全 文 ：Journal of Systematics and Evolution 46 (3): 405–423 (2008) doi: 10.3724/SP.J.1002.2008.08031
(formerly Acta Phytotaxonomica Sinica) http://www.plantsystematics.com
Long-term maintenance of stable copy number in the eukaryotic SMC
family: origin of a vertebrate meiotic SMC1 and fate of
recent segmental duplicates
1,4Alexandra SURCEL 1,2Xiaofan ZHOU* 2,3Li QUAN* 1,2Hong MA**
1(The Intercollege Graduate Program in Cell and Developmental Biology, The Huck Institutes of the Life Sciences, The Pennsylvania State University,
University Park, PA 16802, USA)
2(Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA)
3(The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA)
4(Present address: Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA)
Abstract Members of the Structural Maintenance of Chromosome (SMC) family have long been of interest to
molecular and evolutionary biologists for their role in chromosome structural dynamics, particularly sister chro-
matid cohesion, condensation, and DNA repair. SMC and related proteins are found in all major groups of living
organisms and share a common structure of conserved N and C globular domains separated from the conserved
hinge domain by long coiled-coil regions. In eukaryotes there are six paralogous proteins that form three het-
erodimeric pairs, whereas in prokaryotes there is only one SMC protein that homodimerizes. From recently com-
pleted genome sequences, we have identified SMC genes from 34 eukaryotes that have not been described in
previous reports. Our phylogenetic analysis of these and previously identified SMC genes supports an origin for
the vertebrate meiotic SMC1 in the most recent common ancestor since the divergence from invertebrate animals.
Additionally, we have identified duplicate copies due to segmental duplications for some of the SMC paralogs in
plants and yeast, mainly SMC2 and SMC6, and detected evidence that duplicates of other paralogs were lost,
suggesting differential evolution for these genes. Our analysis indicates that the SMC paralogs have been stably
maintained at very low copy numbers, even after segmental (genome-wide) duplications. It is possible that such
low copy numbers might be selected during eukaryotic evolution, although other possibilities are not ruled out.
Key words cohesin, condensin, meiosis, segmental duplication, SMC.
During eukaryotic cell division, chromosomes
must be distributed correctly into daughter cells.
Improper chromosome segregation results in cell
death or aneuploidy, which is the cause of such disor-
ders as Down’s Syndrome, Cornelia de Lange syn-
drome, and tumorigenesis (Pati et al., 2002; Gilliland
& Hawley, 2005; Ren et al., 2005; Musio et al., 2006;
Deardorff et al., 2007; Ohbayashi et al., 2007). To
ensure that each daughter cell receives a complete set
of chromosomes, two chromosomal processes are
crucial: sister chromatid cohesion and chromosome
condensation.
Sister Chromatid Cohesion (SCC) refers to the
close association of replicated sister chromatids along
the entire length of the chromosome (for a review of
cohesion and condensation, see Nasmyth & Haering,
2005). SCC is in place as sister chromatids are formed
during the S phase of the cell cycle and it is main-
tained while chromosomes condense and shorten
along their axes, until the anaphase-metaphase transi-
tion in mitosis. SCC provides the counter-force to
amphitelic attachments of microtubules originating
from the two poles of the spindle to the kinetochores.
At the completion of amphitelic attachment, SCC is
resolved to allow for the separation of sister chromat-
ids, which are pulled by the spindle to the poles. The
reduction of chromosome length during condensation
is in part due to the formation of solenoidal chromatin
loops that form rosettes along a central axis (Paulson
& Laemmli, 1977; Laemmli, 1978; Marsden &
Laemmli, 1979; Maeshima & Laemmli, 2003). Con-
densation is a prerequisite for mitosis progression and
is inter-dependent on SCC (Nasmyth, 2005; Nasmyth
& Haering, 2005).
Despite the early identification of the ubiquitous
nature of both condensation and cohesion among
eukaryotes, the key players involved in these proc-
esses have only been identified relatively recently
from biochemical and genetic studies (for review see

