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Understanding the development of variable craniofacial phenotypes caused by altered methylation affecting Wnt9b in A‐strain mice
Author(s) -
Green Rebecca M.,
Leach Courtney L.,
Schmidt Eric,
Diewert Virginia,
Marcucio Ralph S.,
Hallgrimsson Benedikt
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.776.14
Subject(s) - phenotype , dna methylation , methylation , craniofacial , biology , genetics , epigenetics , computational biology , gene , gene expression
Variable clinical presentation is common in many structural birth defects, two children with the same genetic mutation often have different clinical presentation. Therefore, understanding the developmental origin of such variability is of fundamental importance to developing patient targeted treatment, or precision medicine. A/WySn mice are genetically identical, inbred mice, but about 20% of them develop cleft lip and palate. This has been linked to loss of methylation at an IAP retrotransposon near Wnt9b (Wnt9bIAP). Using a newly developed protocol for generating RNA and DNA as well as a 3D microCT scan that can be used to quantify shape, we show that loss of methylation at this locus directly correlates with facial shape in precleft embryos. Line1 methylation is unaffected in embryos with abnormal Wnt9bIAP methylation levels. Wnt9bIAP methylation levels are bimodal, but continuous, as are facial shape, Wnt9b and Axin2 levels. We use all of these factors to build a model of how multiple continuous bimodal inputs lead to a discontinuous phenotype (clefting). We also determine how this model relates to underlying changes in the cell biology in the affected tissue. Support or Funding Information NIH R01 2R01DE019638 to RSM and BH. NSERC 238992‐17 to BH. Alberta Children's Hospital Research Institute Fellowship to RG. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .