Qian Yu, Xiong Ziyi, Li Yi, Kayser Manfred, Liu Lei, Liu Fan
CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences Beijing China.
China National Center for Bioinformation Beijing China.
FASEB Bioadv. 2021 Sep 3;3(12):1011-1019. doi: 10.1096/fba.2021-00094. eCollection 2021 Dec.
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.
在独立的全基因组关联研究中，人类 和 基因内部或其附近的DNA变异已反复与面部形态相关联，然而它们在决定面部形态方面的功能作用仍有待明确。我们通过应用一步法CRISPR/Cas9技术生成了 基因敲除（ ）和 基因敲除（ ）小鼠。总共75只成年小鼠用于后续的表型分析，其中包括38只 基因敲除小鼠（10只纯合 ，18只杂合 ，10只野生型 同窝小鼠）和37只 基因敲除小鼠（12只纯合 ，15只杂合 ，10只 同窝小鼠）。面部及其他身体形态表型是通过使用HandySCAN BLACK扫描仪获取的三维（3D）图像获得的。与 同窝小鼠相比， 突变小鼠的面部显著更短（ = 1.08E - 8，R = 0.61），且耳朵位置显著更低（ = 3.54E - 8，R = 0.62），呈现出“耷拉耳”特征。除了这些面部变化外， 突变小鼠的体重显著更低，身体和四肢长度也更短。 突变小鼠相对于 同窝小鼠而言，鼻子显著更长（ = 1.14E - 5，R = 0.46），但除此之外，其形态学改变不如 突变小鼠明显。我们提供了首个直接的功能证据，表明两个著名且经重复验证的人类面部基因 和 会影响小鼠的面部及其他身体形态。我们在基因敲除小鼠中的研究结果与先前全基因组关联研究的结果总体一致，这表明我们在此处小鼠中确立的功能证据在人类中可能也具有相关性。
