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Evolutionary mechanisms forestablishing eukaryotic cellular
complexityFred D. Mast1,2,3, Lael D. Barlow1, Richard A.
Rachubinski1, and Joel B. Dacks1
1Department
of
Cell
Biology,
University
of
Alberta,
Edmonton,
Alberta
T6G
2H7,
Canada2Seattle
Biomedical
Research
Institute,
307
Westlake
Avenue
North,
Seattle,
WA
98109-5240,
USA3 Institute
for
Systems
Biology,
401
Terry
Avenue
North,
Seattle,
WA
98109-5219,
USA
Through a comparative approach, evolutionary cell biol-
ogy makes use of genomics, bioinformatics, and cell
biology of non-model eukaryotes to provide new ave-
nues for understanding basic cellular processes. This
approach has led to proposed mechanisms underpin-ning the
evolution of eukaryotic cellular organization
including
endosymbiotic
and
autogenous
processes
and neutral and adaptive processes. Together these
mechanisms have contributed to the genesis and com-
plexity
of
organelles,
molecular
machines,
and
genome
architecture. We review these mechanisms and suggest
that
a
greater
appreciation
of
the
diversity
in
eukaryotic
form has led to a more complete understanding of the
evolutionary connections between organelles and the
unexpected routes by which this diversity has been
reached.
Bringing
together
cell
biology
and
evolutionary
biologyThe emergence of the eukaryotic state nearly 2
billion
years
ago
transformed
life
on
Earth.
Efforts
to
unravel
the
evolutionary
mechanisms
that
have
shaped,
and
con-
tinue to shape, eukaryotic cells are beginning to address
this
monumental
evolutionary
shift.
Understanding
these
mechanisms
will
help
us
to
make
conceptual
connections
between the cell biology of taxonomically diverse modern
eukaryotes,
porting
knowledge
derived
in
model
systems
to
less
studied
organisms
of
agricultural
(e.g.,
crops,
plant
pathogens),
environmental
(e.g.,
aquatic
primary
produ-
cers like haptophytes and diatoms), or medical (e.g., para-
sites
such
as
Plasmodium
falciparum, the
causative
agent
of
malaria)
relevance.
This
broad
comparative
approach
known as evolutionary cell biology (see Glossary)
facili-tates
the
generation
of
hypotheses
that
attempt
to
explain
the cell
biological
functions
shared
among
the
full
range
of
eukaryotes.
This approach has been applied successfully to many
aspects
of
the
eukaryotic
cell
(e.g.,
[1]).
The
combination
of
ultrastructure
and
molecular
cell
biology
with
genomic
data from a sampling of organisms spanning the taxonomic
breadth of eukaryotes [2,3] (Figure 1) has provided awealth of
knowledge regarding the evolution of eukaryotic
cell
biology
and
its
diversity.
From
the
perspective
of
a
cell
biologist,
this
wealth
of
data
allows
the
integration
of
established evolutionary theory with the study of cellular
mechanisms.
Review
Glossary
Complexity: a measure of the number of components and
interactions of one
system relative to another equivalent system.
Endosymbiosis (primary): the process whereby a prokaryotic cell
(endosym-
biont) is incorporated into the cytoplasm of a eukaryotic cell
(host), with a
relationship being established via metabolic integration and EGT
such that
neither partner can survive on its own.
Endosymbiosis (secondary): the same process as primary
endosymbiosis
exceptthat theendosymbiont is a eukaryotic cell possessing a
primary plastid.
Theprocesscan be extendedto tertiary endosymbiosis (the
endosymbiont is a
cell possessing a secondary plastid) and serial secondary
endosymbiosis (a
lineage possessing one type of secondary plastid replaces its
secondary
plasmid with a secondary plastid of a different lineage).
Endosymbiotic gene transfer (EGT): a special case of horizontal
gene transfer
(see below), whereby thegene in questionis acquired by thehost
lineage from
the genome of the endosymbiont.
Evolutionary cell biology: an emerging discipline that
incorporates compara-
tive perspectives and techniques from cell biology,
protistology, molecular
evolution, and mathematical evolutionary theory to address
questions of the
origins and diversity of cells.
First eukaryotic common ancestor (FECA): the cell (or population
of cells)
belonging to the lineage that gave rise to the modern line of
eukaryotes at the
earliest point at which it possessed cell biological features
distinct from those
in prokaryote-like cells. Although this organism is deduced to
have existed, a
useful way to treat the FECA is as a theoretical reconstruction
with the traits
defining it as an exciting open research question.
