Ameratunga Rohan, Woon See-Tarn, Bryant Vanessa L, Steele Richard, Slade Charlotte, Leung Euphemia Yee, Lehnert Klaus
Department of Virology and Immunology, Auckland City Hospital, Auckland, New Zealand.
Department of Clinical Immunology, Auckland City Hospital, Auckland, New Zealand.
Front Immunol. 2018 Jan 26;8:1965. doi: 10.3389/fimmu.2017.01965. eCollection 2017.
The existence of epistasis in humans was first predicted by Bateson in 1909. Epistasis describes the non-linear, synergistic interaction of two or more genetic loci, which can substantially modify disease severity or result in entirely new phenotypes. The concept has remained controversial in human genetics because of the lack of well-characterized examples. In humans, it is only possible to demonstrate epistasis if two or more genes are mutated. In most cases of epistasis, the mutated gene products are likely to be constituents of the same physiological pathway leading to severe disruption of a cellular function such as antibody production. We have recently described a digenic family, who carry mutations of /TACI as well as genes. Both genes lie in tandem along the immunoglobulin isotype switching and secretion pathway. We have shown they interact in an epistatic way causing severe immunodeficiency and autoimmunity in the digenic proband. With the advent of next generation sequencing, it is likely other families with digenic inheritance will be identified. Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations. We also discuss the clinical implications of digenic inheritance and epistasis in humans with primary immunodeficiency disorders.
上位效应在人类中的存在最早是由贝特森于1909年预测的。上位效应描述了两个或更多基因座的非线性协同相互作用，这种相互作用可显著改变疾病严重程度或导致全新的表型。由于缺乏充分表征的实例，这一概念在人类遗传学中一直存在争议。在人类中，只有当两个或更多基因发生突变时才有可能证明存在上位效应。在上位效应的大多数情况下，突变的基因产物可能是同一生理途径的组成部分，从而导致细胞功能如抗体产生的严重破坏。我们最近描述了一个双基因家族，其成员携带/TACI以及其他基因的突变。这两个基因沿着免疫球蛋白同种型转换和分泌途径串联排列。我们已经表明，它们以上位效应的方式相互作用，在双基因先证者中导致严重免疫缺陷和自身免疫。随着下一代测序技术的出现，可能会鉴定出其他具有双基因遗传的家族。由于双基因遗传并不总是导致上位效应，我们提出了一个上位效应指数，它可能有助于量化这两种突变的影响。我们还讨论了双基因遗传和上位效应在原发性免疫缺陷疾病患者中的临床意义。
