Identifying genes linked to extreme phenotypes in humans has the potential to highlight biological processes not shared with all other mammals. Here, we report the identification of homozygous loss-of-function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein family, a large and rapidly evolving group of epigenetic silencers which target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of regulatory potential contained in the primate-specific transposable elements it represses during early pancreas development. This leads to inappropriate specification of cell fate with induction of genes associated with liver identity. Our results highlight the essential role of ZNF808 in pancreatic development in humans and the contribution of primate-specific regions of the human genome to congenital developmental disease.

识别与人类极端表型相关的基因有可能突显所有其他哺乳动物所不具备的生物过程。在这里，我们报告了灵长类特异性基因ZNF808中纯合功能丧失变异的鉴定，这是胰腺发育不全的原因。 ZNF808 是 KRAB 锌指蛋白家族的成员，该家族是一个庞大且快速进化的表观遗传沉默子组，针对转座元件。我们发现，ZNF808 的体外缺失会导致其在早期胰腺发育过程中抑制的灵长类特异性转座元件中所包含的调节潜力的异常激活。这导致细胞命运的不适当规范以及与肝脏特性相关的基因的诱导。我们的结果强调了ZNF808在人类胰腺发育中的重要作用以及人类基因组灵长类特定区域对先天性发育疾病的贡献。