Department of Biology, and Origins Institute, McMaster University, 1280 Main Street West, Hamilton, ON, L8S4K1, Canada.
J Mol Evol. 2021 Oct;89(8):513-526. doi: 10.1007/s00239-021-10023-3. Epub 2021 Aug 2.
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) is higher than molecular complexity (C), which is higher than DNA complexity (C). The qualitative inequality in complexity is based on the following hierarchy: C > C > C. 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学的期望很高，但并没有实现，因为基因型和表型之间的关系比预期的更为复杂。在之前的一项研究中，我们为复杂性理论奠定了基础，并表明由于进化的盲目性、分子和历史的偶然性，细胞积累了不必要的复杂性，这种复杂性超出了描述生物体所需的和充分的复杂性。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，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造成了不确定性，使得表型复杂性（C）高于分子复杂性（C），而分子复杂性又高于 DNA 复杂性（C）。这种复杂的定性不平等是基于以下层次结构：C>C>C。这种类规律的关系适用于所有复杂特征，包括复杂疾病。我们提出了两种类型的变异，即开放和封闭（隐藏）系统的假设，表明隐藏的变异除了基因型和环境之外，还提供了一个迄今未被发现的表型变异的“第三个来源”，并认为一些复杂疾病的“遗传缺失”很可能是“遗传稀释”的情况。我们需要从根本上改变思考基因型-表型关系的原则。了解细胞如何利用隐藏的、通路的变异来应对压力，可以揭示为什么两个具有相同风险因素的人可能不会患上相同的疾病，或者癌细胞如何逃避死亡。
