Article critique of Epistasis in protein evolution please read the requirements listed in page below thank you. you have to write an Article critique whic

Article critique of Epistasis in protein evolution please read the requirements listed in page below thank you.

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Epistasis in protein evolution
Tyler N. Starr1 and Joseph W. Thornton2*
Graduate Program in Biochemistry and Molecular Biophysics, University of Chicago, Chicago, Illinois 60637
Departments of Ecology and Evolution and Human Genetics, University of Chicago, Chicago, Illinois 60637
Received 2 December 2015; Accepted 27 January 2016
DOI: 10.1002/pro.2897
Published online 2 February 2016
Abstract: The structure, function, and evolution of proteins depend on physical and genetic interactions among amino acids. Recent studies have used new strategies to explore the prevalence, biochemical mechanisms, and evolutionary implications of these interactions—called epistasis—within
proteins. Here we describe an emerging picture of pervasive epistasis in which the physical and
biological effects of mutations change over the course of evolution in a lineage-specific fashion.
Epistasis can restrict the trajectories available to an evolving protein or open new paths to sequences and functions that would otherwise have been inaccessible. We describe two broad classes of
epistatic interactions, which arise from different physical mechanisms and have different effects on
evolutionary processes. Specific epistasis—in which one mutation influences the phenotypic effect
of few other mutations—is caused by direct and indirect physical interactions between mutations,
which nonadditively change the protein’s physical properties, such as conformation, stability, or
affinity for ligands. In contrast, nonspecific epistasis describes mutations that modify the effect of
many others; these typically behave additively with respect to the physical properties of a protein
but exhibit epistasis because of a nonlinear relationship between the physical properties and their
biological effects, such as function or fitness. Both types of interaction are rampant, but specific
epistasis has stronger effects on the rate and outcomes of evolution, because it imposes stricter
constraints and modulates evolutionary potential more dramatically; it therefore makes evolution
more contingent on low-probability historical events and leaves stronger marks on the sequences,
structures, and functions of protein families.
Keywords: epistasis; evolutionary biochemistry; sequence-function relationship; protein evolution;
sequence space; deep mutational scanning; ancestral sequence reconstruction
A protein’s biological functions emerge from its
chemical and physical properties, which in turn are
determined by the interactions between its amino
acid residues in three-dimensional space. It is thereGrant sponsor: NIH; Grant number: R01GM104397; Grant
sponsor: NIH training grant; Grant number: T32-GM007183;
Grant sponsor: National Science Foundation; Grant number:
*Correspondence to: Joseph Thornton, GCIS W504A, 929 E
57th St, Chicago, IL 60637. E-mail:
PROTEIN SCIENCE 2016 VOL 25:1204—1218
fore not surprising that the functional effect of
changing an amino acid often depends on the specific sequence of the protein into which the mutation
is introduced. This dependency on genetic context
has long been called epistasis by geneticists.1 Epistasis is invoked when the combined effect of two or
more mutations deviates from that predicted by adding their individual effects.
Although studies of epistasis have traditionally
focused on genetic interactions between mutations
at different loci,1 recent research has begun to
address epistasis within proteins—its prevalence,
C 2016 The Protein Society
Published by Wiley-Blackwell. V
biochemical mechanisms, and impacts on evolution.
A consensus view of these subjects has not yet
emerged however. Some papers conclude that epistasis is “rampant”2 or even the “primary factor” in protein evolution,3 whereas others claim that the
frequency and magnitude of epistasis is “sufficiently
low” such that it does not strongly affect the patterns of substitution in evolving proteins.4 There is
also no clear picture of the mechanisms that cause
epistasis: many papers have focused exclusively on
epistasis mediated by effects on protein stability,5–9
although a few have addressed effects on protein
conformation, ligand binding, and allostery.10–12
These disagreements reflect, at least in part,
the lack of a unified discussion of the parallels and
contrasts now emerging from the diverse modes of
analysis applied to epistasis and its effects on protein evolution. Here we attempt such a unified view,
focusing on the following specific questions: How
important a factor is epistasis in changing the
effects of mutations during the course of evolutionary history? Does epistasis typically amplify or
dampen the effect of individual mutations? Does
most evolutionarily relevant epistasis reflect very
specific interactions between mutations—for example, with only one potential “permissive” mutation
that can open the path for another specific mutation—or are many-to-one, one-to-many, or many-tomany interactions more common? What are the
molecular mechanisms of interaction that produce
each form of epistasis? And how do epistatic interactions of these various types influence the pathways
and outcomes of long-term protein evolution?