———————————
Received: 5 March 2008 Accepted: 22 April 2008
* These authors contributed equally to this work.
** Author for correspondence. E-mail: hxm16@psu.edu; Tel.: (814)
863-6414.
Abbreviations: SMC, structural maintenance of chromosome; NJ,
neighbor-joining; BLAST, basic local alignment search tool; ML,
maximum likelihood.
Journal of Systematics and Evolution Vol. 46 No. 3 2008 406
Hirano, 2002). Both cohesion and condensation are
mediated by multimeric, protein complexes known
respectively as cohesin and condensin. These com-
plexes are responsible for modulating chromatin
dynamics; furthermore, they share an interesting
characteristic: they both contain proteins belonging to
the Structural Maintenance of Chromosome (SMC)
family.
Members of this evolutionarily conserved
ATP-binding protein family are involved in maintain-
ing chromosome integrity and in DNA metabolism
(Hirano, 2002). In eukaryotes, there are six paralogous
proteins that form three distinctive heterodimers, as
part of protein complexes mainly responsible for
essential chromatin maintenance—SMC1 and SMC3
are part of cohesin, SMC2 and SMC4 are part of
condensin, and SMC5 and SMC6 are part of a DNA
repair complex (Hirano, 2002). In archaea and bacte-
ria, there is a single SMC protein that homodimerizes
and participates in chromosome dynamics, similar to
the eukaryotic cohesin and condensin complexes
(Volkov et al., 2003). Some bacteria, such as Es-
cherichia coli, contain MukB, a protein that has
relatively low levels of sequence similarity, yet a high
degree of secondary structural similarity, to that of
SMC proteins (Niki et al., 1992; Melby et al., 1998;
Cobbe & Heck, 2004). Members of the most abundant
group of archaea, Crenarchaeota, which live in ex-
treme hot and cold environments, have neither SMC
nor MukB orthologs, but they do contain orthologs of
the Rad50 protein, a more distant eukaryotic relative
of SMC proteins (Soppa, 2001).
In addition to being involved in genome stabil-
ity, members of the SMC family of proteins and the
related MukB protein all share a characteristic struc-
ture consisting of five well-defined domains (Melby et
al., 1998). They have conserved globular N- and
C-terminal domains that are attached, respectively, to
two long coiled-coil regions, which are separated by a
flexible hinge domain (Fig. 1: A). The N terminal
domains contain a Walker A motif (consensus G-X-
S/T-G-X-G-K-S/T-S/T) characteristic of ATP-binding
proteins, but surprisingly do not contain a comple-
mentary Walker B motif (h-h-h-h-D, where h is a
hydrophobic residue), which is usually found in
ATP-binding proteins containing a Walker A motif. In
a novel configuration, the Walker B motif is located
over 1000 amino acid residues away from the Walker
A motif in the C-terminally located DA box—a highly
conserved 35-amino acid stretch with alanine and
aspartic acid residues. The N- and C-terminal domains
at either end of the long SMC protein interact in-
tramolecularly to form a functional ATPase similar to
those of the ATP-Binding Cassette (ABC) transporter
proteins (Saitoh et al., 1995). This physical interaction
of the two end domains is facilitated by the formation
of an intramolecular antiparallel coiled-coil domain of
approximately 50 nm in length (Fig. 1: B), which is
made possible by a fold in the flexible hinge domain.
Furthermore, the hinge domain is responsible for the
heterodimerization between components of each
dimer pair (Fig. 1: C).
This conserved domain structure, coupled with
conserved functions in major eukaryotic lineages for
the six SMC paralogs, suggests that they may have
arisen from a single ancestor. A few phylogenetic
analyses have been conducted on the SMC family,
with two different interpretations on the origin of the
six paralogs. Using maximum-likelihood analysis,
Cobbe and Heck investigated the relationship between
SMCs from both prokaryotes and eukaryotes and
included the Rad50 and MukB families encoding ABC
ATPase as outgroups (Cobbe & Heck, 2004). Their
phylogenetic tree shows that eukaryotic SMC genes
evolved from several ancient gene duplication events.
In addition, the DNA repair genes, SMC5 and SMC6,
form a separate branch from SMC1–4, coding for
condensins and cohesins. Moreover, genes for the



Fig. 1. General structure of proteins from the SMC family. A,
domain structure of SMC proteins. The N and C terminal globular
domains are each connected to long coiled-coil regions separated by a
flexible hinge region. The N terminal domain contains the Walker A
sequence that acts as a functional ATPase in conjunction with the
Walker B motif, present in the C terminal domain. These two domains
are brought in close proximity (B) when the hinge region folds. The
folding of an SMC protein brings together the coiled-coil domains that
are now in anti-parallel orientation to each other (shown by the black
arrows). C, Dimerization between SMC partners occurs at the hinge
domain. Interactions with other proteins of the complexes occur at the
ends where the N and C termini are, also known as the head domain
(interactions not shown here).
SURCEL et al.: Evolution of the eukaryotic SMC family

