MBoC | ARTICLE
A statistical anomaly indicates symbiotic origins
of eukaryotic membranes
Suneyna Bansal and Aditya Mittal
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
ABSTRACT Compositional analyses of nucleic acids and proteins have shed light on possible
origins of living cells. In this work, rigorous compositional analyses of ∼5000 plasma membrane lipid constituents of 273 species in the three life domains (archaea, eubacteria, and
eukaryotes) revealed a remarkable statistical paradox, indicating symbiotic origins of eukaryotic cells involving eubacteria. For lipids common to plasma membranes of the three domains, the number of carbon atoms in eubacteria was found to be similar to that in eukaryotes. However, mutually exclusive subsets of same data show exactly the opposite—the
number of carbon atoms in lipids of eukaryotes was higher than in eubacteria. This statistical
paradox, called Simpson’s paradox, was absent for lipids in archaea and for lipids not common to plasma membranes of the three domains. This indicates the presence of interaction(s)
and/or association(s) in lipids forming plasma membranes of eubacteria and eukaryotes but
not for those in archaea. Further inspection of membrane lipid structures affecting physicochemical properties of plasma membranes provides the first evidence (to our knowledge) on
the symbiotic origins of eukaryotic cells based on the “third front” (i.e., lipids) in addition to
the growing compositional data from nucleic acids and proteins.
Monitoring Editor
David G. Drubin
University of California,
Berkeley
Received: Jun 11, 2014
Revised: Dec 22, 2014
Accepted: Jan 22, 2015
INTRODUCTION
Over the years, the evolutionary origins of eukaryotic cells have
been studied with respect to two key components in living systems—nucleic acids and proteins. While genes involved in replication, transcription, and translation indicate similarity between archaea and eukaryotes, metabolic genes indicate eukaryotes are
closer to eubacteria (Rivera et al., 1998). On the other hand, the
universal tree of single-stranded rRNA clusters eukaryotes near to
archaea (Woese, 2000). To date, there are a number (more than 20)
different models to explain the origin of eukaryotic cells (Martin and
Muller, 1998; Martin, 2005; Martin and Koonin 2006; Moreira and
Lopez-Garcia, 1998; Vesteg and Krajcovic, 2006; Forterre, 2011;
Baum and Baum, 2014). The majority of these models are based on
the merger of two prokaryotes to form ancient eukaryotic cells.
This article was published online ahead of print in MBoC in Press (http://www
.molbiolcell.org/cgi/doi/10.1091/mbc.E14-06-1078) on January 28, 2015.
Address correspondence to: Aditya Mittal ([email protected]).
Abbreviations used: G-1-P, glycerol-1-phosphate; G-3-P, glycerol-3-phosphate;
Ga, giga-annum.
© 2015 Bansal and Mittal. This article is distributed by The American Society for Cell
Biology under license from the author(s). Two months after publication it is available
to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
“ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of
the Cell®” are registered trademarks of The American Society for Cell Biology.
1238 | S. Bansal and A. Mittal
There are two basic schools of thought: 1) One-merger theory: the
merger of eubacteria and archaea led to the formation of the nucleus and mitochondria at the same time (around 2 giga-annum
[Ga]; Hartman and Fedorov, 2002). 2) Two-merger theory: the merger
of archaea and eubacteria first formed the nucleus of the eukaryotic
cell around 2.7 Ga; another alpha-Proteobacteria was later engulfed
to produce mitochondria around 2 Ga (Margulis et al., 2006). Literature on the one-merger theory indicates that early eukaryotes (e.g.,
Trichomonas foetus) are not amitochondriates and contain organelles, called hydrogenomas, that are analogous to mitochondria
(Lindmark and Muller, 1973). On the other hand, the two-merger
theory supports the presence of amitochondriates (Fuerst and
Webb, 1991). The majority of these studies are based on genomics
and proteomics data. Only a few scattered reports comment on the
evolution of eukaryotic membranes, and those are also based largely
on membrane proteins and biosynthetic pathways in cells (Pereto
et al., 2004; Daiyasu et al., 2005; Mulkidjanian et al., 2008; Lombard
and Moreira, 2011; Lombard et al., 2012a). Thus, in spite of the
importance of amphipathic lipid molecules in formation of compartments as whole cells and within cells, emphasis on the essential
“third” component (i.e., amphipathic lipid molecules) has been limited. Self-aggregation/assembly of amphipathic molecules was a
crucial step in the origin of life (Monnard and Deamer, 2002;
Rasmussen et al., 2009; Chen and Walde, 2010). Appearance of the
Molecular Biology of the Cell
first single cell(s), unit(s) of life, required a boundary enclosing a “system” separated from the surrounding environment. Formation of this
boundary, the plasma membrane of a cell, was driven by self-aggregation of amphipathic molecules that also subsequently led to intracellular compartment formation, resulting in a eukaryotic cell. In the
course of evolution, cell–cell interactions, including possible exchange of membrane lipids (Reed, 1968; Pagano and Huang, 1975),
might have allowed the emergence of a pool of shared membrane
lipids in their plasma membranes. Simultaneously, direct interaction
of these lipid boundaries with a dynamic outer environment could
also have contributed to compositional modifications in plasma
membranes (Goldfine, 2010; Koga, 2012; Oger and Cario, 2013).
