Download Testing for the Time Dependent Transition from a Rates Across Sites

Model Testing for a Time
Dependent Transition of a Rates
Across Sites to a Covarion Model
of Protein Evolution
Makayla Tisdell, David Liberles
Department of Molecular Biology
University of Wyoming, Honors Program
Abstract
Protein-coding gene sequences typically evolve constrained by the requirements for a
protein to fold into its three dimensional structure. These constraints can dictate
evolutionary rates at different sites, where residues in the hydrophobic core of a
protein typically evolve more slowly than those on the surface. The exceptions to this
are surface residues involved directly in functions of the protein such as binding,
which are conserved. A gamma distribution of rates across sites is typically used to
describe this process of protein evolution in what is called the RAS model. However, it
has been proposed that this model is violated when a functional change in the protein
occurs, and in this case, a covarion model of protein evolution would be more
accurate. It has also been proposed that protein structure may lead to violations of
the gamma distribution over increasing evolutionary time. Because of this, I
hypothesize that the rate of the transition is fold-dependent and that different
protein folds will move from an RAS model to a covarion model at variable rates that
are influenced by selective pressures. In preliminary analysis of an SH2 domain, there
is a time dependent transition from an equal rates to a RAS to a covarion model of
protein evolution.
Molecular Evolution
Amino Acids
•
•
•
General structure
“R” Group denotes side
chain
The physicochemical
properties of the side
chain place constraints
on protein evolution
Protein Folding
𝑷 𝑺, 𝑪𝒏𝒂𝒕
𝒆−∆𝑮(𝑺,𝑪𝒏𝒂𝒕)/𝒌𝒕
=
𝒁
𝒆−∆𝑮(𝑺,𝑪𝒊)/𝒌𝒕
𝒁=
𝒊
Van Der
Waals
Mutation effect on protein folding
Image
courtesy
Johan
Grahnen
Introduce a mutation
Image
courtesy
Johan
Grahnen
An additional mutation
Image
courtesy
Johan
Grahnen
Fixation in a population
• Non-synonymous substitutions
• Positive selection
• Selective sweeps
Mutational Change
Structural Change
Functional Change
Yi, S. 2006 BioEssays
Modeling Protein Evolution
Model
Results
Knowledge
Modeling Protein Evolution
• Increasing degree of
complexity in models
– Equal Rates
– Rates across Sites
– Rate shifting (covarion)
• Prediction of functional
change and the debate that
followed
– Gu
– Philippe
Gaucher et al 2002, Trends in Biochemical Sciences
Well…which is it?
• “Therefore, site-specific rate changes (or altered
selective constraints) are related to functional
divergence during protein (family) evolution.”
-Xun Gu 2003 Genetica
• “In conclusion, protein evolution is a very complex
process. Heterotachy appears to be quite common
and are not related to functional shift.”
-H. Philippe et al 2003 IUBMB
Research Hypotheses
• Hypothesis I
– There is a time-dependent
transition between the rates
across sites model and the
covarion models that occurs
without a functional shift.
• Hypothesis II
– The rate of this transition
depends on specific protein
folds.
The Plan
Tree
Topology
and
Protein
Sequence
Energy
Model
Simulation
with SH2
evolution
program
Model
Testing
Sequence
Analysis
Tree Topology & Src Homology Domain
Simulation strategy
Sequence
known to fold
and bind to
ligand
ATGGACGCT…
Mutate the
sequence
MDA…
ATGGGCGCT…
Evaluate the
effect of the
mutation
MAA…
Fold + Function
Characterize
Viability
Fitness
Model Testing
Sequence alignment and tree
 Procov
 Covarion models (Galtier,
Tuffley, Huelsenbeck, General)
vs. a RAS model.
 ProtTest
 Selects the model of protein
evolution that best fits a given
set of sequences.

Results
25
20
1/P-val
15
10
5
0
general
huelsenbeck
tuffley
ras
equal rates
P-value = 0.05
Results
Results
Expected: 0.3-0.5
So…
• Equal rates model best fits the data
• Excessive drift of surface residues
• Highly variable sequences across populations
Before moving forward
• Improve energy model
• Selection/generation of decoys
• Re-examine parameters
Resources
•
•
•
•
•
Philippe H, Casane D, Gribaldo S, Lopez P, Meunier J. Heterotachy and functional shift in
protein evolution. IUBMB Life. 2003 Apr-May;55(4-5):257-65.
Gu, Xun, Eric A. Gaucher, Michael M. Miyamoto, and Steven A. Benner. "Predicting Functional
Divergence in Protein Evolution by Site-specific Rate Shifts." Trends in Biochemical Sciences
27.6 (2002).
Wang H-C, Susko E. & A. J. Roger, PROCOV
PROTTEST: Selection of best-fit models of protein evolution sponsored by
© 2004-2009 Federico Abascal, Rafael Zardoya and David Posada 2.4 (October 09).
weblogo.berkeley.edu/logo.cgi
Special thanks to Johan Grahnen and David Liberles
for all their patience, advice, and teaching
throughout my undergraduate career.
Questions?