Environmental effects on disease gene penetrance

Homozygous mutations in HES7 and MESP2 — which encode Notch signalling pathway transcription factors — cause the spinal curvature defect congenital scoliosis. In a human mutation screen, Sparrow et al. found that heterozygous mutations in these genes also cause the condition, albeit at lower penetrance. Using mice heterozygous for these genes, the authors revealed that penetrance is increased by hypoxia during gestation. Transient hypoxia during mouse gestation disrupted embryonic WNT, fibroblast growth factor (FGF) and Notch signalling, providing a potential mechanistic explanation for how these genetic and environmental factors converge.