While these theories are certainly of importance, they provide limited
insights into understanding the evolution of eukaryotic cells from the
point of view of their plasma membranes. In view of this, and inspired
by compositional approaches applied to genomics and proteomics,
we initiated a study of plasma membranes of the three domains of life
(archaea, eubacteria, and eukaryotes) to investigate the origin of life
from the point of view of the “third front” (the first two “fronts” being
nucleic acids and proteins, respectively). As a first step, we collected
amphipathic (nonprotein) components of plasma membranes from
273 species in the three domains of life—this yielded more than 5000
membrane lipids. A comprehensive analysis involving chemical composition–based classification of these lipids revealed a remarkable
statistical paradox. For lipids common to plasma membranes of the
three domains, the number of carbon atoms in eubacteria was found
to be similar to that in eukaryotes. However, mutually exclusive subsets of the same data individually show exactly the opposite, that is,
the number of carbon atoms in lipids of eukaryotes was higher than
in eubacteria. This statistical paradox, called the Simpson’s paradox
(Wagner, 1982), was absent for lipids in archaea and for lipids not
common to the plasma membranes of the three domains. This remarkable finding directly indicates (hidden) interaction(s) and/or
association(s) (Simpson, 1951) in lipids forming plasma membranes of
eubacteria and eukaryotes but not for those in archaea. Further exploration of lipid structures responsible for physicochemical properties of plasma membranes leads to the inference that the first compartmentalized cells, that is, eukaryotic single cells, had symbiotic
origins with emphasis on eubacterial components as a source of their
plasma membranes. In addition, membrane lipids of mitochondria
and chloroplasts of eukaryotes suggest that membranes of these key
organelles shared significant similarities with the eubacterial membrane lipids. Thus, through compositional analysis of lipidomics data
and on the basis of the “third front” (i.e., lipids), we provide the first
evidence (to our knowledge) of symbiotic origins of eukaryotic cells,
with a larger role of eubacteria in formation of both plasma membranes and mitochondrial membranes.
RESULTS AND DISCUSSION
Common and uncommon membrane lipids
A comparative analysis of membrane lipids from each domain indicated three common classes that include 10 different compositions
and a total of 3911 chemical structures of membrane lipids. We
called them “common membrane lipids” (Figure 1). The remaining
20 classes (82 different compositions), which include a total of 1471
chemical structures of membrane lipids, were considered “uncommon membrane lipids.” Apart from membrane lipids common to all
three domains, we found that eubacteria and eukaryotes alone
shared 11 more lipid compositions, and archaea and eubacteria
also uniquely shared three more membrane lipid compositions.
These findings are consistent with the observation that eubacteria
and eukaryotes share more similar physiological conditions than
Volume 26 April 1, 2015
archaea—more common lipid classes would be expected to be
found between eubacteria and eukaryotes as compared with archaea and eukaryotes. In our data set, we found the maximum number of common lipids between eubacteria and eukaryotes (=21)
was greater than those shared by eubacteria and archaea (=13) and
eukaryotes and archaea (=10); we also found 21 membrane lipid
types unique to archaea, 21 for eubacteria, and 26 for eukaryotes.
Variation in the total carbon content of membrane lipids
of each domain
Inspired by compositional analysis of nucleic acids and proteins
(Nussinov, 1984; Knight et al., 2001; Kanhere and Bansal, 2005;
Mittal et al., 2010; Mittal and Jayaram, 2011, 2012; Mittal and
Acharya, 2013), we carried out a compositional analysis of chemical
structures of these membrane lipids. For simplicity, we counted the
total number of carbon atoms in each membrane lipid and the
number of carbon atoms in the hydrophobic tails of each membrane lipid. Ten concentric circles, each circle representing an evolutionary time point in Ga units, were drawn to represent the total
number of carbon atoms (Figure 2, A–C) and tail carbon atoms
(Figure 3, A–C) in membrane lipids of each domain across evolutionary time; we show these separately for total (Figures 2A and
3A), common (Figures 2B and 3B), and uncommon membrane lipids (Figures 2C and 3C). To compare the average size and hydrophobic tail lengths of membrane lipids, we calculated the mean
value of carbon atoms for each domain separately for each group
of total, common, and uncommon lipids. Then we further divided
the total number of carbon atoms in each group into two mutually
exclusive subsets; smaller-sized membrane lipids with a number of
carbon atoms less than and equal to 60 and larger membrane lipids
with more than 60 carbon atoms in their structures. Similarly, for tail
carbon atoms in lipids, two subsets were formed in such a way that
one includes those with structures with a number of tail carbon atoms less than and equal to 50, and the other includes those with tail
carbons numbering more than 50. Mean values of carbon atoms
were also computed for these two mutually exclusive subsets
(Figures 2, D–F, and 3, D–F). Three independent t tests (two-sample, assuming equal or unequal variances depending on the F test
for homo- or heteroscedasticity of the data sets) with alpha = 0.05
were applied on each of the above data sets. For lipids common to
plasma membranes of the three domains, the number of carbon
atoms in eubacteria was found to be similar to that in eukaryotes
(extreme left black and gray bars in Figures 2E and 3E) for both total
carbon atoms and carbon atoms in only the fatty acid tails. However, mutually exclusive subsets of the same data showed exactly
the opposite trend, that is, the number of carbon atoms in lipids of
eukaryotes was higher than in eubacteria (middle and extreme right
black and gray bars in Figures 2E and 3E).