Horizontal gene transfer: the acquisition of a gene by a genome
from a source
other than the immediate parental lineage.
Last eukaryotic common ancestor (LECA): the cell (or population
of cells)
belonging to the lineage that gave rise to the modern line of
eukaryotes at the
latest point at which the various descendent lineages diverged
to leave the
extant eukaryotic lineages. Again, this concept is most useful
as a theoretical
reconstruction or reference point to assess the antiquity of var
ious cell
biological features.
Monophyletic: a group is considered monophyletic when it
encompasses all
descendants of a single ancestor.
Paraphyletic:a group is considered paraphyletic when it
encompasses some,
but not all, descendants of a single ancestor.
Paralog: genes that are the result of a gene duplication
process.
Selection: the process by which a factor (including the presence
of another
organism) presents a circumstance that results in the
preferential death of
some organisms in the environment over others.
0962-8924/$ see front matter
2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tcb.2014.02.003
Corresponding author: Dacks, J.B. ([email protected]).
Keywords: constructive neutral evolution; endosymbiosis;
evolutionary cell biology;
organelle paralogy hypothesis; protocoatomer; transfer-window
hypothesis.
Trends in Cell Biology, July 2014, Vol. 24, No. 7 435
http://dx.doi.org/10.1016/j.tcb.2014.02.003mailto:[email protected]:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.tcb.2014.02.003&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.tcb.2014.02.003&domain=pdfhttp://dx.doi.org/10.1016/j.tcb.2014.02.003
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(Figure 2A). Recent cell biological and genomic studies of
these organismshave revealed much about the mechanism
of endosymbiosis.
Indeed,
one
reason
why
endosymbiosis
is
better understood than autogenous mechanisms of organ-
elle
acquisition
is
the
wealth
of
endosymbiotic
intermedi-
ates available for study (e.g., [16]).Recent and independent
occurrences
of
endosymbiosis
have
revealed
the
earliest
stages
of
the
process,
including
several
examples
of
prima-
ry (e.g., Paulinella) and secondary (e.g., Hatena) plastid-
derived
organelles
as
well
as
transiently
acquired
plastids
termed kleptoplasts
[16]. Other
examples
of
where
the
hostand symbiont are at the beginning of their integration
include
dinotoms,
algae
wherein
the
host
lineage
is
a
dinoflagellate that possesses a minimally reduced diatom
endosymbiont.
Recent
work
has
begun
to
uncover
the
extent and nature of their organellar and metabolic inte-
gration [17]. Genome
sequencing
of
organisms
such
as
the
cryptophyte
and
chlorarachniophyte
algae,
whose
photo-
synthetic organelle contains both a secondary plastid ge-
nome
and
the
remnant
of
the
red
or
green
algal
nuclear
genome
(nucleomorph)
and
cytoplasm
[18], have
also
allowed examination of genome reduction and cellular
integration
in endosymbiosis
(Box 2). Because
photosyn-
thesis
has
been
gained,
stolen
and
co-opted
throughout
the
history of eukaryotes, the acquisition of plastids has been
a
particularly
useful
model
for
understanding
the
early
stages
of
endosymbiosis.
However,
a
rare
example
of
a
potential
secondary
mitochondrial
endosymbiont
has
re-
cently been described by genomic methods [19]. The fish
pathogen
Neoparamoeba
contains
what
appears
to
be
an
intracellular
symbiont
related
to Ichthyobodo necator, a
kinetoplastid. Although the atypical mitochondrion of this
symbiont
occupies
nearly
half
of
its
cytoplasmic
volume,
the
extent
to
which
the
endosymbiont
has
progressed
to
become an organelle is unclear. The nuclear genome of the
symbiont
does
not
appear
to
have
undergone
extensive
reduction comparedwith that of otherkinetoplastids.All of
these examples help focus the question of how reduced an
endosymbiont
has
to
be
for
it
to
be
considered
an
organelle
and
no
longer
an
organism.
At the other extreme of endosymbiotic integration exist
organelles
apparently
reduced
from
the
canonical
eukary-
otic
state,
such
as
the
non-photosynthetic
apicoplasts
of
apicomplexans [16] and the hydrogenosomes and mito-
somes,
some
of which
no
longer
possess
organellar
gen-
omes.
