rats (Hubner et al. 2005; Heinig et al. 2010), mice (Mehrabian et al. 2005; Schadt et al. 2005), and humans (Moffatt et al. 2007; Musunuru et al. 2010). A few eQTL studies have also recently been carried out to identify candidate genes for be- havioral 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 norvégiens) that, starting from one wild population, have been selected for in- creased tameness and increased aggression toward humans, respectively. These experimental populations derive from the work of Dmitry K. Belyaev who, along with his famous related work in foxes (Belyaev 1979; Trut 1999), initiated the rat lines to study the evolution and underlying biological mechanisms of tameness as a crucial first step in animal domestication (Diamond 1999; Trut 1999; Wiener and Wilkinson 2011). For >64 generations, the tame rats were selected exclusively based on whether they tolerate or even seek out human con- tact, while the aggressive rats were selected to vigorously de- fend themselves from any attempted handling. This strong selection has resulted in two lines that respond extremely differently to attempts of handling. Whereas the aggressive rats attack and try to escape, the tame rats lack fear or aggres- sion. They tolerate handling and sometimes actively explore the approaching hand. The strong behavioral selection has resulted in a number of differences in morphology, neurotransmitters, and hormone levels (Naumenko et al. 1989; Plyusnina and Oskina 1997; Albert et al. 2008).

Cross fostering experiments excluded postnatal maternal effects as a major influence on tameness and aggression in these animals, suggesting a substantial genetic contribution to the behavior (Albert et al. 2008; Plyusnina et aL 2009). To gain insight into the genetic basis of tameness and associated phenotypes, we earlier bred an F2 intercross between the tame and aggressive rat lines (Albert et al. 2009). Genetic mapping in 700 rats from this population revealed two genome-wide sig- nificant QTL for tameness. …

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