The high hopes for the Human Genome Project and personalized medicine were not met because the relationship between genotypes and phenotypes turned out to be more complex than expected. In a previous study we laid the foundation of a theory of complexity and showed that because of the blind nature of evolution, and molecular and historical contingency, cells have accumulated unnecessary complexity, complexity beyond what is necessary and sufficient to describe an organism. Here we provide empirical evidence and show that unnecessary complexity has become integrated into the genome in the form of redundancy and is relevant to molecular evolution of phenotypic complexity. Unnecessary complexity creates uncertainty between molecular and phenotypic complexity, such that phenotypic complexity (C_P) is higher than molecular complexity (C_M), which is higher than DNA complexity (C_D). The qualitative inequality in complexity is based on the following hierarchy: C_P > C_M > C_D. This law-like relationship holds true for all complex traits, including complex diseases. We present a hypothesis of two types of variation, namely open and closed (hidden) systems, show that hidden variation provides a hitherto undiscovered “third source” of phenotypic variation, beside genotype and environment, and argue that “missing heritability” for some complex diseases is likely to be a case of “diluted heritability”. There is a need for radically new ways of thinking about the principles of genotype–phenotype relationship. Understanding how cells use hidden, pathway variation to respond to stress can shed light on why two individuals who share the same risk factors may not develop the same disease, or how cancer cells escape death.

人类基因组计划和个性化医疗的寄予厚望并没有实现，因为基因型和表型之间的关系比预期的要复杂。在之前的一项研究中，我们奠定了复杂性理论的基础，并表明由于进化的盲目性以及分子和历史的偶然性，细胞积累了不必要的复杂性，复杂性超出了描述有机体的必要和充分程度. 在这里，我们提供了经验证据，并表明不必要的复杂性已经以冗余的形式整合到基因组中，并且与表型复杂性的分子进化有关。不必要的复杂性在分子复杂性和表型复杂性之间产生了不确定性，使得表型复杂性（CP ）高于分子复杂性（_{CM ），分子}复杂性高于DNA复杂性（_CD ）。复杂性的定性不平等基于以下层次结构：C _P  >  C _M  >  C _D. 这种法律般的关系适用于所有复杂的特征，包括复杂的疾病。我们提出了两种变异类型的假设，即开放和封闭（隐藏）系统，表明隐藏变异提供了迄今为止未发现的表型变异“第三来源”，除了基因型和环境，并认为某些复杂的“缺失遗传性”疾病很可能是一个“稀释遗传”的案例。需要一种全新的方式来思考基因型-表型关系的原理。了解细胞如何使用隐藏的通路变异对压力做出反应可以阐明为什么具有相同风险因素的两个人可能不会患上相同的疾病，或者癌细胞如何逃脱死亡。