Simpson’s paradox supports the symbiotic origin of
eukaryotes involving eubacteria
The remarkable and complete reversal of association between the
average tail lengths of eubacterial and eukaryotic common membrane lipids with their mutually exclusive subsets, shown in Figures
2E and 3E, presented a fascinating statistical anomaly to us. After a
substantial literature review, we found that this statistical anomaly,
called “Simpson’s paradox” (Wagner, 1982), has been reported as a
rare phenomenon in biological data, especially clinical data (Tu
et al., 2005; Rucker and Schumacher, 2008). To our knowledge, our
findings in this work are the first example of Simpson’s paradox in
biological data at a molecular level through the compositional analysis of chemical structures. Simpson (Simpson, 1951) established
On the symbiotic origins of eukaryotes | 1239 FIGURE 1: Lipid “class diagram” for all three domains. (A) Representation of a generic chemical structure for a
membrane lipid composed of two regions: a hydrophilic part made up of polar atoms and a hydrophobic part
composed of nonpolar atoms or carbon tails. Membrane lipids usually consist of head rings that are generally made up
of sugar moieties, and hydrocarbon tail regions with multiple bonds, branched methyl groups, and cyclopropane rings.
However, it is important to note here that archaeal lipids contain ether linkages instead of ester bonds, and their
tetraethers usually contain cyclopentane rings instead of cyclopropane rings in their tail region. (B) Different membrane
lipids of all three domains were collected and represented using a Venn diagram. The intersection of two circles
represents the number of common lipids in two respective domains, and the common intersection area of all three
circles represents the common lipids shared by all three domains of life. Red numbers represent organellar membrane
lipids. Red text represents lipids common to eukaryotic plasma membranes and organellar membranes. Blue text
represents lipids found in the membranes of mitochondria but absent in the plasma membranes of eukaryotes.
Abbreviations used in this figure: A-GPL, amino glycophospholipid; APG, acyl phosphatidylglycerol; APGp,
1240 | S. Bansal and A. Mittal
Molecular Biology of the Cell
that this statistical anomaly, called a paradox due to reversal in association of total data when divided into mutually exclusive data
sets, is caused by hidden interactions within the studied variables.
However, the exact nature of the hidden interactions is not extractable from this analysis—it simply shows in a clinical setting that the
variables are related either through interactions, such as possible
exchanges and/or common lineages/origins arising directly out of a
common ancestral population (Lindley and Novick, 1981).
Remarkably, Simpson’s paradox was observed only in the data of
lipids common to eubacteria and eukaryotes and was absent from
the data of uncommon lipids between these two domains—the only
exception was seen in the total carbon content of their uncommon
lipids (Figure 2F). However, this paradox was completely absent
from the data of the total carbon content of eubacterial and eukaryotic uncommon lipids after removal of 11 more uniquely shared
common lipid types between eubacteria and eukaryotes (inset in
Figure 2F). Interestingly, the data from lipids of archaea was independent of this paradox. This significant finding clearly indicates
(hidden) interaction(s) and/or association(s) among only the common membrane lipids in plasma membranes of eubacteria and eukaryotes but not those in archaea (regardless of whether they are
common or uncommon). In further support of our findings, t tests
showed p values > 0.05 for the total carbon and tail carbon content
of membrane lipids of eubacteria and eukaryotes only, which also
indicates the shared similarities between the plasma membranes of
these two domains (Figures 2, D–F, and 3, D–F).
In addition to the above, it is important to consider that the relative abundance of each lipid varies in the plasma membranes of
different cells. To account for this, we collected available mole fractions of more than 2000 membrane lipids of archaea, eubacteria,
and eukaryotes and reanalyzed the data by computing for the
weighted means (i.e., normalized by their relative abundance) of
total carbon atoms and total tail carbon atoms in their membrane
lipids. Remarkably, we found a similar paradoxical trend in weighted
mean values, as observed in the data sets discussed above, using
equal weights for each membrane lipid (see Supplemental Figure
S1). Here Simpson’s paradox was also observed only in the com-
mon lipid types of eubacteria and eukaryotes and was absent in the
data of uncommon lipids between these two domains and in archaea. Student’s t tests on the weighted means of the total carbon
atoms and total tail carbon atoms also showed p values > 0.05 for
the membrane lipids of eubacteria and eukaryotes only (see Supplemental Figure S1). Thus our data clearly indicate that the first eukaryotic single cells had symbiotic origins, with emphasis on eubacterial lipid components as a source of their plasma membranes. To
further explore the nature of the symbiotic origins, we extended our
analyses to more structural and compositional parameters of the
membrane lipids.
