High‐precision genetic mapping of behavioral traits in the diversity outbred mouse population

Abstract

Historically our ability to identify genetic variants underlying complex behavioral traits in mice has been limited by low mapping resolution of conventional mouse crosses. The newly developed Diversity Outbred (DO) population promises to deliver improved resolution that will circumvent costly fine mapping studies. The DO is derived from the same founder strains as the Collaborative Cross (CC), including three wild derived strains. Thus the DO provides more allelic diversity and greater potential for new discovery compared to crosses involving standard mouse strains. We have characterized 283 male and female DO mice using open-field, light-dark box, tail-suspension, and visual-cliff avoidance tests to generate 38 behavioral measures. We identified several quantitative trait loci (QTL) for these traits with support intervals ranging from 1 to 3 Mb in size. These intervals contain relatively few genes (ranging from 5 to 96). For a majority of QTL, using the founder allelic effects together with whole genome sequence data, we could further narrow the positional candidates. Several QTL replicate previously published loci. Novel loci were also identified for anxiety- and activity-related traits. Half of the QTLs are associated with wild-derived alleles, confirming the value to behavioral genetics of added genetic diversity in the DO. In the presence of wild-alleles we sometimes observe behaviors that are qualitatively different from the expected response. Our results demonstrate that high-precision mapping of behavioral traits can be achieved with moderate numbers of DO animals, representing a significant advance in our ability to leverage the mouse as a tool for behavioral genetics.

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…The CC, OS, and HMDP tend to show a somewhat different picture. A QTL study using the DO strains identified seven QTLs that each accounted for 11%-14% of the variance for behavioral tests related to open-field, light-dark box, tail suspension, and a visual cliff (Logan et al 2013). These effects are considerably larger than those found in humans.…”

“…As a result, CSSs can detect weaker and hence more QTLs than other resources given similar sample sizes. A striking example involves results from two recent studies (Logan et al 2013;Spiezio et al 2014). One study focused on behavioral traits in DO mice and the other on metabolic traits in CSSs.…”

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

“…If this "humanized" mouse model phenocopies ARPKD, then we will generate a mutant F 2 cohort using the newly described resource, Diversity Outbred mice. 39 The Diversity Outbred stock is derived from eight inbred mouse lines and is an ideal resource for high-resolution genetic mapping, obviating the need for costly fine-mapping studies. Taken together, these efforts will provide complementary strategies for identifying ARPKD-related QTL.…”

Comment la souris est devenue, timidement, une espèce modèle pour la recherche en génétique animale et humaine

“…Il est inutile d'élever les souris du DO, il suffit de les commander au Jackson Laboratory. La mesure du phénotype d'intérêt chez quelques centaines d'individus du DO permet d'identifier des gènes ségrégant avec le phénotype d'intérêt (Logan et al 2013). Dans les années à venir, l'utilisation combinée du CC et du DO devrait faciliter dans l'analyse génétique des caractères complexes, un des domaines les plus difficiles de la génétique formelle (Chesler, 2014).…”