407
larger cohesin and condensin subunits (SMC1 and
SMC4) formed a clade separate from those for the
smaller subunits (SMC3 and SMC2). They also
showed a strong correlation between the terminal
domains of the same SMC, but low correlation be-
tween the N- and C-terminal domains of the paralogs
that form the heterodimer, consistent with in-
tramolecular N-C interaction. Finally, their consensus
tree showed that plant and animal SMC genes group
together with fungi as the outgroup, in contradiction to
rRNA trees that show plants being outside of the
animal-fungi clade.
In addition to the DNA and protein sequences,
information about the secondary structures of proteins
can also be used for phylogenetic analyses. Studies on
the secondary structure of the long SMC arms con-
taining coiled-coil domains using the COILS program
indicate that each SMC arm contained two or more
coiled-coil regions, with “breaks” in between (Beasley
et al., 2002). For each pair of two paralogous proteins
that form a heterodimer, the patterns of these breaks
are different. In SMC1, SMC4, and SMC5 proteins,
one break occurred in the coiled-coil arm between the
N-terminal domain and hinge (left arm) and two
occurred in the coiled-coil between the hinge and the
C-terminal domain (right arm), whereas for SMC2,
SMC3, and SMC6, two breaks were found in the left
arm and one in the right arm. The patterns of the
secondary structure of the coiled-coil arms suggest
that unlike the tree generated by Cobbe and Heck
(2004), the SMC genes could be categorized into two
groups, implying that an early gene duplication event
in the ancestral SMC gave rise to two heterodimer
partners. Subsequent duplication events then produced
three copies of each subunit of the heterodimer,
allowing divergence to fulfill various functions.
Additionally, a study by Liu and Wang using hy-
dropathy profiles of amino acids generated phyloge-
netic relationships different than those using sequence
information alone (Liu & Wang, 2006). In this study,
SMC4 and SMC1 form a clade with archael SMC and
eubacterial SMC, separate from the SMC2 and SMC3
clade. SMC6 still forms a clade separate from the
cohesin and condensin SMCs, but its hydropathy
similarities with eukaryotic Rad50 joins these two
disparate groups together (Liu & Wang, 2006). The
various topologies of SMC trees from different studies
suggest that the phylogenetic relationship among
SMCs is still uncertain.
During meiosis, a diploid cell undergoes one
round of DNA replication followed by two rounds of
chromosome segregation, homologous chromosomes
in meiosis I and sister chromatids in meiosis II, gener-
ating four haploid cells. SCC and recombinational
cross-overs maintain homolog association from late
prophase I to the onset of anaphase I, when cohesin is
removed along the chromosome arms to allow for the
separation of homologs, but not sister chromatids
(Siomos et al., 2001; Yu & Koshland, 2007). This
preferential dissolution of cohesin on the chromosome
arms is in part accomplished by the presence of
meiosis-specific isoforms of cohesin proteins. In
mouse and human, two SMC1 isoforms exist—
SMC1α (or SMC1L1 for SMC1-like 1) and SMC1β (or
SMC1L2 for SMC1-like 2) (Revenkova et al., 2004).
SMC1β-deficient mice are sterile and defective in
cohesin maintenance, chromosome recombination,
and synapsis (Revenkova et al., 2004; Revenkova &
Jessberger, 2005; Hodges et al., 2005). In addition,
meiosis-specific cohesin isoforms of SCC1 and SCC3
(the two proteins that form the cohesin multiprotein
complex with SMC1 and SMC3), have also been
identified (Eijpe et al., 2000; Hodges et al., 2005;
Revenkova & Jessberger, 2005). The presence of
these meiotic cohesin proteins supports the idea that
the regulation of cohesin in meiosis may be different
than that in mitosis. However, it was not clear whether
other vertebrates and invertebrates also have two
SMC1 paralogs, and what the evolutionary relation-
ship of the SMC1 genes is. In addition, it was not
known whether any other SMC paralogs also have two
or more forms in some lineages. In particular, genome
duplication events have been proposed for plants and
the budding yeast (Simillion et al., 2002; Kellis et al.,
2004); the relationship between such genome duplica-
tion and SMC gene family evolution has not been
addressed.
The steady increase in sequenced genomes in re-
cent years has provided a wealth of information
