Evolvability

Presented by Clayton Badeaux2nd December 2008

Evolvability

Evolvability attempts to define the relationshipbetween genetic mutation and variation and selectable phenotypical traits (upon which Natural Selection can act.)

Thus, evolvability aka evolutionary adaptability is the capacity to generate heritable selectablephenotypical variation.

Variation and Mutation

Mutation can act anywhere within a genome, but many of these changes are maladaptive, and will result in a non-functional gene or protein, thus constraining the mutations available for selection to act upon.

Additionally, mutations may produce changes that are either silent, negligible, or do not produce a selectable trait.

Too much change, or not enough change?

Warning!

Because of the smaller amount of variationrequired to effect changed, its easier to discuss evolvability in terms of molecular and cellular biology, than in the case of actual morphological change.

That being the case, I'll attempt to demonstrate an example using a biochemical system or pathway,giving an overview of each pathway and what itdoes ( and where and when it does it).

Constraint

A single mutation in a eukaryotic gene can affectthe resulting protein/RNA in its structure, target location, production frequency and timing, or theway it interacts with other proteins or substrates.

The genes most critical to cell function will be theleast likely to exhibit variation (examples : CDK/ cyclin, replication, metabolism), since changing these genes will result in cell inviability.

The Problem, or Why do we care?

Changes in phenotype therefore require theaccumulation of MULTIPLE mutations, of whichonly rare intermediates and the total end product can be the target of selection pressure.

Therefore, suddenly Darwin's time problem reappears in the amount of time required by random chance to accumulate all the mutations for each step between phenotypical changesresponsible for evolution.

Constraint Again

The more specific the requirements for transcriptionand translation, AA sequence, and other requirements for function, the less places that mutation can positive-ly affect that protein.

Side note: Constraint is not the driver of evolution, the process being constrained must still be under positive selection in order for its functional constraintto matter.

Selection and Conservation

Selection can only act on a proteins function,not its sequence. This selection therefore is mostoften exhibited by conserving the structure of the protein (by exchanging similar amino acids), or bydirect conservation of the genomic sequence,such as in tRNA, ribsomal RNA, and many coreproteins.

Mutational change cannot be selected upon,only phenotypical results are selectable. Conversely, mutations can be conserved against by selection.

Transitions & Versatility

One of Darwin's concerns with natural selectionwas the method by which complex organs (eyes,wings) should develop in a stepwise fashion, since the intermediate forms would offer little increase in function.

Molecular biology offers better examples of this kind of versatility in the regulation of enzymes by inhibitors capable of broadly affecting whole families of enzymes, which can then respond toa preset cellular event.

Deconstraint

Each of the processes I'll be discussing serve to deconstrain pathways by allowing flexible proteins and processes to allow for variation in processes that are required for viability or survival, and are constrained by selection.

By allowing these flexible participants we can allow for and facilitate small evolutionary changes at several steps in the overall process, leading to phenotypical change.

Regulation & VersatilityOne area that shows the kind of versatility required to explain

evolvability is in enzyme regulation networks. These networks compose both the inhibitors of protein function and regulation, and the proteins which function to inhibit the direct inhibitors.

In many cases of protein regulation one or more of these pairs of proteins is highly specific to the pathway, while the other is more general. The generalist of the pair provides the flexibility and versatility in the pathway that evolvability describes. The specific proteins allow for specific conditions of activation or deactivation in response to a more specific stimulus than the generalist.

Regulation Versatility (Ex.)Calmodulin is a inhibitor protein used extensively throughout

many protein networks particularly in muscle and nerve cells.

It has several areas on its surface which stick to another proteins surface to inhibit the action of that protein.

It responds to the presence of free calcium ions in the cell, and undergoes a radical transformation in response to the binding of free calcium which cause some of those binding areas to lose contact with the inhibited protein, and allow the activation of that protein.

Calmodulin acts both as a direct inhibitor, and as an activator, by inhibiting the action of another inhibitor.

