Riordan Jesse D, Nadeau Joseph H
Pacific Northwest Research Institute, Seattle, WA 98122, USA.
Am J Hum Genet. 2017 Aug 3;101(2):177-191. doi: 10.1016/j.ajhg.2017.06.004.
Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called "modifier genes" that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.
表型在不同的遗传背景和环境中很少是一致的，而是会因等位基因变异、非连锁基因、表观遗传因素和环境暴露等多种因素而在许多方面有所不同。极端情况下，携带相同致病DNA序列变异但背景不同的个体可被归类为患有不同的疾病。同样，一些携带疾病等位基因的个体，尽管处于相同环境中的家庭成员患病，但他们自己却依然健康。这些遗传背景效应通常是由所谓的“修饰基因”作用导致的，这些修饰基因以上位性方式调节靶基因的表型表现。虽然这些效应使基因发现的前景和机制研究的可行性变得复杂，但它们也为深入了解基因相互作用网络提供了机会，这些网络赋予生物体形态、功能以及对干扰的恢复能力。在此，我们回顾修饰基因遗传学的原理，并评估在简单和复杂性状中修饰基因及其靶标的研究进展。我们提出，修饰效应源自基因相互作用网络，其结构和功能随遗传背景而变化，并认为这些效应可被用作预防、稳定和逆转疾病及功能障碍的安全有效方法。