available to address these questions. Here, we report
the identification and prediction through extensive
data mining of one or more additional SMC genes
from 34 species. Our phylogenetic analysis of the
SMC genes results in phylogenetic trees with similar
topologies to those published previously (Melby et al.,
1998; Cobbe & Heck, 2004). Detailed analysis of the
mitotic and meiotic SMC1 isoforms suggests that the
gene duplication event responsible for the meiotic
isoform occurred in early vertebrate evolution and that
the two isoforms have been subjected to differential
selective pressure. Additionally, we provide support to
a hypothesis that SMCs from plant genomes show a
stable copy number with the exception of very recent
duplications. Our genome analysis of these plant
Journal of Systematics and Evolution Vol. 46 No. 3 2008 408
sequences, as well as those of budding yeast, supports
the hypothesis that losses of additional copies of
SMCs occurred after recent genome duplications.
1 Material and Methods
1.1 Phylogenetic analysis of SMC genes
Sequences of SMC genes were obtained from
public databases (TAIR, NCBI, TIGR, and JGI)
initially using BLAST with each SMC protein se-
quence from Saccharomyces cerevisiae as query; a
BLAST score cutoff of 22% similarity was used to
avoid sequences of other ABC ATPases. Additional
SMC genes were identified from genomic sequences
using tBLASTn with human and Arabidopsis se-
quences as queries for animal and plant genomes,
respectively, and predicted manually. The protein
sequences of the SMC homologs were aligned using
MUSCLE version 3.6 (Edgar, 2004) with the default
settings, followed by manual adjustment using Gene-
Doc V.2.6.002 software (http://www.nrbsc.org/gfx/
genedoc/index.html, Nicholas et al., 1997). Neighbor
joining trees were constructed using MEGA 4.0
(Tamura et al., 2007). The reliability of internal
branches was calculated with 1000 bootstrap pseu-
doreplicates using the “pairwise deletion option” of
amino acid sequences. Maximum likelihood analysis
was performed by using PHYML 2.4.4 (Guindon &
Gascuel, 2003) using the WAG model with gamma
correction; bootstrap support was obtained using 100
replicates. Maximum parsimony (MP) analysis was
carried out using PAUP* 4.0 beta 10 (Swofford, 2001)
with default settings, and bootstrap support was
determined by using 100 replicates.
1.2 Detection of segmental duplication
To find evidence for the ancient segmental du-
plications in the SMC genes in yeast, we checked the
available information about the yeast whole genome
duplication analysis through the supplemental material
of Kellis et al. (2004) available at http://www.nature.
com/nature/journal/v428/n6983/extref/nature02424-s1.
htm.
Additionally, to search for recent segmental du-
plication evidence for the SMC genes in Arabidopsis
and poplar, we collected 50kb genomic DNA se-
quences both upstream and downstream of all of the
existing SMC genes from both species. Among the 8
AtSMCs and 7 PtSMCs, AtSMC2a & AtSMC2b are the
pair that has been retained since the genome duplica-
tion, as well as AtSMC6a & AtSMC6b and PtSMC2a
&PtSMC2b. We compared the 100kb regions of each
of the gene pair using the DotPlot function of the
PipMaker program (Schwartz et al., 2000) at http://
pipmaker.bx.psu.edu/pipmaker/. For the rest of the
SMC genes that lost the other duplicated copies, we
used the 100kb regions of the SMC genes to run
BLAST searches against NCBI Arabidopsis (http://
www.ncbi.nlm.nih.gov/genome/seq/BlastGen/BlasGen.
cgi?taxid=3702) and JGI poplar (http://genome.jgi-psf.
org/cgi-bin/runAlignment?db=Poptr1_1&advanced=1)
databases to look for the duplication evidence of the
flanking regions near SMC genes. Upon the BLAST
results, we picked another 100kb sequences from the
subject regions that have the best hits with the query
flanking sequences. Afterwards, we used the Pipmaker
program to compare the two corresponding 100kb
regions where we found segmental duplication evi-
dence.
2 Results and Discussion
2.1 Identification of SMC genes
We performed numerous BLAST searches for
homologs to each of the six SMC proteins from
animals, plants and fungi, with an emphasis on those
with completely sequenced genomes. In total, 273
SMC genes were collected from 43 species (Tables 1
and 2; complete sequences will be provided upon
request). In addition to 92 known eukaryotic SMC
sequences identified in previous phylogenetic studies