Initially
these
latter
organelles
were
seen
as
distinct
classes;
however,
recent
studies
have
clearly
established
them as derivatives of mitochondria and found various
intermediates
possessing
aerobic
or
anaerobic
metabo-
lisms
and
different
genomic
organizations
(e.g.,
[20]).
The range of genomic and cytoplasmic minimalization
found
for
endosymbiotically
derived
organelles
raises
the
question
of
what
mechanism
determines
and
limits
the
extent of this reductive trend in any given lineage. The
passage
of
time
cannot
explain
this
reduction
because
a
wide
range
of
reduction
is
observed
in
organelles
clearly
derived
from
the
same
founding
event
(e.g.,
the
mitochon-
drion). However, it was proposed that because the main
Box 1. Eukaryotic diversity
Eukaryotic diversity (Figure 1B inmain text) is currently
divided into
six large taxonomic groupings, or supergroups [2]. The
Opistho-
konta encompasses the lineages of animals and fungi, as well
as
their single-celled relatives. The Amoebozoa houses a diversity
of
amoeboid lineages with, and without, flagellated stages. It
includes
the pathogens Balamuthia, Acanthamoeba, and, most famously,
Entamoeba histolytica, the causative agent of amoebic
dysentery.
The Opisthokonta and Amoebozoa
are united in large-scalemolecular phylogenetic analyses and
thought to represent a
monophyletic grouping, named the Amorphea [2]. The Archae-
plastida incorporates the lineages
of red
algae, green algae
(including land plants), and the glaucophytes, which are
derived
from a single founding primary-endosymbiotic event. The SAR
clade unites the seemingly disparate lineages of
stramenopiles
(diatoms, brown algae, and the causative agent of the Irish
Potato
Famine, Phythophthora) and alveolates (ciliates like
Paramecium,
the dinoflagellates that cause red tides, and apicomplexans such
as
Plasmodium, which causes malaria). The supergroup Excavata
includes important disease-causing agents such as
Trypanosoma,
Leishmania, Giardia, and Trichomonas, as well as their
free-living,
or nonpathogenic, relatives. Finally, the CCTH supergroup
currently
contains the lineagesof cryptophytes, centrohelids, telonemids,
and
haptophytes; however, the most recent large-scale molecular-
evolutionary analyses have cast doubt on the unity of these in
asingle group [3] and the CCTH should be treated as tentative at
best.
Box 2. Endosymbiosis
The types of endosymbiosis are classified based on thenature of
the
host and of the endosymbiont. The simplest form, or primary
endosymbiosis, involves a eukaryotic host and a bacterial
endo-
symbiont (Figure 2A in main text). Two such primary events
have
been transformative in the history of eukaryotes and involved
the
incorporation of an a-proteobacterium and a cyanobacterium
to
give rise to mitochondrion- and plastid-derived organelles,
respec-
tively. Both events are known to have occurred early in
eukaryotichistory, with the mitochondrial event now convincingly
shown to
have predated the LECA [20]. A primary plastid endosymbiosis
is
very likely to have occurred at the base of the
Archaeplastida
lineage, conferring photosynthetic capacity and giving rise to
all red
and green algae and land plants. The photosynthetic ability
was
clearly advantageous, as it spawned the subsequent evolution
of
complex plastids [16] through secondary and tertiary
endosym-
bioses (Figure 2A in main text).
As a mechanism, the process of endosymbiosis can be divided
into initiation and integration. Initiation may stem from
various
possible microbial associations, including mutualistic exchange
of
metabolites, intracellular invasion of the host by a parasite,
or
predatory ingestion of an eventual endosymbiont by a
phagotroph.
After initiation, the success of the resulting chimera depends
on the
ability to synchronize the cell growth and division cycles of
the host
and endosymbiont. In all cases, gradual transfer of genetic
materialfrom the endosymbiont genome to the host genome promotes
this
synchronization (Figure 2B in main text). This ratchet-like
mechan-
ism of EGT drives the establishment of an obligate
relationship
between the endosymbiont and i ts
host. Af ter acquir ing an
endosymbiont, the organism has two genomes, one in the
nucleus
and one in the endosymbiont (Figure 2B, i inmain text). Whether
by
lysis or by improper fission and fusion events of the
endosymbiont
during replication, endosymbiont DNA released into the
cytoplasm
can be integrated into the host genome (Figure 2B, ii in main
text).
