Genetic Causation in Complex Regulatory Systems: An Integrative Dynamic Perspective

Abstract

The logic of genetic discovery has changed little over time, but the focus of biology is shifting from simple genotype–phenotype relationships to complex metabolic, physiological, developmental, and behavioral traits. In light of this, the traditional reductionist view of individual genes as privileged difference‐making causes of phenotypes is re‐examined. The scope and nature of genetic effects in complex regulatory systems, in which dynamics are driven by regulatory feedback and hierarchical interactions across levels of organization are considered. This review argues that it is appropriate to treat genes as specific actual difference‐makers for the molecular regulation of gene expression. However, they are often neither stable, proportional, nor specific as causes of the overall dynamic behavior of regulatory networks. Dynamical models, properly formulated and validated, provide the tools to probe cause‐and‐effect relationships in complex biological systems, allowing to go beyond the limitations of genetic reductionism to gain an integrative understanding of the causal processes underlying complex phenotypes.

Somite surface tension buffers imprecise segment lengths to ensure left-right symmetry

“…In tissue engineering and regenerative medicine, where recent applications using organoids and other ex vivo analogs of developmental tissue strive for reproducible shapes, 38 our findings suggest that understanding how mechanics contributes to precision in these settings could help to overcome current limitations. Our findings also raise the possibility that during the evolution of new developmental patterns via mutations to the underlying genetic regulatory networks, 39,40 resulting fluctuations in morphology may be stabilized by tissue mechanics, potentially facilitating a 9 greater search of sequence space while maintaining a precise body architecture.…”

Dynamical modules in metabolism, cell and developmental biology

“…These generative processes constitute the epigenotype of the organism [15][16][17][18][19], which is often represented as a complex mapping from genotype to phenotype (figure 1b) [20][21][22]. If we are to properly understand the evolutionary sources of phenotypic variability-the substrate on which natural selection can act-we must study the structure of this mapping in a mechanistic manner [1,12,13,23,24]. What we are ultimately interested in are the causal processes that generate the variational properties of an adaptive and evolvable complex system.…”

Homology of process: developmental dynamics in comparative biology

“…Homologous morphological traits are often generated by processes involving non-homologous genes ( developmental system drift ), while homologous genes are often co-opted in the generation of non-homologous traits ( deep homology ) [20–24]. We now know that the relationship between evolution at the genotypic and the phenotypic levels is surprisingly fluid, degenerate, multi-level and complex (see [24–26]). As a result, homology between processes cannot always be traced in terms of homology between genes.…”

“…To explain how a lineage gets from one state to a later state—rather than merely describing the sequence of states—it is often not enough to rely on simple statistical models of genetic architecture and linear genotype–phenotype mapping [25]. Because the genotype–phenotype map is degenerate, and most traits are generated by nonlinear hierarchical regulatory processes, bridging the gap between genotype and phenotype calls for a causal understanding of complex dynamic mechanisms [25,26,34].…”