Epistasis and Protein Sequence Space
The concept of sequence space provides a useful
metaphor for understanding the relationship
between a protein’s sequence, its physical or biological properties, and its evolution. Sequence space is a
multidimensional representation of all possible protein genotypes, each connected to its neighbors by
edges representing changes in a single residue.13
Assigning physical or biological properties to each
genotype yields a “topological map” of the sequence
space, just as a topological map of a geographic landscape assigns elevations to locations defined by their
latitudinal and longitudinal coordinates. Epistasis
makes the topology of sequence space “rugged”,14 in
that the physical or biological effect of a mutation
differs in sign or magnitude depending on the
sequence background into which it is introduced;
similarly, on a rugged geographical landscape, the
change in elevation caused by a step in some direction varies dramatically depending on the starting
As proteins evolve, they follow trajectories
through sequence space, so this topology also determines how mutation, drift, selection, and other
Starr and Thornton
forces can drive genetic and functional evolution. A
typical trajectory in natural or directed protein evolution consists of iterative mutational steps between
functional proteins; trajectories involving strongly
deleterious mutations are considered unlikely,
because nonfunctional variants of biologically important proteins will usually reduce fitness and therefore be removed by natural selection.13,15–17 In the
absence of epistasis, any mutation that changes protein properties in a beneficial way can be fixed by
natural selection, irrespective of the genetic background in which it occurs; the result is a large number of passable trajectories through sequence space
to the functional optimum that combines all of the
beneficial sequence states. When epistasis is present, however, a mutation may be beneficial in some
backgrounds but deleterious (or neutral) in others;
the number of passable trajectories becomes smaller,
the fixation of any one mutation may be contingent
on the prior occurrence of other specific mutations,
and there may be multiple local optima, consisting
of mutually conditional beneficial states, isolated
from each other by trajectories of low fitness.
Epistasis can therefore affect evolutionary processes in dramatic ways. First, it can create a strong
path-dependency in trajectories of protein evolution,18–21 because the mutations that are stochastically fixed may determine which functional optimum
an evolving protein ultimately occupies, and these
optima may differ not only in primary sequence but
also in interesting physical or biological properties.
Second, epistasis can yield evolutionary “dead-ends”
in sequence space, from which a potentially beneficial mutation is not immediately accessible; in such
cases, a relaxation of selection or even selection for
other protein properties is necessary before a trajectory is opened to a superior optimum.10,22–28 Third,
epistasis can cause a mutation that confers or
improves a function in one protein to have no effect
or even be strongly deleterious in a related protein;2,21,29 as a result, attempts to leverage natural
sequence variation or experimental observations to
predict mutational effects or engineer proteins with
desired properties often fail.30 These issues highlight
why characterizing epistasis—including the breadth
of its effect, its mechanistic underpinnings, and its
evolutionary impact—is important for our basic
Prevalence and Strength of Epistasis
How prevalent is epistasis within proteins, how
strongly does it modulate the effects of mutations,
and to what extent does this context-dependence
affect long-term evolution? Studies of these questions have used two primary approaches—deep
mutational scanning of large numbers of mutations
in individual proteins, and analyses of changes in
mutational effects across long-term trajectories of
protein evolution.
Epistasis in a protein’s local sequence
A recently developed technique called deep mutational scanning makes it possible to characterize a
very large library of mutant versions of some protein
of interest with respect to some physical or biological
property. By analyzing many or all variants that differ by one or two amino acids from a starting protein, it is possible to comprehensively characterize
pairwise epistatic interactions in that protein’s local
sequence neighborhood.31–35 In the absence of epistasis, the behavior of double mutants can be predicted with perfect accuracy by adding the effects of
their constituent single mutations. (That is, R2
approaches 1 for the correlation between observed
and predicted double mutant function.) In contrast,
on a completely epistatic landscape, the effect of a
mutation is completely independent in every background (so R2 approaches 0). Experiments reveal an
intermediate prevalence of epistasis: the properties
of single mutants predict double mutant behavior
moderately well (R2 0.65–0.75).31–33 This result
indicates that strong epistasis is not all-pervasive,
pointing instead to epistasis that is pervasive and
weak or relatively rare and strong. In fact, it
appears that both types of interactions are important: a comprehensive study of pairwise interactions
in protein G domain 1 (GB1) found strong deviations
from additivity (by a factor >2) in 5% of all pairs
of mutations, while weak epistasis (
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