Abstract
<jats:title>Abstract</jats:title> <jats:p> Congenital abnormalities of eye formation show remarkably variable penetrance with phenotypes even varying between left and right eyes. Here we explore this phenomenon through analysis of the mechanistic basis of low penetrance retinal coloboma in zebrafish <jats:italic> yap1 <jats:sup>nl13/nl13</jats:sup> </jats:italic> mutants and identification of factors that modify the probability of this phenotype. We find that the low penetrance stochastically occurring coloboma in <jats:italic> yap1 <jats:sup>nl13/nl13</jats:sup> </jats:italic> mutants is due to rupture in the ventral retina at the point of apposition of the lips of the closing choroid fissure and that provision of wild-type Yap in the retinal pigment epithelium suppressed this phenotype. Decreasing actomyosin contractility increased the penetrance of coloboma whereas increasing myosin phosphorylation rescued the phenotype suggesting that altered mechanical properties of the RPE sensitize the eye to stochastic failure of choroid fissure closure. Genetic interaction screening revealed enhanced and synthetic eye phenotypes in <jats:italic> yap1 <jats:sup>nl13/nl13</jats:sup> </jats:italic> mutants upon abrogation of function of genes encoding extracellular matrix and other genes implicated in eye formation. Our data reveal that the variable penetrance of congenital eye abnormalities can be due to genetic and environmental factors impacting the stochastic variability inherent in the developmental processes underlying eye morphogenesis. </jats:p>