Table 1 Numbgr of SMC genes in this study
SMC1 Organisms: number of species
α β
SMC2 SMC3 SMC4 SMC5 SMC6
Vertebrates: 15 (7)1) 14 (7) 14 (3) 14 (5) 14 (7) 14 (5) 14 (3) 14 (3)
Invertebrates: 11 (3) 11 (3) 11 (3) 11 (3) 13 (4)2) 11 (3) 12 (4) 2)
Plants: 7 (2) 7 (1) 9 (3)3) 7 (2) 7 (2) 7 (2) 9 (3) 3)
Fungi: 11 (4) 11 (4) 11 (3) 11 (3) 11 (3) 11 (4) 11 (3)
Total: 44 (16) 279 (87)
1) Numbers in parentheses indicate the numbers of species or sequences which have been reported previously. 2) Caenorhabditis elegans has two
copies of SMC4 and SMC6. 3) Arabidopsis and poplar each have two copies of SMC2; Arabidopsis and Selaginella moellendorffii each have two
copies of SMC6.
SURCEL et al.: Evolution of the eukaryotic SMC family

409
Table 2 SMC genes included in this study
SMC1 Common name Scientific name
α β
SMC2 SMC3 SMC4 SMC5 SMC6
Human Homo sapiens x x x x x x x
Chimpanzee Pan troglodytes x x x x x x x
Mouse Mus musculus x x x x x x x
Rat Rattus norvegicus x x x x x x x
Dog Canis familiaris x x x x x x x
Cat Felis catus x x
Cow Bos taurus x x x x x x x
Opossum Monodelphis domestica x x x x x x x
Pig Sus scrofa x x x x x
Macaque Macaca mulatta x x x x x x x
Horse Equus caballus x x x x x x x
Chicken Gallus gallus x x x x x x x
Frog Xenopus tropicalis x x x x x x x
Zebrafish Danio rerio x x x x x x x
Pufferfish Takafugu rubripes x x x x x x x
Yellow fever mosquito Aedes aegypti x x x x x x
Malaria mosquito Anopheles gambiae x x x x x x
Honey bee Apis mellifera x x x x x x
Nematode Caenorhabditis elegans x x x x1) x x1)
Caenorhabditis briggsae x x x x1) x x
Fruit fly Drosophila melanogaster x x x x x x
Drosophila pseudoobscura x x x x x x
Beetle Tribolium castaneum x x x x x x
Sea urchin Strongylocentrotus purpuratus x x x x x x
Sea squirt Ciona intestinalis x x x x x x
Sea anemone Nematostella vectensis x x x x x x
Arabidopsis Arabidopsis thaliana x x1) x x x x1)
Rice Oryza sativa x x x x x x
Poplar Populus trichocarpa x x1) x x x x
Moss Physcomitrella patens x x x x x x
Spikemoss Selaginella moellendorffii x x x x x x1)
Wine grape Vitis vinifera x x x x x x
– Ostreococcus lucimarinus x x x x x x
– Aspergillus fumigatus x x x x x x
– Aspergillus nidulans x x2) x x x x
– Aspergillus oryzae x x x3) x3) x x
– Candida albicans x x x x x x
– Candida glabrata x x x x x x
– Eremothecium gossypii x x x x x x
– Gibberella zeae x x x x x x
– Kluyveromyces lactis x x x x4) x x
– Neurospora crassa x x x x x x
Budding yeast Saccharomyces cerevisiae x x x x x x
Fission yeast Schizosaccharomyces pombe x x x x x x
Available common names are shown next to the scientific names.
1) These species have two copies of each of these genes. 2) The Aspergillus nidulans SMC2 gene was previously mistakenly annotated as SMC3. 3)
The Aspergillus oryzae SMC3 and SMC4 genes were previously mistakenly annotated as SMC2 and SMC1, respectively. 4) The Kluyveromyces lactis
SMC4 gene was previously mistakenly annotated as SMC1.
Journal of Systematics and Evolution Vol. 46 No. 3 2008 410
(Melby et al., 1998; Cobbe & Heck, 2004), we identi-
fied and/or predicted 181 new SMC genes from ten
vertebrates, seven invertebrates, seven plants, and six
fungi. In most cases, we found one copy of each of the
six SMC paralogs; however, we recovered two copies
of SMC1 in 14 vertebrates, two copies of SMC4 and
SMC6 in the nematode Caenorhabditis elegans and
additional copies of SMC2 and SMC6 in some plants.
Furthermore, we were able to detect several pseu-
dogenes in plants, such as a SMC2 pseudogene in
grapevine and a SMC3 pseudogene in Populus (not
shown). These pseudogenes lack half of the coding
region and have accumulated stop codons in the
remaining half.
2.2 Phylogenetic analysis of the SMC family
Alignments of SMC sequences showed the ex-
pected highly conserved regions of the terminal
globular domains and the hinge domain (the alignment
will be provided upon request). The coiled-coil or arm
domains are more divergent, even among members of
the same clade, although SMC1 sequences showed
more conservation than the other SMC proteins within
the arm domains. Using the three conserved regions,
we generated Neighbor-Joining (NJ) and Maximum
Likelihood (ML) trees for the SMC family (see Fig. 2
for an ML tree with bootstrap support from ML and
NJ analyses). The results show strong support for the
six clades, for the SMC1–6 paralogs, respectively, and
for the relationship among these six clades. Consistent
with the previous analysis of eukaryotic genes, those