Structural variations responsible for physicochemical
properties of plasma membranes reveal a possible
exchange of common membrane lipids among domains
We counted the total number of multiple bonds, branched methyl
groups, and rings in the tail region of each membrane lipid. Ten
concentric circles, each circle representing an evolutionary time
point in Ga units, were drawn to represent unsaturation, branched
methyl groups, and cyclic rings in the tail regions of membrane lipids of each domain across evolutionary time; we show these separately for total (Figure 4A), common (Figure 4B), and uncommon
(Figure 4C) membrane lipids. Further, the mean values of multiple
bonds, branching, and tail rings were calculated separately for each
domain for each group of total, common, and uncommon lipids
(Figure 4, D–F). From archaea to eukaryotes, we observed the increasing mean value of multiple bonds for both common and uncommon lipids, which indicates enhanced lipid mobility, membrane
disorder, and fluidity from archaea to eukaryotes (Figure 4D). It is
also important to observe here that only common membrane lipids
of archaea showed the presence of unsaturation, which is completely absent in their uncommon lipids. It is also interesting that the
appearance of oxygen (∼2 Ga) might have aided the introduction of
unsaturation in the tails of membrane lipids as the presence of multiple bonds was seen in all domains only after ∼2 Ga (see Figure 4,
A–C). As a lipid’s tail branching provides structural stability at high
temperatures, resistance to oxidation, reduction of permeability to
amino phosphatidyl glycerol plasmalogens; APT, aminopentanetetrol; BMP, bis monoacyl glycerol phosphate; BOL,
brassicasterol; CAG, cholesteryl acyl glucoside; CBS, cerebroside; CE, cholesteryl ester; CER, ceramides; CGL,
cholesteryl glucoside; CHOL, cholesterol; CHPG, cholesteryl phosphatidyl glucoside; CL, cardiolipin; CLp, cardiolipin
plasmalogen; CPC, ceramide phosphorylcholine; CPE, ceramide phosphorylethalonamine; CPG, phosphatidylglycerol
ceramides; CS, cholesterol sulfate; CST, campesterol; DAG, diacylglycerol; DAT, 2,3-di-O-acyltrehalose; DGDG,
digalactosyl diacylglycerol; DGS, diglycosyl sulfate; DGT, digalatofuranosyl caldearcheol; DGTS, diacylglyceryl
trimethylhomoserine; DHCHOL, dehydrocholesterol; DO, diols; EST, ergosterol; FST, fucosterol; GBA, gentiobiosyl
archeol; GCL, glycocardiolipin; GCS, galactosyl ceramide sulfate; GDGT, glycerol dialkyl glycerol tetraether; GDNT,
glycerol dialkyl nonitol tetraether; GPE, glyco-phosphatidyl ethalonamine; GPI, glyco-phosphatidyl inositol; GPL,
glycophospholipid; GPS, glyco-phosphatidyl serine; HGDGT, H-shaped glycerol dialkyl glycerol tetraether; IPC, inositol
phosphoryl ceramide; LCL, lysyl cardiolipin; LPA, lyso-phosphatidic acid; LPC lyso-phosphatidyl choline; LPE, lysophosphatidyl ethanolamine; LPG, lyso-phosphatidyl glycerol; LPI, lyso-phosphatidyl inositol; LPS, lyso-phosphatidyl
serine; LST, lanosterol; MAG, monoglycerides; MDE, macrocyclic diether; MGDG, monogalactosyl diacylglycerol; MIPC,
mannosyl phosphatidyl inositol ceramide; MPM, mannosyl-β-1–phosphomycoketides; NAG, N-acetyl glucasamine;
NAPE, N-acylphosphatidyl ethanolamine; NAPS, N-acylphosphatidyl serine; NL, neutral fatty acids; PA, phosphatidic
acid; PAT, polyacyltrehalose; PC, phosphatidylcholine; PDIM, phthiocerol dimycocerosates; PDME, phosphatidyl
dimethyl ethanolamine; PE, phosphatidyl ethanolamine; PEp, phosphadityl ethalonamine plasmalogens; PG,
phosphatidyl glycerol; PGDGT, polar glycerol dialkyl glycerol tetraether; PGL, glucopyranosyl galactofuranosyl; PGMP,
phosphatidyl glycerol methyl phosphate; PGp, phosphadityl glycerol plasmalogens; PGS, phosphatidyl glycerol sulfate;
PI, phosphatidyl inositol; PIM, mannosides acyls phosphatidyl inositol; PME, phosphatidyl-N-methylethanolamine; PS,
phosphatidyl serine; RGDG, rhamnosyl galactosyl diacylglycerol; S-DGD-5PA, sulfated diglycosyl diether phosphatidic
acid; S-GL, sulfated glycolipids; S-GPL, sulfated glycophospholipids; SM, sphingomyelin; SN, sphinganine; SQ, squalene;
SQDG, sulfoquinovosyl diglycerol; SST, stigmasterol; ST, sterol; S-TeGD, sulfated tetraglycosyl diether; S-TGD, sulfated
triglycosyl diether; S-TGD-1-PA, sulfated triglycosyl diether phosphatidic acid; STOL, β-sitosterol; TAG, triglycerides;
TGDG, trigalactosyl diacylglycerol; THM, tetrahymenol.
Volume 26 April 1, 2015
On the symbiotic origins of eukaryotes | 1241 FIGURE 2: Variation in the total carbon content of membrane lipids of each domain. Total number of carbons in (A) all
membrane lipid types (5382 lipid structures), (B) 10 common membrane lipid types (3911 lipid structures), and (C) 82
uncommon membrane lipid types (1471 lipid structures) were plotted against the time of evolution of their respective
species. Ten concentric circles represent the evolutionary timescale; the innermost circle represents 4.5 Ga, and the
outermost circle represents the most recent time (0 Ga). (D–F) Mean ± SE for the total number of carbons, carbons less
than and equal to 60 and carbons greater than 60 in all membrane lipids for all membrane lipids, common membrane
lipids, and uncommon membrane lipids, respectively, of archaea, eubacteria, and eukaryotes. Inset in F shows
uncommon lipids after excluding 11 more common lipid compositions between eubacteria and eukaryotes. For D–F,
three independent t tests (alpha = 0.05) were applied to three data sets for archaea, eubacteria, and eukaryotes; only
p values > 0.05 are labeled on the respective bars. Empty circles and bars represent archaeal lipids, gray circles and bars
represent eubacteria, and black circles and bars represent eukaryotes. Black arrows on the bars represent the presence
of Simpson’s paradox in the respective bars.
