Primate-specific ZNF808 is essential for pancreatic development in humans.

Area of Science:

• Genetics
• Developmental Biology
• Human Evolution

Background:

• Identifying genes linked to extreme human phenotypes can reveal unique mammalian biological processes.
• Primate-specific genes, particularly those involved in epigenetic regulation, are crucial for understanding human development.
• Transposable elements and their regulation play a significant role in genome evolution and disease.

Purpose of the Study:

• To identify genetic causes of pancreatic agenesis.
• To investigate the function of primate-specific genes in human development.
• To understand the role of ZNF808 in early pancreatic organogenesis.

Main Methods:

• Whole-exome sequencing to identify homozygous loss-of-function variants.
• In vitro studies to assess ZNF808 function.
• Analysis of gene expression and cell fate specification during pancreas development.

Main Results:

• Homozygous loss-of-function variants in ZNF808 were identified as a cause of pancreatic agenesis.
• ZNF808, a KRAB zinc finger protein, acts as an epigenetic silencer targeting transposable elements.
• Loss of ZNF808 leads to aberrant activation of primate-specific transposable elements, causing inappropriate cell fate specification and induction of liver identity genes during pancreas development.

Conclusions:

• ZNF808 is essential for normal human pancreatic development.
• Primate-specific transposable elements and their regulation by genes like ZNF808 are critical for preventing congenital developmental diseases.
• This study underscores the importance of primate-specific genomic regions in human health and disease.