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

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 polygenic architecture with conditionally neutral effects underlies ecological differentiation in Silene

Ecological differentiation can drive speciation but it is unclear how the genetic architecture of habitat-dependent fitness contributes to lineage divergence. We investigated the genetic architecture of cumulative flowering, a fitness component, in second-generation hybrids between Silene dioica and S. latifolia transplanted into the natural habitat of each species. We used reduced-representation sequencing and Bayesian Sparse Linear Mixed Models (BSLMMs) to analyze the genetic control of cumulative flowering in each habitat. Our results point to a polygenic architecture of cumulative flowering. Allelic effects were mostly beneficial or deleterious in one habitat and neutral in the other. The direction of allelic effects was associated with allele frequency differences between the species: positive-effect alleles were often derived from the native species, whereas negative-effect alleles, at other loci, tended to originate from the non-native species. We conclude that ecological differentiation is governed and maintained by many loci with small, conditionally neutral effects. Conditional neutrality may result from differences in selection targets in the two habitats and provides hidden variation upon which selection can act. Polygenic architectures of adaptive differentiation are expected to be transient during lineage divergence and may therefore be unrelated to high genetic differentiation at the underlying loci.

Measurement and models accounting for cell death capture hidden variation in compound response

Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have distinct effects on the tumor microenvironment, immune responses, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound responses. Using an alternative assay and drug response analysis amenable to high-throughput measurement, we find that compounds with identical viability outcomes can have very different effects on cell growth and death. Moreover, compound pairs with additive cell growth and death effects can appear synergistic when only assessed by viability. Overall, these results demonstrate an approach to incorporating measurements of cell death when characterizing a pharmacologic response.Summary PointsMeasurements of solely live cell numbers mask important differences in compound effects.Additive effects on growth and death rates can appear synergistic when analyzed solely via live cell number.Automated imaging can provide reasonable throughput to analyze cell response in terms of cell growth and death, and endpoint analysis is similarly informative.

Hidden variation in polyploid wheat drives local adaptation

Wheat has been domesticated into a large number of agricultural environments and has a remarkable ability to adapt to diverse environments. To understand this process, we survey genotype, repeat content and DNA methylation across a bread wheat landrace collection representing global genetic diversity. We identify independent variation in methylation, genotype and transposon copy number. We show that these, so far unexploited, sources of variation have had a massive impact on the wheat genome and that ancestral methylation states become preferentially ‘hard coded’ as SNPs via 5-methylcytosine deamination. These mechanisms also drive local adaption, impacting important traits such as heading date and salt tolerance. Methylation and transposon diversity could therefore be used alongside single nucleotide polymorphism (SNP) based markers for breeding.