1242 | S. Bansal and A. Mittal
Molecular Biology of the Cell
FIGURE 3: Variation in the total carbon content of tails of membrane lipids of each domain. Total number of tail carbons
in (A) all membrane lipid types (5382 lipid structures), (B) 10 common membrane lipid types (3911 lipid structures), and
(C) 82 uncommon membrane lipid types (1471 lipid structures) were plotted against the time of evolution of their
respective species. Concentric circles represent evolutionary time, with the innermost circle representing 4.5 Ga and the
outermost circle represents the most recent time (0 Ga). (D–F) Mean ± SE for the total number of tail carbons, tail
carbons less than and equal to 50, and tail carbons greater than 50 in all membrane lipids for all membrane lipids,
common membrane lipids, and uncommon membrane lipids, respectively, of archaea, eubacteria, and eukaryotes. Inset
in F shows uncommon lipids after excluding 11 more common lipid compositions between eubacteria and eukaryotes.
For D–F, three independent t tests (alpha = 0.05) were applied for three data sets of archaea, eubacteria, and
eukaryotes; only p values > 0.05 are labeled on the respective bars. Empty circles and bars represent archaeal lipids,
gray circles and bars represent eubacteria, and black circles and bars represent eukaryotes. Black arrows on the bars
represent the presence of Simpson’s paradox in the respective bars.
Volume 26 April 1, 2015
On the symbiotic origins of eukaryotes | 1243 FIGURE 4: Structural variation in membrane lipids of each domain. Total number of multiple bonds, branched methyl
groups, and rings in the tail region of (A) all membrane lipid types (5382 lipid structures), (B) 10 common membrane
lipid types (3911 lipid structures), and (C) 82 uncommon membrane lipid types (1471 lipid structures) were plotted
against the time of evolution of their respective species. Concentric circles represent evolutionary time, with the
innermost circle representing 4.5 Ga and the outermost circle representing the most recent time (0 Ga). (D–F) Mean ±
SE for the total number of multiple bonds, branched methyl groups, and rings, respectively, in the tail regions of all
membrane lipids, all common membrane lipids, and all uncommon membrane lipids of archaea, eubacteria, and
eukaryotes. For D–F, three independent t tests (alpha = 0.05) were applied for three data sets of archaea, eubacteria,
and eukaryotes; only p values > 0.05 are labeled on the respective bars. Empty circles represent multiple bonds, dots
represent branching, and a plus sign (+) was used for tail branching in archaeal, eubacterial, and eukaryotic lipids. Blue
symbols and bars represent archaeal lipids, red symbols and bars represent eubacterial lipids, and black symbols and
bars represent eukaryotes.
1244 | S. Bansal and A. Mittal
Molecular Biology of the Cell
nonelectrolytes (Balleza et al., 2014), and promotion of tubulation/
curvature formation in ether lipids (Kozlov et al., 2014), we found tail
branching in abundance in archaea but decreased in eubacteria and
completely vanished from the common membrane lipid types of
eukaryotes (Figure 4, A–C and E). In contrast with the above, tail
rings completely disappeared not only from common membrane
lipid types of eukaryotes but also from archaeal common lipids
(Figure 4, A–C and F). Tail rings were found only in the archaeal uncommon lipids and were completely replaced by a new class of
lipids having fused ring-like structures (known as sterols) in eubacteria and eukaryotes. All these structural changes in membrane lipids
clearly show increased disorder and mobility of lipids, which in turn
enhances the fluidity of the plasma membrane of these domains in
favor of changing environmental conditions.
The key observations and inferences from the above are as
follows: 1) the presence of multiple bonds only in archaeal common
membrane lipids, which was completely absent in their uncommon
lipids; 2) a lower amount of branching in common membrane lipids
than the uncommon membrane lipids of archaea; 3) complete disappearance of tail rings only in common membrane lipid types of
archaea and eukaryotes; 4) complete disappearance of branching
only in common membrane lipids of eukaryotes; and 5) these favorable changes, based on comparative analysis of common and uncommon lipids, were more pronounced in the chemical structures of
common lipids as compared with uncommon lipids of all three domains (Figure 4, D–F). These observations clearly indicate that only
common membrane lipids of archaea were altered in their hydrophobic tail regions in response to the changing environment and
thus were preferably selected and exchanged and survived as integral structural features of plasma membranes over time in all domains. Thus structural adaptability of common membrane lipids allowed their successful exchange and/or incorporation into different
domains. On the other hand, each domain also evolved with a few
more membrane lipid types specific to their own niche (uncommon
membrane lipids). Alternatively, transfer of genetic components of
common membrane lipids’ biosynthetic machineries might have
allowed their codevelopment into plasma membrane assemblies.
Literature studies revealed that the homologues of key enzymes for
fatty acid synthesis and degradation were found to be universally
present in all three domains (Lombard et al., 2012a). Apart from this,
enzymes that synthesize phospholipids (which is one out of the three
common membrane lipid classes) and facilitate attachment of glycerol phosphate to their tail and polar head regions were also found
to be commonly conserved in all three domains (Lombard et al.,
2012b). Common membrane lipids of the three domains of life
strongly indicated the possible exchanges of the membrane lipids
or transfer of genetic components of common lipids biosynthetic
machineries among domains and/or their common origins from
an ancestral population that gave rise to the statistical paradox
(Simpson’s paradox) that is observed for these lipids only. To our
knowledge, this is the first evidence, based on the “third front”
(i.e., lipids) and achieved through compositional analysis of lipidomics data, on the symbiotic origins of eukaryotic cells and demonstrating a larger role for eubacteria in formation of plasma
membranes.
Proposed model to explain the origin of eukaryotes based
on the membrane lipidomics of three domains
Remarkably, we were able to capture significant statistical signatures
(from Simpson’s paradox and t test analysis) from the plasma membranes of the three domains of life, despite their being highly dynamic and exposed to diverse environmental conditions. The data
Volume 26 April 1, 2015
clearly support the idea that the eukaryotes inherit the majority of
their plasma membrane lipids from eubacteria. Further, to investigate the origin of mitochondria/chloroplasts (i.e., energy-producing
organelles) in eukaryotes, we collected available ∼400 lipids from
the membranes of mitochondria and chloroplasts of 13 eukaryotes.
