The Collaborative Cross (CC) is a research population of inbred mouse strains derived from an eight way cross using five classical inbred strains and three wild-derived strains representing three subspecies. The CC is genetically diverse because it combines together the genomes of the eight strains; A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ. This genetic diversity is essential for trait mapping studies, as classical inbred mouse strains can only capture a fraction of genetic variation found in the CC. However, this high level of genetic diversity may also act as a double-edged sword. The Dobzhansky-Muller model of hybrid incompatibility predicts that crosses between closely related species may produce inviable or infertile offspring. This is the result of allelic incompatibles across different loci that have evolved during the process of speciation. We observe an unusually high level of extinction in the CC strains, over 90%, which is much higher than comparable inbred reference panels. To investigate this high extinction rate, we are taking several different approaches. First, we will use living and extinct CC strains to find significant genotype ratio distortion sites that indicate allelic incompatibilities. We will also investigate genotype ratio distortion in the Diversity Outbred (DO) population that was created from 160 CC strains, but does not have the same infertility and inviability issues. We also will collect approximately 1000 pairs of productive and non productive mice that represent the last two generation of each extinct CC strain. This data set will be used in a mapping study to identify genetic factors that led to strain infertility. Finally, we will validate candidate allelic incompatibilities by using selective crosses of living DO and CC strains.