With an endosymbiont gene now encoded and expressed by the
host, it must be successfully retargeted to the endosymbiont
(Figure 2B, ii i in main text). When this occurs, the
endosymbiont
copy is redundant and sustains mutational decay, and the
endosymbiont genome is reduced (Figure 2B, iv in main text).
The
directionality imposed by this
transfer results in an iterative ratchet-
like mechanism. The window of opportunity permitting EGT
remains open until only a single endosymbiont genome remains
(Figure 2B, v and vi in main text) [16,20].
Loss of genes, coincident
with loss of function, in the organism-to-organelle transition
is also
a major source of genome reduction [16,20].
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Independent acvity Binding and presuppression Mutaon and
dependence Ratchet-l ike increase in dependence
Acvity A
Factor A Factor A
Factor B
Acvity A
Factor A
Factor B
Acvity A
Factor A
Factor B
Acvity A
(i)
(i)
(ii)
(iii)
(ii) (iii) (iv)
x yz
x yz
x yz
x yz
x yz
x yz
(v)
x
x yz
x yz
(vi)
x
yz
yz
yz
yz
x zxy
Endosymbiosis(A)
(B)
(C)
(D)
EGT and transfer window hypothesis
Organelle paralogy hypothesis
Construcve neutral evoluon
Primary
Secondary Terary
(i) (ii) (iii)
(i) (ii) (iii) (iv)
TRENDS in Cell Biology
Figure 2.
Mechanisms of cellular evolution. (A) The variety of plastids
arising from iterative acquisition of photosynthetic endosymbionts.
(i) Primary endosymbiosis is
established following engulfment of a cyanobacterium (green) by
a eukaryotic host cell. A similar primary endosymbiotic process
would also have produced the
mitochondrion from a proteobacterium. (ii) In secondary plastid
endosymbiosis, a green or red algal cell is engulfed by a new host
cell. (iii) This process is repeated
intertiaryendosymbiosis.Althoughprimary, secondary, and
tertiaryendosymbioses are conceptuallyinterconnected,they arenot
consecutivesteps of a single colonization.
(B) The steps of endosymbiotic gene transfer (EGT) from a newly
acquired endosymbiont: lysis of the endosymbiont and (ii) transfer
of the gene to the host nucleus; (iii)
retargetingand (iv) endosymbiont-encodedgene loss; and (v)
repetition until (vi) a single endosymbiontremains. (C)
Theorganelle-paralogy hypothesis (OPH). (i) Different
protein families interact cooperatively to specify
organelle-defining properties such as tethering, docking, fission,
or fusion. (ii) Specificity-encoding protein families evolve
by geneduplicationanddivergence, as representedby this
hypothetical phylogeny. (iii) Increases in the complexity of
specificity-encoding protein familiesaremirroredby
increases in the complexity of themembrane-traffickingsystem.
Paralogsof the specificity-encoding protein family reside in
andhavetheir effect on distinct compartments.
Modified from [59].
(D) A generalized outline of constructive neutral evolution
(CNE). (i) Protein factor A possesses a given activity. (ii)
Through random steric collisions, a
stochastic interactionwith a separate factor B occurs that has
little or no effect on the activity of factor A. (iii) A mutation
(representedby a yellowstar) occurs in factor A
that reduces itsactivity, but due to theinteraction of factorA
with factorB, themutation is suppressed and theactivityof factorA
ismaintained at near-original levels. This
could be due to stabilization of thestructure of factorA,
masking of itscharge or exposed hydrophobicresidues, or altered
localization of factorA allowing better accessto
its substrate. (iv) Subsequent mutationsof theoriginalfactor A,
and compensatory mutations in the interacting factor B, further
integrate factor B in the activity of factorA
via a ratchet-like mechanism that may also lead to the
recruitment of additional factors.
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mechanism
of
DNA
transfer
to
the
host
nucleus
comes
from
lysed
organelles,
the
rate
of
transfer
is
proportional
to
the
copy
number
of
the
endosymbiont
in
the
cell
(Figure 2B).
This idea became known as the transfer-window hypothe-
sis
[21], which
implies
that
transfer
cannot
continue
once
the
number
of
organelles
has
reached
a
single
copy.
Indeed,
experimental [22] and comparative [23] genomic analyses
revealed
far
fewer
transfers
from
plastids
to
nuclear
gen-omes in organisms possessing a low plastid copy number.
