Nonlinear gene expression-phenotype relationships contribute to variation and clefting in the A/WySn mouse

Rebecca M. Green, Courtney L. Leach, Virginia M. Diewert, Jose David Aponte, Eric J. Schmidt, James M. Cheverud, Charles C. Roseman, Nathan M. Young, Ralph S. Marcucio, Benedikt Hallgrimsson

Research output: Contribution to journalArticlepeer-review


Background: Cleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the Wnt9b locus in clefting animals, which results in decreased Wnt9b expression. Results: Using a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three-dimensional morphology for the first time. We find that methylation at the retrotransposon relates to Wnt9b expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among-individual variance in facial shape. Conclusions: Methylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among-individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.

Original languageEnglish (US)
Pages (from-to)1232-1242
Number of pages11
JournalDevelopmental Dynamics
Issue number12
StatePublished - Dec 1 2019


  • CL/P
  • IAP-retrotransposon
  • Wnt9b
  • facial development
  • methylation

ASJC Scopus subject areas

  • Developmental Biology


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