### abstract ###
One of the striking features of evolution is the appearance of novel structures in organisms.
Recently, Kirschner and Gerhart have integrated discoveries in evolution, genetics, and developmental biology to form a theory of facilitated variation.
The key observation is that organisms are designed such that random genetic changes are channeled in phenotypic directions that are potentially useful.
An open question is how FV spontaneously emerges during evolution.
Here, we address this by means of computer simulations of two well-studied model systems, logic circuits and RNA secondary structure.
We find that evolution of FV is enhanced in environments that change from time to time in a systematic way: the varying environments are made of the same set of subgoals but in different combinations.
We find that organisms that evolve under such varying goals not only remember their history but also generalize to future environments, exhibiting high adaptability to novel goals.
Rapid adaptation is seen to goals composed of the same subgoals in novel combinations, and to goals where one of the subgoals was never seen in the history of the organism.
The mechanisms for such enhanced generation of novelty are analyzed, as is the way that organisms store information in their genomes about their past environments.
Elements of facilitated variation theory, such as weak regulatory linkage, modularity, and reduced pleiotropy of mutations, evolve spontaneously under these conditions.
Thus, environments that change in a systematic, modular fashion seem to promote facilitated variation and allow evolution to generalize to novel conditions.
### introduction ###
The origin of the ability to generate novelty is one of the main mysteries in evolution.
Pioneers of evolutionary theory, including Baldwin CITATION, Simpson CITATION, and Waddington CITATION, CITATION, suggested how useful novelty might be enhanced by physiological adaptations and by the robustness of the developmental process.
These early theories were limited by a lack of knowledge of the molecular mechanisms of development.
Recent decades saw breakthroughs in the depth of understanding of molecular and developmental biology.
Many of these findings were unified in the theory of facilitated variation CITATION, presented by Kirschner and Gerhart, that addresses the following question: how can small, random genetic changes be converted into complex useful innovations?
In order to understand novelty in evolution, Kirschner and Gerhart integrated observations on molecular mechanisms to show how the current design of an organism helps to determine the nature and the degree of future variation.
The key observation is that the organism, by its intrinsic construction, biases both the type and the amount of its phenotypic variation in response to random genetic mutation CITATION, CITATION, CITATION CITATION.
In other words, the organism seems to be built in such a way that small genetic mutations have a high chance of yielding a large phenotypic payoff.
To understand FV, it is important to compare it to the related concept of evolvability.
A biological system is evolvable if it can readily acquire novel functions through genetic changes that help the organism survive and reproduce in future environments CITATION.
Evolvability is composed of two aspects: variability: the capacity to generate new phenotypes fitness: the fitness of the new phenotypes in future environments.
Most studies of evolvability focused on the first aspect, variability.
Such studies measured the range and diversity of the phenotypic variation that can be generated by a given mutation, usually without discerning between potentially useful phenotypes and non-useful ones CITATION CITATION.
FV theory adds to previous considerations by focusing on the nature of the generated variation, and specifically on the organism's ability to generate novel phenotypes which are potentially useful.
Facilitated variation is made possible by certain features of biological design.
One of these is the existence of weak regulatory linkage CITATION, CITATION, CITATION, where general and non-instructive signals can trigger large pre-prepared responses.
For example, changes in growth hormone concentration at a localized position can trigger large useful changes in the shape of the limb, driven by the conserved mechanisms for growth of bones, muscles, blood vessels, and nerves CITATION.
A good example is the ease of changing beak shapes with any of many possible mutations that affect the concentration of a single morphogenic factor CITATION.
In weak regulatory linkage, the information about the output is pre-built into the regulated system without instruction from the regulator, which only selects between states.
Such regulatory organization reduces the constraints for evolving new regulations and for generating complex potentially useful phenotypes.
An additional feature that is important for FV is modular design CITATION CITATION, seen for example, in the highly conserved body-plan of the embryo CITATION, CITATION and in the compartmental organization of gene regulation and signaling networks CITATION.
Modularity helps to relieve the concern that a mutation might interfere with many different parts of the organism.
With properly designed modularity, variation within each module can be generated without harming other modules CITATION CITATION .
Facilitated variation can be in principle studied experimentally, for example by generating mutants and scanning the types of phenotypes generated.
For example, a study on mutants of the lac regulatory region indicated that the shape of the gene input function is channeled in directions of AND-like and OR-like functions, rather than other possibilities CITATION .
An open question is how does FV spontaneously evolve?
It is not clear how selection in a present environment can lead to designs that increase the probability of useful changes in future environments.
How does evolutionary theory account for the emergence of special designs that make it easy to generate novel and useful variation?
The key point in our study is the observation that environments in nature do not vary randomly, but rather seem to have common rules or regularities CITATION CITATION.
Specifically, environmental goals faced by organisms or molecules may be thought of as composed of a combination of subgoals CITATION.
When environments change, the organisms encounter a new goal that is still made of the same or similar subgoals.
For example, on the level of the organism, the same subgoals, such as digesting food, avoiding predation, and reproducing, must be fulfilled in each new environment but with different nuances and combinations.
On the level of cells, the same subgoals such as adhesion and signaling must be fulfilled in each tissue type but with different input and output signals.
On the level of proteins, the same subgoals, such as enzymatic activity, binding to other proteins, regulatory input domains, etc., are shared by many proteins but with different combinations in each case.
One may thus propose that in many cases, the different possible environments share a language of modularity, in the sense that they are all made of certain combinations of a set of subgoals.
We thus test the possibility that under such patterned varying environments, the organism can learn over many generations the language common to the environments encountered in its past.
We ask whether FV arises in such systematically varying environments, by measuring the ability of simple model systems to adapt to new, previously unseen goals, which are in the same language as past goals.
We employ two well-studied model systems: combinatorial logic circuits CITATION, CITATION and RNA secondary structure CITATION.
We find that the standard experiment of setting a goal which remains constant over time leads to highly optimized systems that show little FV.
In contrast, FV is readily generated under modularly varying goals, in which goals change over time but share the same subgoals CITATION.
We find that MVG evolution enhances the ability to generate novel phenotypes as long as novelty is modular: phenotypes with novel modules or novel combinations of modules.
We show that organisms under MVG store information about past goals in their genomes, and evolve weak linkage that allows small genetic changes to unleash large phenotypic responses that do not ruin the modular structure of the organism.
Our study thus suggests that environments that change in a systematic fashion promote the evolution of facilitated variation, and leave an imprint on the evolvability properties of the organisms, allowing them to generalize to new conditions that are in the same language as past conditions.