We observed that membranes of these organelles consist of 24 different chemical compositions that include 10 compositions common to all three domains, eight compositions uniquely common to
eubacterial plasma membranes, and six unique to the mitochondria
(but also present in the plasma membranes of eukaryotes; see
Figure 1). Here it is important to note that these eight commonly
shared lipid compositions between mitochondrial membranes and
plasma membranes of eubacteria were found to be different from
11 uniquely shared lipids between plasma membranes of eubacteria and eukaryotes. However, 10 membrane lipid types common to
all three domains were found to be exactly similar to the common
lipids of their plasma membranes. Further, quantitative comparisons
revealed that the mean value of the total number of carbon atoms
and tail carbon atoms was found to be higher in the membrane lipids of eukaryotic organellar membranes than in their plasma membranes (Figures 2, 3, and 5). Student’s t tests show that the variation
found in the total carbon and tail carbon content of membrane lipids of mitochondria/chloroplasts of eukaryotes and plasma membranes of eubacteria is not statistically significant and thus they
might have derived these membranes from the same ancestral population (see Figure 5, A–F). Clearly, since the extrinsic environment
for organellar membranes is different from the plasma membranes
of eukaryotes and eubacteria, similarities found in the membrane
lipids of mitochondria/chloroplasts of eukaryotes and plasma membranes of eubacteria are not as prominent or evident compared with
their plasma membranes.
In view of above observations, we propose a hypothetical model
to illustrate the evolution of mitochondriate eukaryotes based on
membrane lipidomics (Figure 6). It is important to note that the
composition of the plasma membrane of the cenancestor remains a
topic of debate in evolutionary studies. There are recent reports
supporting the idea that the plasma membrane of the cenancestor
was composed of two stereotypes; glycerol-1-phosphate (G-1-P)
and glycerol-3-phosphate (G-3-P), that is, ether- and ester-bond
membrane lipids (Lombard et al., 2012b). Lombard et al. (2012b)
proposed that the diversification of these two stereotypic lipids
might have led to the emergence of two different lineages, that is,
archaea and eubacteria. On the other hand, our results indicate that
the diversification of these two stereotypic lipids (included in common membrane lipid types) from the cenancestral plasma membrane led to the emergence of prearchaeal and prebacterial cell
lineages. Then these common membrane lipids of prearchaeal cells
might have adapted several structural changes and acquired unique
membrane lipid types to survive in their niche environments, thus
evolving into archaeal cells. Similarly, pre-eubacterial cells might
have acquired several changes in the structure of their common lipids and synthesized new lipids to adapt to the changing environment. During this process of evolution of pre-eubacterial cells to
eubacteria, some pre-eubacterial cells might have engulfed eubacteria, giving rise to primitive mitochondriate eukaryotes. Hence,
while these endosymbiont eubacteria gave rise to the formation of
mitochondria, host pre-eubacterial cells shared the nucleic acids
and protein pools present in their cytoplasm with the eukaryotes.
As these pre-eubacterial cells evolved from the cenancestral cells,
eukaryotes shared significant similarities in their information system
(i.e., components of replication, transcription, and translation) with
archaea (Gribaldo et al., 2010). Later these primitive eukaryotes
On the symbiotic origins of eukaryotes | 1245 FIGURE 5: Variation in the hydrophobic content of membrane lipids of organellar membranes of eukaryotes and plasma
membranes of archaea and eubacteria. (A–C) Mean ± SE for the total number of carbons, carbons less than and equal to
60, and carbons greater than 60 for all membrane lipids (2343 lipid structures), common membrane lipids (1775 lipid
structures) and uncommon membrane lipids (568 lipid structures), respectively, of archaea, eubacteria, and eukaryotes.
(D–F) Mean ± SE for the total number of tail carbons, tail carbons less than and equal to 50, and tail carbons greater
than 50 in all membrane lipids for all membrane lipids, common membrane lipids, and uncommon membrane lipids,
respectively, of archaea, eubacteria, and eukaryotes. Insets in B and E show common lipids after including eight more
common lipid compositions shared by eubacteria and eukaryotes. Insets in C and F show uncommon lipids after
excluding eight more common lipid compositions shared by eubacteria and eukaryotes. For A–F, three independent
t tests (alpha = 0.05) were applied for three data sets of archaea, eubacteria, and eukaryotes; only p values > 0.05 are
labeled on the respective bars. Empty bars represent archaeal lipids, gray bars represent eubacteria, and black bars
represent eukaryotes.
might have undergone several structural changes in their shared
membrane lipids and also might have synthesized numerous unique
membrane lipid types. Further, generation of an endomembrane
1246 | S. Bansal and A. Mittal
system from a host plasma membrane might have led to the formation of membrane-bound compartments and a nucleus around the
host genetic material.