for the larger subunits of cohesin and condensin,
SMC1 and SMC4, respectively are sister clades, as are
the SMC2 and SMC3 genes encoding smaller subunits,
while SMC5 and SMC6 form a separate clade. Com-
pared with previous reports, the trees in this study
have higher bootstrap values. Our results support the
idea that the common ancestor of SMC5 and SMC6
was separated from the ancestor of the other 4
paralogs due to a duplication event in early eukaryo-
tes, although the possibility of long-branch attraction
could not be ruled out.
Our phylogenetic analyses also showed that sev-
eral genes were previously annotated incorrectly
(Table 2). The previously designated SMC2 and
SMC1 from the filamentous fungus Aspergillus oryzae
were in fact SMC3 and SMC4, respectively. Likewise,
the putative SMC1 sequence for the yeast Kluyvero-
myces lactis was in fact SMC4 and the putative SMC3
sequence for the filamentous fungus Aspergillus
nidulans was its SMC2 paralog. A recent review of
these BLAST searches reveals that the correct annota-
tion for the K. lactis and the A. nidulans sequences
have been assigned in the interim, while the A. oryzae
genome has been removed from the NCBI database
and will be restored upon completion of genome
assembly.
2.3 Origin of Smc1β and the evolution of meiotic
cohesin function
Previous studies of SMC1 genes have reported a
meiotic isoform for SMC1, called SMC1β, in addition
to the non-specific SMC1α, in human, mouse, and a
fish (Cobbe & Heck, 2004; Revenkova et al., 2004). It
is possible that the two SMC1 isoforms originated in
the most recent common ancestor of vertebrates;
alternatively the two SMC1 isoforms were produced
by a duplication event in an earlier ancestor, but the
meiotic isoform has been lost in non-vertebrate or-
ganisms. To investigate the origin of the vertebrate
meiosis-specific isoform SMC1β, we performed
phylogenetic analyses on the SMC1 sequences that we
retrieved, including both the SMC1α and SMC1β
isoforms from 14 vertebrates (10 mammals, chicken,
frog, and two fish), and the single copy SMC1 genes
from 27 other organisms (Tables 1 and 2). Vertebrates
are members of the chordates, which also include
urochordates and cephalochordates; chordates and
echinoderms represent two major lineages of deu-
terostomes, distinct from the protostomes, including
insects and nematodes. To address the origin of the
SMC1 isoforms, we have identified SMC1 sequences
from the recently sequenced genomes of sea squirt (a
urochordate) and sea urchin (an echinoderm), as well
as from a sea anemone, which is a basal metazoan.
Because there is greater sequence conservation
among SMC1 genes than between the six SMC
paralogs, in addition to the conserved domains (N and
C termini and the hinge domain) used in the above
phylogenetic analyses, the less conserved coiled-coil
regions were also included in the analyses. We have
performed phylogenetic analyses using ML and NJ
methods with most of the sequences, as well as a third
analysis using NJ with the coiled coil domains; these
analyses resulted in very similar topologies (Fig. 3).
These analyses indicate that (1) all animal SMC1
sequences form a single clade with 100%/100%/99%
bootstrap support; (2) all vertebrate SMC1 genes form
a monophyletic group with strong bootstrap support
(100%/80%/96%); and (3) the two SMC1 isoforms
form respective clades with 100%/100%/100% sup-
port. Therefore, the SMC1α and SMC1β isoforms
were likely the result of a duplication that occurred in
the most recent common ancestor of vertebrates, since
the divergence of vertebrates from urochordates and
echinoderms.
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Fig. 2. A phylogenetic tree for the SMC family, shown in three parts. A. Details for clades containing the genes for the large subunits—SMC1 and
SMC4—of cohesins and condensins, respectively. B. Details for clades containing the genes for the smaller SMC subunits of the cohesin and
condensin complexes—SMC3 and SMC2, respectively. C. Details of the clades for SMC5 and SMC6, which are subunits of a DNA repair complex.
Bootstrap supports are shown for ML/NJ analyses on a ML tree. Some of the taxa represented here are: frog, Xenopus tropicalis; zebrafish, Danio
rerio; pufferfish, Takafugu rubripes; sea squirt, Ciona intestinalis; beetle, Tribolium castaneum; moss, Physcomitrella patens; spikemoss, Selaginella
moellendorffii. For complete taxon information, please see Table 2.
Journal of Systematics and Evolution Vol. 46 No. 3 2008 414


