Decoding ‘Unnecessary Complexity’: A Law of Complexity and a Concept of Hidden Variation Behind “Missing Heritability” in Precision Medicine

Abstract

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 (CP) is higher than molecular complexity (CM), which is higher than DNA complexity (CD). The qualitative inequality in complexity is based on the following hierarchy: CP > CM > CD. 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.

A Law of Redundancy Compounds the Problem of Cancer and Precision Medicine

“…Details of the mechanisms for the origin of redundancy are presented elsewhere (Singh 2021 ). Ever since the publication of Ohno’s “Evolution by Gene Duplication” (Ohno 1970 ) redundancy is generally equated with “extra, unnecessary, and spendable” information.…”

“…Molecular redundancy would have given them recourse from this situation. The redundancy would have evolved from a single-cell organism with gene–gene interactions, whereby one gene affected many functions, redundant pathways, and physiological redundancies (Noble and Hunter 2020 ; Singh 2021 ). Redundancy would have expanded in sexual organisms with gene duplication, copy number variation, increased metabolic pathways, cell-specific variants, non-coding DNA, and other factors.…”

“…Complexity implies a network of gene–gene interactions, redundancy, a flow of information through the network of biochemical pathways. Three types of complexity were suggested with the following relationship: Phenotypic complexity (Cp) > molecular complexity (Cm) > DNA sequence complexity (Cd) (Singh 2021 ). DNA complexity is defined here as DNA sequence complexity, molecular complexity as complexity in all cellular molecules, and phenotypic complexity as all aspects of structural phenotypic complexity above the molecules.…”

“…This inequality is not simply quantitative but it implies “many to fewer” relationships in the flow of information content from DNA to proteins, and from proteins to phenotypes. The concept of redundancy was elaborated through the idea of hidden variation and the proposition that two kinds of variation exist: segregating variation in genome sequences and non-segregating or fixed regulatory variation in biochemical pathways (Singh 2021 ). Organisms were assumed to use both of these methods of variation for adaptation, with segregating variation more readily adopted than hidden variation.…”

Medicine and health of 21st Century: Not just a high biotech-driven solution

“…An organism’s genetic redundancy and multiple molecular pathways are complex, related, and integrated and they also affect traits and thus complicate interpretation. It should not be surprising that individuals with similar risk factors for a disease may have different phenotypes 52 , 53 . Genetic backgrounds, gene interaction networks, environments, and histories impact PM making it “uncertain, chance-ridden, and probabilistic” 52 .…”