Molecular Biology of the Cell
also, for the first time, carried out a comprehensive chemical composition–based analysis on the “third front” (i.e., lipids) of plasma
membranes of 273 species collected from
the three domains of life. Qualitative comparative analysis of classified lipids resulted
in three classes of lipids common to all three
domains. Further, extensive quantitative
analysis of the chemical structures of these
common lipids revealed the remarkable
Simpson’s paradox. Common membrane
lipids of eubacteria and eukaryotes showed
reverse average trends in their carbon content as compared with their two mutually
exclusive subsets. Interestingly, this paradoxical condition was not observed in the case
of archaea and for uncommon membrane
lipids. This revealed the significant presence
of (hidden) interaction(s) and/or association(s)
in membrane lipids of eubacteria and eukaryotes. This indicates the symbiotic origin
of eukaryotic cells, which utilized eubacterial
lipids as a major source of their plasma
membranes. We provide further compositional evidence that the common membrane
lipids having chemical structures contributing
to key membrane functionalities (e.g., permeability, lipid mobility, membrane fluidity)
were selected in response to changing environments (passed to the next generation or
exchanged) in the three domains individually.
Hence the possible exchange of common
membrane lipids or the transfer of genetic
components of their biosynthetic machineries and/or their emergence from a common
ancestral population were found to be the
source of this hidden interaction(s) and gave
rise to the statistical anomaly discussed earlier. We also observed significant similarities
FIGURE 6: Proposed model for the origin of eukaryotes based on the membrane lipidomics of
between the mitochondrial membrane lipids
three domains. The plasma membrane of the cenancestor has been proposed to be made up of
of eukaryotes and plasma membrane lipids
two stereotypes of G-1-P and G-3-P, ether- and ester-bond membrane lipids (Lombard et al.,
of eubacteria. Thus, through compositional
2012b). Divergence of prearchaeal and pre-eubacterial lineages is thought to have emerged
after encapsulation of one of these two specific stereotypic lipids (including common membrane analysis of “third front” (i.e., lipids) data, we
provide the first evidence on the symbiotic
lipid types with different stereochemistry) in their respective membranes. Later the plasma
origins of eukaryotic cells majorly involving
membrane of prearchaeal cells might have incorporated several structural changes in their
eubacterial lipids in the formation of their
common membrane types and acquired unique membrane lipids favorable to their
environmental conditions and specific to their archaeal lineage. Pre-eubacterial cell membranes
plasma membranes and mitochondrial memmay also have evolved to form eubacterial membrane-like lipids. During this process, some
branes. Further, as the assembly of lipid ampre-eubacterial cells might have endocytosed eubacterial cells to give rise to the primitive
phipaths resulting in membrane structures is
mitochondriate eukaryotes.
largely govern by their molecular shapes
(Tanford, 1973; Baumgart et al., 2003; Bansal
and Mittal 2013), future work on shape/structural classification of lipConclusions
ids in light of the compositional analysis here may shed more light on
Comparative compositional studies of two key components of cendevelopment of cell structures.
tral dogma (i.e., nucleic acids and proteins) have provided major insights into the origins of eukaryotes. However, to date, few reports
MATERIALS AND METHODS
have been available on the evolution of eukaryotic membranes
Membrane lipid compositions of a total of 273 species (74 archaea,
based on the study of components of plasma membranes. Biological
144 eubacteria, and 55 eukaryotes) were collected from the literamembranes are essential primary building blocks for the formation of
ture along with the species’ estimated time of evolution (Hedges
stable and dynamic living systems. Polymerization of lipid amphipaths
et al., 2006; see Supplemental Table S1). A total of 5714 membrane
not only possibly provided the very first compartment for the origin
lipids were collected from all of these species. Of these membrane
of life on earth but also changed with the evolution of various species
lipids, complete chemical structures of 5382 membrane lipids were
in response to their changing environmental conditions. Thus we
Volume 26 April 1, 2015
On the symbiotic origins of eukaryotes | 1247 available and were therefore recorded. Of these 5382 membrane
lipids, molar fractions of 2343 lipids were available and were therefore collected from the literature. On the basis of their chemical
composition, these membrane lipids were first classified into 23
different classes with a total of 92 different chemical compositions
(see Supplemental Figure S2). Classification of lipids was done by
analyzing the chemical composition of each membrane lipid for
1) the type and 2) the number of sugars, sulfates, and/or amines of
the core, tail, and other additional molecules present in the head
and/or tail region of these lipids (we ignored the difference of
ether and ester linkages in archaea and other domains). Archaea
consisted of a total of 11 different classes with 34 different membrane lipid compositions, eubacteria contained a total of 14 classes
with 45 compositions, and eukaryotes consisted of a total of
16 classes with 47 membrane lipid compositions. We also collected 408 chemical structures of membrane lipids of mitochondria and chloroplasts from 13 eukaryotes (out of the 55 eukaryotes). Organellar membranes consist of eight classes with 24
membrane lipid compositions.
ACKNOWLEDGMENTS
S.B. is grateful to the Council of Scientific and Industrial Research,
Government of India, for research fellowship support.
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Molecular Biology of the Cell
Supplemental Materials
Molecular Biology of the Cell
Bansal et al.
1 Supplementary Information
A statistical anomaly indicates symbiotic origins of eukaryotic membranes
Suneyna Bansal and Aditya Mittal
Running Head: Membrane based evidence on symbiotic origins of eukaryotes
2 Figure S1. Variation in the hydrophobic content of membrane lipids of each domain.
Panels A, B and C represent weighted mean ± standard error (SE) for the total number of
carbons, carbons less than and equal to 60 and carbons more than 60 for all membrane lipids
(2343 lipid structures), for common membrane lipids (1775 lipid structures) and for
uncommon membrane lipids (568 lipid structures), respectively, of archaea, eubacteria and
eukaryotes. Similarly, Panels D, E and F represent weighted mean ± standard error (SE) for
the total number of tail carbons, tail carbons less than and equal to 50 and tail carbons more
than 50 in all membrane lipids for all membrane lipids, for common membrane lipids and for
uncommon membrane lipids, respectively, of archaea, eubacteria and eukaryotes. Insets
inserted in panels C and F show uncommon lipids after excluding 11 more common lipid
compositions between eubacteria and eukaryotes. For each of the panels D, E and F, three
independent t-Tests (alpha=0.05) were applied for three datasets of archaea, eubacteria and
eukaryotes, and only p-value > 0.05 was labelled on the respective bars. Empty bars were
used for archaeal lipids, grey for eubacteria and black filled bars represent eukaryotes. Black
arrows on the bars represent the presence of Simpson’s paradox in the respective bars.