Versatility Cont'dAnother method of versatility has to do with the activation

cascade of genes such as Eyeless in drosophila. The activation of this single gene causes in turn the action of whole families of other genes which create a functional (though not nervously connected) eye at any point on the body. While this gene is constrained, its targets are not and can each have variations which change its properties without disrupting the function of the overall organ, or its development.

A final word on versatility concerns protein domains (functional amino acid sequences within the larger protein) and the promiscuity of specific structures and sequence, particularly those used in protein-protein binding, and in catalytic activity.

Weak LinkagesStrong linkage refers to the interdependence of two or more

proteins on one another, either because of aggregation into complexes (hetero-multimerization), or because of product

substrate dependance (as in metabolism).

Weak linkages are when the activity of a process depends only minimally on other components of the process.

Signal Transduction, neural relays, and transcriptional control are all examples of weak linkages.

Weak Linkages Example:Eukaryotic Transcription

Transcription in eukaryotes is completed by the binding of RNA polymerase and a number of transcription factors, which positively and negatively enhance the rate of transcription of the mRNA.

These transcription factors have no part in the final product (the RNA) but the final product depends on this highly variable and versatile array of components, allowing for variation to act within these components to enhance transcription levels cheaply.

Exploratory systemsExploratory systems deconstrain evolution by

allowing functions which do not require mutation to act to allow for variability. They generate many states from which one state is selected by other components to determine an outcome.

Example: Microtubule formation during chromosomal separation in cell replication.

Microtubules grow randomly from the mitotic spindles, and are stabilized only by finding a chromosome to latch onto, thus allowing for variation without the need for additional input.

CompartmentationCompartmentation in multicellular eukaryotes is created

by the many forms of developmental differentiation and the splicing patterns expressed within the differentiated cells. This reduces the interdependence of process and decreases the chance of mutations destroying all or a significant part of a processes function.

Gene duplication is also a form of compartmentalization, allowing one or both genes to accumulate mutations that don't prohibit the overall function of the gene, and allowing for greater diversification within the cell network by endorsing greater modularity in the pathway.

Compartmentation of Body PlansTo link all this back to our earlier discussions:

Within each of the ~30 phyla there is a characteristic body plan that is first evident during development. These body plans are a spatially arranged collection of compartments of developmental processes.

Each compartment has identifying transcription factors, homeobox (hox) genes, and signaling factors.These compartments are largely independent from the other compartments, both in the subsequent development, and in its evolution.

Early developmental processes (2 RNAs, 2 Proteins) create the axes for development, which in turn activate the compartments in their spatial areas leading to the development of the bodyplan.

Review

Flexible Proteins can interact with a variety of targets because of their broad specificity for binding sites, allowing for small mutations to a target protein to induce regulation mechanisms.

Weak Linkages allow the conveyance of information about the state of a process without dependence on direct interactions.

Review

Exploratory systems generate random variations in configuration to fulfill the needs of the cell or organism, thus freeing those processes from the need for specific instruction or input.

Compartmentalization buffers the developmental stages from damage by inaccuracy and mutations and preserve the overall viability of the organism, while allowing for variation to act within these compartments.

References

Kirschner & Gerhart Evolvability PNAS Vol. 95, 8420-8427, Juy 1998 Isalan, Lemerle et. al. Evolvability and heirarchy in rewired bacterial gene networks Nature

Vol 452 840-845 (17 April 2008) Lopez-Bigas, De and Teichmann Functional Protein Divergence in the evolution of Homo

Sapiens Genome Biology Vol 9 Issue 2 (15 February 2008) Basu, Carmel, Rogozin and Koonin Evolution of protein domain promiscuity in eukaryotes

Genome Research Vol 18 449-461 (2008) Sole and Valeverde Spontaneous Emergence of modularity in cellular networks Journal of the

Royal Society Volume 5, issue 18, (Jan 6 2008)