Diversity is valued in most workplaces, except among laboratory animals. Although most animal populations are genetically diverse, the animal strains commonly studied in the laboratory are not. Quantitative trait loci (QTLs) map regions of the intact genome that associate with phenotypes, but mapping precision depends upon genetic diversity. Valdar et al. developed a genetically diverse strain of laboratory mice and an analysis technique to identify regions of the genome contributing to 101 phenotypes in a recent article in Nature Genetics.
The authors crossed 8 inbred strains of mice, including BALBc/J, CBA/J, C3H/HeJ, C57BL/6J and DBA/2J, for 50 generations to yield a genetically heterogeneous strain of mice with a large number of recombination events. Analysis of such a highly variable population required a large sample size, and the authors obtained genotypes for 13,459 single nucleotide polymorphisms in 1904 mice. The authors recorded 101 phenotypes for each mouse, including body weight, wound healing, startle response and cue freezing.
A genome-wide scan determined the QTLs associated with each trait. This technique yielded hundreds of QTLs per phenotype, which together explained more than 100% of the variance of many phenotypes. Therefore, to eliminate spurious data and evaluate the relative contributions of each QTL to phenotypic variance, the authors developed their own bootstrapping technique.
Using the bootstrapping technique, the authors found 843 QTLs associated with 97 phenotypes. They were unable to identify QTLs for four phenotypes, including glucose and insulin decline in the glucose tolerance test, defecation in the open field and entries into closed arms of an elevated plus maze. For most of the phenotypes, the QTLs together explained 75% of the phenotypic variance. Only 10 of the QTLs accounted for more than 5% of the variance, and 109 QTLs accounted for 2% or less of the variance, suggesting that complex traits result from small contributions from many genes.
Fine mapping of the QTLs identified in this study will identify the genes that contribute to nearly 100 complex traits. The authors have made access to their entire dataset freely available. Therefore, in addition to a new analysis tool and a genetically diverse strain of mice, the authors created a foundation for future studies for the genetics community.