Short-term selective breeding as a tool for QTL mapping: Ethanol preference drinking in mice

Short-term selective breeding starting from an F₂ intercross of two inbred strains is a largely unexploited but potentially useful tool for quantitative trait locus (QTL) mapping. The selection lines can also serve as a valuable confirmation test of recombinant inbred (R1) QTL results when the same two progenitor strains are used. Starting from an F₂ from a C57BL/6J (B6) x DBA/2J (D2) cross (B6D2F2), this approach was used in a population of ~72 mice per generation bidirectionally selected for two-bottle choice 10% ethanol (alcohol) preference for four generations. The high-preference line diverged significantly from the low line in the first generation with a realized heritability of .32. By generation 4, the preference ratios in the high line were double those seen in the low line. Regions of the genome previously implicated by BXD R1 QTL analysis as containing QTLs were searched using microsatellite markers. The test for the presence of QTLs was based on the divergence of marker allele frequencies in the two oppositely selected lines significantly exceeding that expected from random (genetic) drift and allele frequency estimation error. Combining the BXD and two-way selection line results, the most probable QTL was found on chromosome 3 (near the Adh1 locus; LOD ~2.9), other probable QTLs were found with LOD 2.4-2.6.