Evolvability

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Evolvability

• Presented by Clayton Badeaux
• 2nd December 2008

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Evolvability

• Evolvability attempts to define the relationship
• between 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 selectable
• phenotypical variation.

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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?

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Warning!

• Because of the smaller amount of variation
• required 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 it
• does ( and where and when it does it).

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Constraint

• A single mutation in a eukaryotic gene can affect
• the resulting protein/RNA in its structure,
  target
• location, production frequency and timing, or the
• way it interacts with other proteins or
  substrates.
• The genes most critical to cell function will be
  the
• least likely to exhibit variation (examples
  CDK/
• cyclin, replication, metabolism), since changing
• these genes will result in cell inviability.

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The Problem, or Why do we care?

• Changes in phenotype therefore require the
• accumulation of MULTIPLE mutations, of which
• only 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 changes
• responsible for evolution.

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Constraint Again

• The more specific the requirements for
  transcription
• and 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
  constraint
• to matter.

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Selection and Conservation

• Selection can only act on a proteins function,
• not its sequence. This selection therefore is
  most
• often exhibited by conserving the structure of
  the
• protein (by exchanging similar amino acids), or
  by
• direct conservation of the genomic sequence,
• such as in tRNA, ribsomal RNA, and many core
• proteins.
• Mutational change cannot be selected upon,only
• phenotypical results are selectable. Conversely,
• mutations can be conserved against by selection.

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Transitions Versatility

• One of Darwin's concerns with natural selection
• was 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 to
• a preset cellular event.

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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.

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Regulation Versatility

• One 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.

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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.

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Versatility Cont'd

• Another 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.

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Weak Linkages

• Strong 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.

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Weak Linkages ExampleEukaryotic 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.

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Exploratory systems

• Exploratory 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.

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Compartmentation

• Compartmentation 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.

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Compartmentation of Body Plans

• To 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.

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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.

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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.

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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)?