In addition,
the
nuclear
genomes
of
a
cryptophyte
and
of
a
chlorarachniophyte
alga,
each
possessing
a
single
nucleo-
morph, have been sequenced and were reported in 2012
[24].
These
findings
revealed
a
complete
lack
of
recent
DNA
transfer from either the plastid or the nucleomorph ge-
nome
despite
evidence
of
transfer
from
mitochondria,
which
is
consistent
with
a
reduction
to
a
single
organelle
that is responsible for halting endosymbiotic gene transfer
(EGT)
and
hence
organelle
reduction.
Endosymbiosis
has
repeatedly
allowed
for
increased
overall complexity in eukaryotic cells compared with their
pre-merged
state.
Ironically,
because
the
cell
is
at
its
most
complex state immediately after endosymbiosis begins,with
integration
progressing
principally
via
EGT
or
gene
loss, the process of endosymbiosis actually involves
decreases
in
complexity.
Autogenous (non-endosymbiotic) organelles
Although
endosymbiosis
has
undoubtedly
been
a
powerful
force
in
building
some
aspects
of
eukaryotic
cellular
com-
plexity, it does not explain them all.A simpler, alternative
explanation
for
the
origin
of
organelles
delimited
by
a
single
lipid
bilayer
and
devoid
of
genetic
material
is
that
they are autogenous. The organelles most commonly
proposed
to
have
an
autogenous
origin
are
those
of
the
membrane-trafficking
system,
including
the
endoplasmicreticulum
(ER),
Golgi
apparatus,
endosomes,
and
plasma
membrane [25]. Although these endomembrane organelles
are
dynamically
connected
to
one
another,
they
are
main-
tained
as
distinct
compartments
through
the
action
of
membrane trafficking machineries such as Rabs, SNAREs,
coatomer,
and
adaptin
(AP)
complexes
[26]. These
speci-
ficity-encoding
protein
families
have
different
members
that perform the same function (e.g., inducing membrane
curvature
or
facilitating
membrane
fusion)
at
distinct
locations within the membrane-trafficking system [26].
Although each protein family could play an individual role,
part of the information encoding specificity in membrane
trafficking
appears
to
result
from
combinatorial
protein
protein
interactions
between
members
of
the
different
families [27]. Comparative genomic and phylogenetic anal-
yses
of
these
various
protein
families
have
revealed
details
of
their
primary
diversification
by
gene
duplication
(e.g.,
[1]). Surprisingly, theduplications giving rise toparalogs
of
the
various
specificity-encoding
proteins
associated
with
each
cellular
location
occurred
before
the
LECA.
However,
examination of the endocytic paralogs of the SNARE, Rab,
and
AP
families
revealed
a
pattern
whereby
some
organ-
elle-specific
paralogs
had
not
duplicated
before
the
LECA,
with
parallel
duplications
occurring
instead
in
lineages
after the LECA [28]. These patterns provide an under-
standing
of
the
timing
of
these
events
and
suggest
a
possible
mechanism
underpinning
them,
which
is
formal-
ized
in
the
organelle-paralogy
hypothesis
(OPH)
[28,29].
The
OPH
(Figure 2C) proposes
that
a
set
of
specificity-
encoding proteins with complementary functions that de-
fine organelle
properties
produce
sets
of
interacting
para-
logs
by
undergoing
duplications.
Through
coevolution,
these sets of specificity-encoding proteins accumulate
mutations
that
fix
their
specific
functional
binding,
thusdefining separate organelles [30]. Iterations of this
process
could
therefore
account
for
the
array
of
organelles
in
the
endomembrane
systems
of
extant
eukaryotes
that
arose
via differentiation from an original prototypical internal
compartment
in
the
FECA.
Recently, the OPH has been tested by computer simu-
lation.
Mathematical
modeling
of
specificity-encoding
genes
in
populations
of
vesicles
showed
that
gene
duplica-
tion and differential interactions between paralogs pro-
duced
novel
vesicular
compartments
[31]. The
OPH
further
predicts
that
the
order
of
evolutionary
emergence
for
each
member of a specificity-encoding protein family should
correspond
to
the
order
of
emergence
of
the
different
organelles they define and on which they have effect.Two
recent
studies
have
reported
phylogenetic
resolution
for important specificity-encoding protein families, thereby
allowing
hypotheses
to
be
proposed
based
on
empirical
evidence
regarding
an
order
of
evolutionary
emergence
beyond the establishment of extensive complexity in mem-
brane
trafficking
in
the
LECA.
