Hutchinson Michael, Spanaki Cleanthe, Lebedev Sergey, Plaitakis Andreas
Department of Neurology, New York University, School of Medicine, 400 E. 34th Street, Suite RR311, New York, NY 10016, United States.
Med Hypotheses. 2005;65(2):282-6. doi: 10.1016/j.mehy.2005.02.034.
Common diseases tend to appear sporadically, i.e., they appear in an individual who has no first or second degree relatives with the disease. Yet diseases are often associated with a slight but definite increase in risk to the children of an affected individual. This weak pattern of inheritability cannot be explained by conventional interpretations of Mendelian genetics, and it is therefore commonly held that there is "incomplete penetrance" of a gene, or that there are polygenic, or multifactorial modes of inheritance. However, such arguments are heuristic and lack predictive power. Here, we explore the possibility that "incomplete penetrance" means the existence of a second, disease-related, gene. By examining in detail a specific common condition, Parkinson's disease (PD), we show that the sporadic form of the disease can be fully explained by a compact fully penetrant genotype involving an interaction between two, and only two, genes. In this model, therefore PD is fundamentally genetic. Our digenic model is complementary to Mendelian recessive genetics, but taken together with the latter forms a complete description for recessive genetics on one chromosome. It explains the slight increase in risk to the children if one parent has sporadic PD, and makes strict predictions where both parents coincidentally have sporadic PD. These predictions were verified in two large and carefully selected kindred, where the data also argue against other genetic models, including oligogenic and polygenic schemes. Since the inheritance patterns of sporadic PD are reminiscent of what is seen in many common diseases, it is plausible that similar genetic forms could apply to other diseases. Seen in this light, diseases wash in and out of every family, so that in a sense, over time every human family is equally at risk for most diseases.
常见疾病往往呈散发性出现，也就是说，它们出现在没有患该疾病的一级或二级亲属的个体身上。然而，疾病通常与患病个体的子女患该病的风险略有但明确的增加有关。这种微弱的遗传模式无法用孟德尔遗传学的传统解释来解释，因此人们普遍认为存在基因的“不完全外显率”，或者存在多基因或多因素遗传模式。然而，这些观点只是启发式的，缺乏预测能力。在这里，我们探讨“不完全外显率”意味着存在第二个与疾病相关的基因的可能性。通过详细研究一种特定的常见疾病——帕金森病（PD），我们表明该疾病的散发性形式可以完全由一个紧凑的完全外显基因型来解释，该基因型涉及两个且仅两个基因之间的相互作用。因此，在这个模型中，帕金森病从根本上说是遗传性的。我们的双基因模型与孟德尔隐性遗传学互补，但与后者结合起来形成了对一条染色体上隐性遗传学的完整描述。它解释了如果父母一方患有散发性帕金森病，其子女患病风险的轻微增加，并对父母双方都巧合地患有散发性帕金森病的情况做出了严格预测。这些预测在两个经过精心挑选的大家族中得到了验证，在这些家族中，数据也反驳了其他遗传模型，包括寡基因和多基因模式。由于散发性帕金森病的遗传模式让人联想到许多常见疾病的情况，所以类似的遗传形式可能适用于其他疾病是有道理的。从这个角度看，疾病在每个家庭中时隐时现，所以从某种意义上说，随着时间的推移，每个人类家庭患大多数疾病的风险是均等的。