Fig. 3. A phylogenetic tree for the SMC1 genes. Shown here is an ML-tree with all SMC1 sequences, including both SMC1α and SMC1β from
vertebrates, as well as SMC1 from other animals, plants, and fungi. Bootstrap values are from analyses using ML/NJ/(NJ with the coiled-coil regions).
SURCEL et al.: Evolution of the eukaryotic SMC family

415
The SMC1 genes of the two nematodes, C. ele-
gans and C. briggsae, form a basalmost group outside
of all other animal sequences. This can be explained
by long-branch attraction because of the rapid evolu-
tion of the nematode genes, as observed for other gene
families, such as the highly conserved recA/RAD51
gene family (Lin et al., 2006). All three analyses (Fig.
3) also support the monophyly (bootstrap values of
65%/85%/88%) of the genes from vertebrates, sea
squirt and sea urchin, all of which are deuterostomes,
supporting the idea that they are more closely related
than those from other animals. The sea anemone
SMC1 gene was placed outside the combined clade of
deuterostome and insect SMC1 genes. To investigate
the relationship of other invertebrate SMC genes
further, we also conducted phylogenetic analyses on
the other five SMC subfamilies (Figs. 4–6). In the NJ
trees of the SMC2, SMC3, and SMC4 subfamilies
(Figs. 4 and 5), the sea squirt is placed outside of the
sea urchin, whereas the opposite is observed in the
SMC6 subfamily, although with low support (Fig. 6).
In the SMC5 subfamily, the sea squirt sequence is
separated from all of the other genes (Fig. 6). There-
fore, the phylogenetic positions of the SMC genes
from sea squirt, sea urchin and sea anemone are not
consistent.
To investigate the relationship of the SMC1
genes further, we compared their sequences in detail
at the residue level using a multi-sequence alignment.
As an example, Fig. 7A shows the portion of the
alignment for the hinge with conserved residues
highlighted. We found that 10 amino acid residues
were identical for the vertebrate SMC1α genes and the
sea squirt and sea urchin SMC1 genes (Fig. 7: B). In
addition, 37 amino acid residues were conserved in
vertebrate SMC1α genes and invertebrate SMC1 genes
(Fig. 7: B), whereas only 12 residues were shared in
vertebrate SMC1α and SMC1β sequences, but not in
invertebrate SMC1 genes (not shown). Most of the 37
residues conserved among the SMC1α genes and
invertebrate SMC1 genes are in the conserved regions,
while the majority of the twelve residues conserved
among the vertebrate sequences occur in the less
conserved domains—seven in the coiled-coil domains,
one in the N terminus, one in the hinge, and three in
the C-terminal domain. Because both the vertebrate
SMC1α and the invertebrate SMC1 genes have con-
served functions in both mitosis and meiosis, the
relatively large number of residues shared among
these genes suggests that these residues might be
important for conserved functions. The small number
of residues that are in common between the
SMC1α and SMC1β genes suggests that these two
paralogs have divergent protein activities.
It has been shown that another cohesion subunit,
Scc1, has a meiotic isoform, known as Rec8, found in
fungal, animal and plant species (Parisi et al., 1999;
Watanabe & Nurse, 1999; Pasierbek et al., 2001;
Dong & Makaroff, 2001; Wang et al., 2003; Zhang et
al., 2006). Its wide distribution suggests that meio-
sis-specific cohesin machinery originated early in
eukaryotic evolution. An early-animal origin of the
meiotic isoform SMC1β would be consistent with the
distribution of conserved residues shown in Fig. 7B;
however, the absence of such a meiotic isoform in all
examined invertebrate animals, as well as in fungi and
plants, unlike the situation for Scc1, makes it unlikely
that the duplication for SMC1α and SMC1β occurred
before the divergence of animals.
2.4 Divergence of vertebrate SMC1 isoforms
In the tree shown in Fig. 3, the SMC1β genes
have longer branches than the SMC1α genes, sug-
gesting that the SMC1β genes might have evolved
more rapidly. To further investigate the evolution of
the meiosis-specific SMC1 isoforms, we performed
dN/dS analyses for two vertebrate pairs—human vs.
mouse and human vs. chicken (Fig. 8). Our analysis
suggests that SMC1α genes have been under purifying
selection with dN/dS values lower than 0.1 (Fig. 8:
A), consistent with the findings that SMC1α are more
similar to the single copy SMC1 genes in inverte-
brates. Although the dN/dS values were generally low
across the SMC1α genes, there is a region near the 3′
end with slightly higher dN/dS values, suggesting
potentially relaxed selection (Fig. 8: A). Moreover, the
dN/dS values were higher for the human/chicken pair
than for the human/mouse pair, perhaps reflecting
functional divergence between human and chicken. To
examine the divergence of SMC1α genes further, we
performed pair-wise comparisons among vertebrate
SMC1α genes (Table 3). The very low dN/dS ratios
indicate that the vertebrate SMC1α genes have been
under purifying selection, with mammalian genes
generally having experienced the greatest pressure.
Compared with those of the SMC1α genes, the
dN/dS values for SMC1β pairs were greater, between
0.1 and 0.4 (see Fig. 8B), suggesting that the meiotic
isoform has been under reduced selection pressure.
Also, the dN/dS values were similar between the pair
of human/chicken and the pair of human/mouse,
suggesting a possible acceleration of divergence
between human and mouse because these two mam-
mals have separated more recently than human and
Journal of Systematics and Evolution Vol. 46 No. 3 2008 416