AP
complexes
aid
in sorting
the
vesicular
traffic
between
organelles
found
between
and
including the plasma membrane and the trans-Golgi net-
work
[32,33]. Comparative
genomic
and
phylogenetic
anal-
ysis
resolved
the
order
of
emergence
of
the
members
of
the
AP complex family, withAP3 andAP5 first diverging from
the
remaining
AP
complexes,
followed
by AP4
and
AP1/2
[32]. Based
on
their
known
locations
of
action,
this
ordersuggests
that
adaptins
first
acted
at
an
organellar
inter-
face between the secretory system and the phagocytic
system,
before
the
establishment
of the
trans-Golgi
net-
work.
In
addition,
recent
evidence
provides
clues
to
the
conservation among the Rab family of GTPases, which are
molecular
switches
involved
in
specifying
organelle
iden-
tity
in
the
membrane-trafficking
system
[34]. Although
it
is
well established that Rab GTPases are ancient and that
the
LECA
possessed
a
large
complement
of
such
proteins
[35], the extent to which Rab families are conserved
remained unknown. Rigorous homology searching resulted
in the expansion of the Rab complement in LECA to 15
subfamilies
[36]. However,
robust
phylogenetic
resolution
between
the
paralogs
of
the
Rab
gene
families
increased
the estimated number of Rab subfamilies in the LECA to
between
19
and
23
[37]. Surprisingly,
this
analysis
also
revealed
two
ancient
sets
of
Rabs,
one
inferred
to
be
involved in exocytosis and one predominantly in endocyto-
sis,
potentially
reflecting
the
earliest
establishment
of
these
pathways.
As
improved
comparative
and
phyloge-
netic methods are applied to other trafficking families, it
will
be
important
to
compare
the
evolutionary
patterns
that
emerge
and
to
delve
further
into
events
pre-LECA.
Although the OPH is a
mechanism for evolving
in-
creased compartment number and specialization within
an organellar system,
it is currently limited
to
the
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membrane-trafficking
system.
However,
an
idea
thatcom-
plements
theOPH is theprotocoatomer hypothesis,which
proposes,
based
on
protein-structural evidence,
that ho-
mology exists between the membrane deformation com-
ponents
of
vesicular trafficking
and the nuclear pore [38].
Specifically, proteins
integrated
into
the COP I,
COP II,
clathrin, and nuclear pore complexes share a structure of
b-propellers
followed bya-solenoid
domains.
These pro-teins are suggested to be homologous and therefore
de-
rived from
a
single ancestral protocoatomer protein
[39].
Recent
analyses
have also
firmly established relation-
ships between protocoatomer-derived proteins of the
intraflagellar complex [40].
These proteins,
which are
dispersed throughout the cell and essential for organ-
elle-specific functions, appear to
have
expanded
along
with their organelles
via the process
described in the
OPH. Therefore, the overlap between the two hypotheses
extends
themechanism
of
autogenousorganelleevolution
to
potentially
all organelles
for
whicha
non-endosymbiotic
origin appears likely.
Examples
exist
of
organelles
whose
origins
blur
the
divisions of autogenous and endosymbiotic organellar
evo-lution.
The
origin
of
the
peroxisome
has
been
contentiously
explained by both mechanisms. Although the evidence,
both
functionally
[41]
and
evolutionarily
[42], strongly
favors
an
autogenous
origin
for
peroxisomes,
there
have
undoubtedly been, and continue to be, molecular and
functional
interactions
between
peroxisomes
and
orga-
nelles
of
endosymbiotic
origin,
notably
the
mitochondrion
[43]. Many proteins that localize to the peroxisome are
encoded
by
genes
of
bacterial
origin
and
function
in
meta-
bolic
processes
shared
with
mitochondria
(e.g.,
fatty-acid
oxidation). Determining how endosymbiotic organelles
have
become
integrated
within
the
cell
and
interact
with
non-endosymbiotically
derived
systems
is
an
emergingarea
of
investigation
for
cell
biology
and
evolutionary
cell
biology. Work in the past few years has uncovered several
protein
complexes
mediating
protein,
lipid,
and
ion
trans-
port
between
the
ER
and
mitochondria
[44]
and
it
was
recently shown that protein complexes bridging the ER
and
mitochondria
in
fungi
are
more
widely
present
in
eukaryotes
than
previously
suspected
[45,46].
