Poster Presentation ANZSCDB National Scientific Meeting 2019

Studying Gene-Environment Interactions in Embryonic Midline Formation Using Automated Embryo Phenotyping (#Poster 8)

Kyle Drover 1 , Ruth Arkell 1 , Hannah Glanville-Jones 1
  1. John Curtin School of Medical Research, The Australian National University, Acton, ACT, Australia

The embryonic midline acts as a signalling centre for critical events during development. For example, signals from the anterior embryonic midline (i.e. the prechordal plate) pattern the overlying neuroectoderm and are responsible for the division of the developing forebrain into distinct left and right (L-R) hemispheres. The developing forebrain failing to divide results in a devastating congenital defect called Holoprosencephaly (HPE). HPE occurs in 1 in 250 human conceptuses, suggesting that specification of the L-R embryonic body plan is a delicate process that can be easily disturbed. Factors that lead to HPE are, however, poorly understood. For instance, advanced genomic techniques have only implicated fourteen HPE-associated genes in humans with the likely genetic cause unidentified for ~75% of HPE cases with normal chromosomes. This suggests, among other reasons, an underlying environmental causation and/or a gene-environment interaction. One environmental insult that causes midline defects in both man and mouse and is a potential modifier of HPE is maternal exposure to ethanol at gastrulation.

To determine the role of maternal ethanol exposure in HPE aetiology, we will investigate via automated embryo phenotyping whether a known murine HPE causing genetic variant (Zic2Ku/Ku) in its silent heterozygous form (i.e. Zic2Ku/+) can interact with maternal ethanol exposure to confer HPE. Gene-environment interactions typically produce variable expressivity and/or incompletely penetrant phenotypes. This complicates analysis as both large samples sizes and robust statistical methods are required to identify phenodeviants in these studies. As an initial step to objectively analyse gene-environment interactions, I will establish automated 3D volume analysis of µCT scans of 12.5-15.5 days post coitum embryos using a modified Pydpiper software package.