High-resolution mapping of quantitative trait loci for emotionality in selected strains of mice

While a genetic contribution to many behavioral traits is not in doubt, attempts to find the genes themselves have not met with much success. One advance towards this goal has been the demonstration that it is possible to map genes that determine variation in quantitatively measured behavioral traits with crosses between inbred strains (both rodents and insects have been used). Further progress requires high-resolution mapping of quantitative trait loci (QTL). Current detection methods place QTLs within an interval of about half a chromosome, far too large for positional cloning to be a viable option, and a number of approaches have been advocated to increase resolution (Darvasi 1998). Here we report a novel, high-resolution mapping strategy that exploits the effects of artificial selection followed by inbreeding. The strategy requires prior information about the likely position of QTLs, such as would be available from an F 2 or backcross genome scan, and the localizations it provides need to be confirmed by further tests of segregation. For the latter purpose, we describe a variant of the recombinant inbred segregation test (RIST; Darvasi 1998), which can be employed for confirmation and further fine-mapping of QTLs. We have previously shown, using an F 2 genome scan, that three QTL (on Chrs 1, 12, and 15) contribute to the genetic variance of a psychological trait in mice termed emotionality. In that experiment, we used two measures of emotionality: total distance the animal traverses in 5 minutes in an open-field arena (open-field activity, OFA) and the number of fecal boli produced in the open field during the 5-min test period (open-field defecation, OFD; Flint et al. 1995). Calvin Hall devised the open-field arena in the 1930s (Hall 1934) as a way of assessing emotionality in rats primarily because strong emotion, especially fear, is known to result in defecation and urination in humans (Stouffer et al. 1949). The open-field arena is a white box or circular arena that is brightly lit and considered to be unpleasant for rats and mice. Animals that are relatively inactive (low OFA scores) and have high defecation scores are regarded as having higher emotionality scores (or being more emotionally reactive) than active animals with low defeca-tion scores. The two inbred strains in which we detected QTLs influencing emotionality are the product of an earlier selection experiment for open-field activity: BALB/cJ and C57BL/6 mice were intercrossed and offspring selected for differences in activity scores …