Social hierarchies are ubiquitous in social species and profoundly influence physiology and behavior. Androgens like testosterone have been strongly linked to social status, yet the molecular mechanisms regulating social status are not known. The African cichlid fish Astatotilapia burtoni is a powerful model species for elucidating the role of androgens in social status given their rich social hierarchy and genetic tractability. Dominant A. burtoni males possess large testes and bright coloration and perform aggressive and reproductive behaviors while nondominant males do not. Social status in A. burtoni is in flux, however, as males alter their status depending on the social environment. Due to a teleost-specific whole-genome duplication, A. burtoni possess two androgen receptor (AR) paralogs, ARα and ARβ, providing a unique opportunity to disentangle the role of gene duplication in the evolution of social systems. Here, we used CRISPR/Cas9 gene editing to generate AR mutant A. burtoni and performed a suite of experiments to interrogate the mechanistic basis of social dominance. We find that ARβ, but not ARα, is required for testes growth and bright coloration, while ARα, but not ARβ, is required for the performance of reproductive behavior and aggressive displays. Both receptors are required to reduce flees from females and either AR is sufficient for attacking males. Thus, social status in A. burtoni is inordinately dissociable and under the modular control of two AR paralogs. This type of nonredundancy may be important in facilitating social plasticity in A. burtoni and other species whose social status relies on social experience.
Motivation This article introduces Vivarium—software born of the idea that it should be as easy as possible for computational biologists to define any imaginable mechanistic model, combine it with existing models and execute them together as an integrated multiscale model. Integrative multiscale modeling confronts the complexity of biology by combining heterogeneous datasets and diverse modeling strategies into unified representations. These integrated models are then run to simulate how the hypothesized mechanisms operate as a whole. But building such models has been a labor-intensive process that requires many contributors, and they are still primarily developed on a case-by-case basis with each project starting anew. New software tools that streamline the integrative modeling effort and facilitate collaboration are therefore essential for future computational biologists. Results Vivarium is a software tool for building integrative multiscale models. It provides an interface that makes individual models into modules that can be wired together in large composite models, parallelized across multiple CPUs and run with Vivarium’s discrete-event simulation engine. Vivarium’s utility is demonstrated by building composite models that combine several modeling frameworks: agent-based models, ordinary differential equations, stochastic reaction systems, constraint-based models, solid-body physics and spatial diffusion. This demonstrates just the beginning of what is possible—Vivarium will be able to support future efforts that integrate many more types of models and at many more biological scales. Availability and implementation The specific models, simulation pipelines and notebooks developed for this article are all available at the vivarium-notebooks repository: https://github.com/vivarium-collective/vivarium-notebooks. Vivarium-core is available at https://github.com/vivarium-collective/vivarium-core, and has been released on Python Package Index. The Vivarium Collective (https://vivarium-collective.github.io) is a repository of freely available Vivarium processes and composites, including the processes used in Section 3. Supplementary Materials provide with an extensive methodology section, with several code listings that demonstrate the basic interfaces. Supplementary information Supplementary data are available at Bioinformatics online.
Motivation: This paper introduces Vivarium -- software born of the idea that it should be as easy as possible for computational biologists to define any imaginable mechanistic model, combine it with existing models, and execute them together as an integrated multiscale model. Integrative multiscale modeling confronts the complexity of molecular and cellular biology by combining heterogeneous datasets and diverse mechanistic modeling strategies into unified representations. These integrated models are then run to simulate how the hypothesized mechanisms operate as a whole. But building such models has been a labor-intensive process that requires many contributors, and they are still primarily developed on a case-by-case basis with each project starting anew. New software tools that streamline the integrative modeling effort and facilitate collaboration are therefore essential for future computational biologists. Results: Vivarium is a software tool for building integrative multiscale models. It provides an interface that can make any mechanistic model into a module that can be wired together into larger composite models and then parallelized and run across multiple CPUs with Vivarium's simulation engine. The utility of this software is demonstrated by building multi-paradigm composite models that combine several popular modeling frameworks: agent based models, ordinary differential equations, stochastic reaction systems, constraint-based models, solid-body physics, and spatial diffusion. This demonstration shows just the beginning of what is possible -- future efforts can integrate many more types of models and at many more biological scales.
Bacterial behavior is the outcome of both molecular mechanisms within each cell and interactions between cells in the context of their environment. Whereas whole-cell models simulate a single cell's behavior using molecular mechanisms, agent-based models simulate many agents independently acting and interacting to generate complex collective phenomena. To synthesize agent-based and whole-cell modeling, we used a novel model integration software, called Vivarium, to construct an agent-based model of E. coli colonies where each agent is represented by a current source code snapshot from the E. coli Whole-Cell Modeling Project and interacts with other cells in a shared spatial environment. The result is the first "whole-colony" computational model that mechanistically links expression of individual proteins to a population-level phenotype. Simulated colonies exhibit heterogeneous effects on their environments, heterogeneous gene expression, and media-dependent growth. Extending the cellular model with mechanisms of antibiotic susceptibility and resistance, our model also suggested that variation in the expression level of the beta-lactamase AmpC, and not of the multi-drug efflux pump AcrAB-TolC, was the key mechanistic driver of survival in the presence of nitrocefin. We see this as a significant step forward in the creation of more comprehensive multi-scale models, and it broadens the range of phenomena that can be modeled in mechanistic terms.
Competing interest:We have no competing interests. Author's contributions: Conceptualization, B.A.A., R.D.F., S.A.J.; Methodology, B.A.A, S.A.J, C.J.S.; Investigation, B.A.A., C.J.S., R.A.Y, V.L.; Writing -Original Draft, B.A.A.; Writing -Review & Editing, B.A.A., R.A.Y, S.A.J.; Supervision, B.A.A. AbstractSocial hierarchies are ubiquitous in social species, yet the mechanisms underlying social status are unclear. In the African cichlid fish Astatotilapia burtoni, males stratify along a dominance hierarchy that varies based on testes mass, coloration, and behavior. Using androgen receptor (AR) mutant A. burtoni generated using CRISPR/Cas9, we find that two AR genes control social dominance. ARb, but not ARa, is required for testes growth and bright coloration, while ARa, but not ARb, is required for the performance of reproductive behavior and aggressive displays. Neither receptor is required for attacking males. Analysis of AR double mutants revealed that either AR is sufficient for attacking males. Social status in A. burtoni males is modularly controlled by ARa and ARb, indicating that these genes have undergone subfunctionalization.One Sentence Summary: Genetic dissection of social dominance in a cichlid using CRISPR/Cas9 gene editing reveals dissociable roles for distinct androgen receptor genes. Main textSocial animals -such as humans, non-human primates, mice, and fish -often organize into hierarchies (1). Within these social hierarchies dominant and non-dominant individuals exist, differing markedly along multiple behavioral and physiological dimensions. Dominant individuals typically behave more aggressively and have more mating opportunities than non-dominant individuals. Higher-ranking animals also tend to have higher levels of sex steroid hormones such as androgens (e.g., testosterone) and estrogens and larger gonads. Despite these compelling patterns, the mechanistic basis of social status remains to be established. Understanding what controls social status is important for several reasons. For instance, the underlying mechanisms of social status likely are involved in an animal's ability to interpret and navigate their social
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