3 Figure S2. Classification of membrane lipids on the basis of their chemical composition.
On the basis of their chemical composition, we grouped 5382 collected membrane lipid
structures into 23 different classes and found 92 different compositions of membrane lipids.
Number given in each square bracket represents the number of different compositions of
membrane lipids found in the each class.
4 Supplementary Table S1: Species analysed in the study
S. No. 1 2 Species Name Aciduliprofundum boonei (T469) Aeropyrum pernix (K1) Domain Archaea Archaea 3 4 5 Archaeoglobus fulgidus Archaeoglobus profundus Caldisphaera lagunensis ( IC‐154T) Archaea Archaea Archaea References Schouten et al. (2008) Extremophiles Nishida et al. (1999) FEMS Microbiol Lett ; Koga and Morii (2005) Biosci Biotechnol Biochem Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol 6 Caldivirga maquilingensis (IC‐167T ) Archaea Schouten et al. (2007) Appl Environ Microbiol 7 8 9 10 Candidatus Nitrosopumilus maritimus Desulfurococcus mobilis Ferroglobus placidus Ferroplasma acidarmanus (Fer1T) Archaea Archaea Archaea Archaea Schouten et al. (2008) Appl Environ Microbiol Blumenberg et al. (2004) Proc Natl Acad Sci USA Hafenbradl et al. (1996) Arch Microbiol Macalady et al. (2004) Extremophiles 11 12 13 14 15 16 17 Ferroplasma acidiphilum (Y‐2) Halobacterium halobium Halobacterium minutum Halobacterium noricense Halobacterium salinarum Halococcus morrhuae (14039) Haloferax volcanii Archaea Archaea Archaea Archaea Archaea Archaea Archaea 18 19 20 21 22 23 24 25 26 27 28 Halorubrum lacusprofundi Hyperthermus butylicus Ignicoccus islandicus (Kol8T) Ignisphaera aggregans Metallosphaera hakonensis Metallosphaera sedula Methanobacter thermautotrophicus Methanobrevibacter ruminantium Methanobrevibacter smithii Methanococcoides burtonii Methanococcus jannaschi Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea 29 Methanolobus bombayensis (B‐lT ) Archaea Golyshina and Timmis (2005) Environ Microbiol Tenchov et al. (2006) J Biol Chem Tenchov et al. (2006) J Biol Chem Gruber et al. (2004) Extremophiles Lobasso et al. (2009) Chem Phys Lipids Tenchov et al. (2006) J Biol Chem Sprott et al. (2003) Biochim Biophys Acta; Tenchov et al. (2006) J Biol Chem; Lobasso et al. (2009) Chem Phys Lipids Gibson et al. (2005) Syst Appl Microbiol Ulrih et al. (2009) Appl Microbiol Biotechnol Schouten et al. (2007) Appl Environ Microbiol Knappy et al. (2011) Extremophiles Takayanagi et al. (1996) Int J Syst Bacteriol Huber et al. (1989) Syst Appl Microbiol Knappy et al. (2009) J Am Soc Mass Spectrom Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Nichols et al. (2004) J bacteriol Comita et al. (1984) J Biol Chem; Sprott et al. (1991) J Bacteriol Schouten et al. (2007) Appl Environ Microbiol 30 31 Methanopyrus kandleri Methanosarcina barkeri (MST ) Archaea Archaea Koga and Mori (2005) Biosci Biotechnol Biochem Koga and Mori (2005) Biosci Biotechnol Biochem 32 33 34 35 36 37 Methanosarcina mazei (LYC) Methanosphaera stadtmanae Methanospirillum hungatei (JF1) Methanothermus fervidus Methanotorris igneus Nanoarchaeum equitans Archaea Archaea Archaea Archaea Archaea Archaea Tenchov et al. (2006) J Biol Chem Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Knappy et al. (2011) Extremophiles Schouten et al. (2007) Appl Environ Microbiol Jahn et al. (2004) Arch Microbiol 5 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Natronobacterium magadii Palaecoccus ferrophilus Picrophilus oshimae Picrophilus torridus Pyrobaculum aerophilum (IM2) Pyrobaculum islandicum Pyrococcus abyssi Pyrococcus furiosus (Vc1) Pyrococcus horikoshii Pyrococcus woesei Pyrolobus fumarii Stygiolobus azoricus Sulfolobus acidocaldarius (DSM639T) Sulfolobus shibatae (DSM538YTa) Sulfolobus solfataricus (1616T) Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea Archaea 53 Thermococcus Aegaeus Archaea Tenchov et al. (2006) J Biol Chem Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Ulrih et al. (2009) Appl Microbiol Biotechnol Schouten et al. (2007) Appl Environ Microbiol Knappy et al. (2011) Extremophiles Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Segerer et al. (1991) Int J Syst Bacteriol Schouten et al. (2007) Appl Environ Microbiol Schouten et al. (2007) Appl Environ Microbiol Cavagnetto et al. (1992) Biochem Biophys Acta; Cassinadri et al. (1996) Biophys J Sugai et al. (2004) J Oleo Sci T
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