Constructive neutral evolution (CNE)
Evolutionary processes are not limited to the organellar
level. Individual cellular machines in the eukaryote (e.g.,
ribosomes, proteasomes) also show increased complexity
over
their
prokaryotic
counterparts.
In
some
cases,
this
increased
complexity
could
result
in
new
functions,
pro-
viding a selective advantage to the eukaryotic cell. How-
ever,
the
role
of
selection
as
the
only
driver
in
the
evolution
of
complexity
is
increasingly
being
questioned.
The theory of CNE [47] posits that many biological
phenomena
can
arise,
or
be
elaborated
on,
by
neutral
evolutionary
processes
that
promote
increased
complexity
without additional functionality [48]. CNE is predicated on
an idea
of
presuppression
(Figure 2D); that
is,
interactions
between
factors
that
are
the
initial
result
of
random
colli-
sions
or
cytosolic
overcrowding
and
that
minimally
affect
function [49] may become stabilized due to random muta-
tion
in
a
factors
partner
or
in
both
factors.
On
their
own,
these
mutations
may be slightly deleterious for
the origi-
nal function, but if binding of
the partner
restores
func-
tionality, the
interaction becomes
fixed.
Therefore,
the
mutation is not selective in the traditional sensebutneeds
to
be sufficiently compensatory
to
avoid negative
selection
and to
allow the organism to
survive.
These mutations
may be extremely rare; nevertheless, once established
they result in
a
ratchet
that promotes
tighter bindingand, potentially, recruits other factors. These
interactions
could involve
protein
interactions with nearly any mole-
cule
or
surface
in the cell (e.g., diffusible small
molecules,
cellular membranes).
Among
these
biological
phenomena,
the
origin
of
the
spliceosome has been proposed to require CNE [47,48].
Comparative
genomic
studies
of
spliceosomal
components
have
demonstrated
that
the
spliceosome
is
a
eukaryotic
innovation that was present in its highly elaborate state
before
the
LECA
[50]. Comprising
well
over
100
different
protein
and
RNA
components,
the
spliceosome
is
a
candi-
date for one of the most complex cellular machines in
existence.
However,
it
has
long
been
appreciated
that
the underlying essential process could have evolved froma
simple
self-splicing
group
II-class
intron.
Rather
than
being the result of selective forces, the spliceosome is
best
explained
as
a
product
of CNE
whereby
mutations
in
the
self-splicing
RNA
molecule
were
suppressed
through
a
pre-
existing interaction with a RNA or RNA/protein complex
[47,48]. As
protein
and
RNA
components
accumulated
over
time,
the
basic
function
of
splicing
remained
unaltered.
A recently well elaborated example involving experi-
mental
testing
of
hypothesized
CNE
processes
is
the
vacu-
olar
V0-ATPase ring of yeast [49,51]. Although the ancestor
of the yeast V0-ATPase ring comprises two subunits, sev-
eral
yeasts
require
three
subunits,
with
the
third
subunit
resulting
from
an
ancient
gene
duplication
that
was
fol-lowed
by
gene
suppression.
To
verify
this
sequence
of
events, investigators reconstructed the common ancestral
gene
of
extant
two-subunit
rings
and
three-subunit
rings
and
revealed
specific
suppressive
interactions
required
to
enforce the adoption of the three-subunit system [51].
When
suppression
succeeds,
the
system,
because
of
this
dependency,
is
more
complex;
however,
the
net
effect
of
the
increased complexity remains neutral in that no altera-
tions
in
the
cells
ability
to
produce
the
phenotype
have
occurred. Therefore, CNE allows the accumulation of
greater complexity combined with a dilution of responsi-
bility for maintaining a phenotype among multiple factors.
Ironically,
this
dilution,
via
redundant
functionality
of
components,
would
reduce
the
risk
of
negative
selection
on a single mutational target and, as such, the CNE
mechanism
itself
may
be
under
positive
selective
pressure
[48].
Concluding remarks
The
above
overview
was
organized
into
processes
acting
at
the level of the organelle or at the level of the underlying
molecular
complex,
but
such
divisions
are
by no
means
absolute.
Molecular
machineries
clearly
cooperate
to
build
and define
organelles.
At
the
same
time,
the
compartmen-
talization of specific molecular machineries within a given
organelle
limits
the
range
of
proteins
with
which
these
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molecular
machines
will
frequently
interact
and
thereby
increases
the
opportunities
for
distinct
environments
that
would
lead
to
complexity
via
CNE
mechanisms.
