The effects of and on facial and other physical morphology in mice.

DNA variants in or close to the human and genes have been repeatedly associated with facial morphology in independent genome-wide association studies, while their functional roles in determining facial morphology remain to be understood. We generated knockout ( ) and knockout ( ) mice by applying the one-step CRISPR/Cas9 method. A total of 75 adult mice were used for subsequent phenotype analysis, including 38 mice (10 homozygous , 18 heterozygous , 10 wild-type littermates) and 37 mice (12 homozygous , 15 heterozygous , 10 littermates). Facial and other physical morphological phenotypes were obtained from three-dimensional (3D) images acquired with the HandySCAN BLACK scanner. Compared to littermates, the mutant mice had significantly shorter faces ( = 1.08E-8, R = 0.61) and their ears were in a significantly lower position ( = 3.54E-8, R = 0.62) manifesting a "droopy ear" characteristic. Besides these face alternations, mutant mice displayed significantly lower weight as well as shorter body and limb length. mutant mice showed significantly longer noses ( = 1.14E-5, R = 0.46) relative to littermates, but otherwise displayed less obvious morphological alterations than mutant mice did. We provide the first direct functional evidence that two well-known and replicated human face genes, and , impact facial and other body morphology in mice. The general agreement between our findings in knock-out mice with those from previous GWASs suggests that the functional evidence we established here in mice may also be relevant in humans.