Thread by @thatdnaguy

#ASHG21 EDF: Elisa De Franco.
loss of the primate specific gene ZNF808 causes pancreatic disease.

#ASHG21 EDF: studying human development to better understand common and rare diseases. specifically interested in diabetes.

#ASHG21 EDF: Mice can offer important insights, but there are fundamental differences between humans and mice.

#ASHG21 EDF: thinking about pancreas, mice have two insulin genes and humans have one. Different architecture. Del Gata6 in mice, no pancreatic effect. Human GATA6 haploinsufficiency can cause absent pancrease.

#ASHG21 EDF: human genetics can help identify novel genes regulating human pancreas development. 2877 neonatal diabetes patients from 111 countries.

#ASHG21 EDF: studying pancreatic agenesis to identify novel genes regulating human pancreas development [ i.e. look at the variants in people born without a pancreas ]

#ASHG21 EDF: exome sequencing in 2 consanguineous probands with pancreatic agenesis. Focused on rare homozygous coding variants. Found vars in ZNF808 in both probands.

#ASHG21 EDF: Proband 1 homozygous for a premature stop. Proband 2 homozygous with exon 4&5 deletion

#ASHG21 EDF: replication in 232 neonatal diabetes probands. Found 11 individuals with loss-of-function (LoF) in ZNF808.

#ASHG21 EDF: ZNF808 is a primate specific KRAB-Zinc finger transcription factor targeting transposable elements.

#ASHG21 EDF: They weren't able to identify any other developmental genes with a lower level of conservation [ i.e. no others that were as primate specific ]

#ASHG21 EDF: Homozygous deletion in human embryonic stem cells results in aberrant activation of transposable elements. [ how weird ] Shows H3K27 increase at transposons in the knockout.

#ASHG21 EDF: think ZNF808 is essential to regulate pancreas vs liver fate during human development. As a result loss of ZNF808 causes more cells to go to a liver fate and a functional pancreas never develops.

#ASHG21 EDF:
preprint - medrxiv.org/content/10.110…