Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
Development. 2020 Jul 17;147(21):dev191064. doi: 10.1242/dev.191064.
Developmental biologists rely on genetics-based approaches to understand the origins of congenital abnormalities. Recent advancements in genomics have made it easier than ever to investigate the relationship between genes and disease. However, nonsyndromic birth defects often exhibit non-Mendelian inheritance, incomplete penetrance or variable expressivity. The discordance between genotype and phenotype indicates that extrinsic factors frequently impact the severity of genetic disorders and vice versa. Overlooking gene-environment interactions in birth defect etiology limits our ability to identify and eliminate avoidable risks. We present mouse models of sonic hedgehog signaling and craniofacial malformations to illustrate both the importance of and current challenges in resolving gene-environment interactions in birth defects. We then prescribe approaches for overcoming these challenges, including use of genetically tractable and environmentally responsive systems. Combining emerging technologies with molecular genetics and traditional animal models promises to advance our understanding of birth defect etiology and improve the identification and protection of vulnerable populations.
发育生物学家依赖基于遗传学的方法来了解先天性异常的起源。基因组学的最新进展使得研究基因与疾病之间的关系变得前所未有地容易。然而，非综合征性出生缺陷通常表现出非孟德尔遗传、不完全外显率或可变表达性。基因型和表型之间的不一致表明，外在因素经常影响遗传疾病的严重程度，反之亦然。在出生缺陷病因学中忽视基因-环境相互作用限制了我们识别和消除可避免风险的能力。我们提出了 sonic hedgehog 信号传导和颅面畸形的小鼠模型，以说明解决出生缺陷中基因-环境相互作用的重要性和当前挑战。然后，我们规定了克服这些挑战的方法，包括使用遗传上可追踪和环境响应的系统。将新兴技术与分子遗传学和传统动物模型相结合，有望提高我们对出生缺陷病因学的理解，并改善对脆弱人群的识别和保护。