At present, tremendous opportunities exist for the ad-
vancement
of
evolutionary
cell
biology
as
a
discipline.
While
the
field
brings
evolutionary
biology
from
the
popu-
lation and the large organism down to the scale of the cell,
it
also
brings
a
comparative
approach
over
species
andspace to cell biologists focused on specific organisms or
organelles.
However,
there
is
also
a
potential
for
miscon-
ceptions.
In
many
ways,
the
study
of
cell
biology
shares
conceptual commonalities with the discipline of reverse
engineering
[52]. Cell
biology
is
typically
understood
from
a reductionist approach whereby the cell is disassembled,
both
conceptually
and
physically,
into
its
components
(proteins,
organelles,
and
complexes)
and
then
laid
out,
manipulated, andunderstood.Therefore, it isunsurprising
that
questions
regarding
evolutionary
mechanisms
that
give
rise
to
cells
are
sometimes
misframed
as
a
forward-
engineering problem; that is, How did the cell find the
most
efficient
way
of
performing
process
x?
However,
there is a fundamental difference between evolution
andengineering.
Evolution
does
not
always
proceed
along
an
optimized path leading to the observed modern state.
Viewing
each
trait
as
the
result
of
an
iterative
and
mechanistic,
rather
than
teleological,
process
leading
to
these solutions changes the way investigations are under-
taken
and
data
are
interpreted.
Although
it
may
remain
useful
to
ask
What
is
the
selective
advantage
of
a
given
trait?, knowing that the evolutionary path is not always
direct
and
constant
allows
the
investigator
to
consider
multiple
advantages
and
possibly
entertain
alternative
explanations beyond selection. Therefore, it may be more
productive
to
answer
the
how
behind
evolutionary
cell
biological
questions
and
to
reconstruct
the
steps
and
evo-lutionary
details
for
the
emergence
of
a
given
trait,
thus
deriving process from the patterns observed across multi-
ple
examples.
Although
significant
progress
has
been
made
in devel-
oping model cell-biological systems across eukaryotes (e.g.,
Dictyostelium, Toxoplasma, Trypanosoma, Arabidopsis)
and analyzing
molecular
evolution
to
deduce
the
origins
ofprotein complexes and their resident organelles, yielding
some of
the
discoveries
described
above,
many
areas
re-
main unexplored. For example, the consequences of popu-
lation genetics have not been fully explored in the context
of cellular evolution [53]. Similarly, although there have
been
attempts
to
correlate
geology
with
cellular
evolution
[54], particularly
regarding
the
origin
of
life
[55], this
aspect is often overlooked by cell biologists. Furthermore,
the
mechanisms
of
emergence
of
evolutionary
innovations,
such
as
organelle
inheritance,
that
combine
multiple,
well
adapted cellular components remains to be better eluci-
dated
[56]. Finally,
as
our
understanding
of
systems
biolo-
gy
matures
and
omic
data
types
become
increasingly
available, we will be able to integrate information about
the
timing
and
context
of
genes
and
proteins
into
various
models
of
cellular
evolution
[57].
With tractable
progress
being
made
on
concrete
mecha-
nistic questions, this is truly an exciting time as the
biology
of
the
cell
can
now
be
parsed
in
the
light
of
evolution
[58].
Acknowledgments
Theauthorsthankthe members of theDackslaboratory, aswell
asW.Ford
Doolittle andHolly Goodson, for critical comments on
themanuscript and
for discussion. J.B.D.and L.D.B. also thank thestaff at theBanff
Centrefor
the Arts for their generosity and
hospitality during the flooding that
occurred in Alberta in June 2013, at which time significant work
on the
writing of this manuscript took place. F.D.M. is the recipient
of a Vanier
Canada Graduate Scholarship from the Canadian Institutes of
Health
Research (CIHR) and a Full-Time Studentship from Alberta
Innovates
Health Solutions. L.D.B. was supported by a National Science
andEngineering Council of Canada (NSERC) Undergraduate Student
Re-
search Award. J.B.D. is Canada Research Chair (Tier II) in
Evolutionary
CellBiology. Researchin theRachubinski laboratory is supported
bygrants
9208,15131, and 53326fromtheCIHR. Researchin theDacks laboratory
is
supported by a NSERC discovery grant and an Alberta
Innovates
Technology Futures New Investigator Award to J.B.D.
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