Fig. 4. NJ trees for the SMC2 and SMC3 subfamilies. A, A tree for the SMC2 subfamily, with bootstrap values from NJ analysis. B, A tree for the
SMC3 subfamily, with bootstrap values from NJ analysis.
SURCEL et al.: Evolution of the eukaryotic SMC family

417


Fig. 5. An NJ tree for the SMC4 subfamily, with bootstrap values
from NJ analysis.

chicken. These results suggest that following gene
duplication, the SMC1α isoform has been highly
conserved under selection for its essential role in
mitosis, whereas the SMC1β isoform has been allowed
to diversify because it is only needed for meiosis,
which represents a subset of the function of the ances-
tral SMC1 gene.
2.5 Plants and nematodes have additional copies
of some SMC genes
To understand the evolutionary history of SMC2–
SMC6 genes, we have performed phylogenetic analy-
sis for each of these five paralogous sets (Figs. 4–6).
To obtain stronger supports, we generated trees for
representative subsets of sequences using three meth-
ods (Fig. 9). We found several relatively recent dupli-
cates in some of these groups, including two copies of
SMC2 in both poplar and Arabidopsis, two copies of
SMC4 in nematodes, and two copies of SMC6 in
nematodes, Arabidopsis and spikemoss (Selaginella



Fig. 6. NJ trees for the SMC5 and SMC6 subfamilies. A, A tree for
the SMC5 subfamily, with bootstrap values from NJ analysis. B, A tree
for the SMC6 subfamily, with bootstrap values from NJ analysis.

Journal of Systematics and Evolution Vol. 46 No. 3 2008 418


Fig. 7. Sequence analysis of SMC1 proteins. A, An alignment of Smc1α and Smc1β residues in the hinge domain. The residue marked by the
question mark supports the node joining the vertebrate animal SMC1α and SMC1β clades. Residues marked by an asterisk (*) support the grouping
of vertebrate SMC1α with the insect SMC1. B, A generalized phylogeny of the SMC1 family with conserved amino acid residues. Residue numbers
are from the human SMC1β.

moellendorffii) (Tables 1 and 2). An NJ tree of the
SMC2 and SMC3 clades with plant sequences shows
that the two copies of SMC2 in Arabidopsis and
poplar (Fig. 9, middle) were produced by two inde-
pendent recent duplication events after the divergence
of Arabidopsis and poplar. We noticed that grape had
only one copy of SMC2, but as mentioned above, we
identified a SMC2 psedogene in the grape genome,
demonstrating that grape also had a second copy of
SMC2 until recently. An NJ tree of the SMC5 and
SMC6 groups with plant sequences shows that dupli-
cated Arabidopsis SMC6 copies form a clade (Fig. 9,
bottom), indicating that they are recent duplicates. The
other duplicated SMC6 copy from spikemoss does not
group together, suggesting that an ancient gene dupli-
cation mechanism occurred in the early ancestor of
plants and that the SMC6Β is only retained in
spikemoss, although other permutations are also
SURCEL et al.: Evolution of the eukaryotic SMC family

419
Table 3 Substitution rates between vertebrate animal SMC1α genes
Human Chimpanzee Monkey Mouse Rat Dog Cow Horse Opossum Chicken Frog Zebrafish Pufferfish
Human 0.009 0.035 0.362 0.381 0.233 0.252 0.211 1.169 1.097 1.443 1.429 1.563
Chimpanzee 0.189 0.029 0.349 0.365 0.226 0.249 0.202 1.164 1.075 1.448 1.417 1.531
Monkey 0 0.062 0.362 0.391 0.222 0.247 0.197 1.142 1.070 1.447 1.447 1.511
Mouse 0.006 0.011 0.006 0.131 0.455 0.471 0.438 1.406 1.557 1.668 1.577 1.724
Rat 0.004 0.010 0.004 0.026 0.464 0.457 0.443 1.380 1.570 1.752 1.640 1.704
Dog 0 0.008 0 0.007 0.006 0.225 0.193 1.142 1.088 1.413 1.434 1.632
Cow 0 0.007 0 0.006 0.006 0 0.206 1.203 1.118 1.418 1.454 1.537
Horse 0 0.009 0 0.007 0.006 0 0 1.148 1.110 1.410 1.481 1.479
Opossum 0.011 0.013 0.011 0.012 0.011 0.011 0.010 0.011 1.572 1.620 1.910 1.779
Chicken 0.037 0.040 0.039 0.028 0.028 0.038 0.037 0.038 0.030 1.651 1.848 1.309
Frog 0.023 0.025 0.024 0.022 0.021 0.024 0.024 0.025 0.025 0.038 1.811 1.725
Zebrafish 0.043 0.045 0.043 0.041 0.040 0.044 0.043 0.042 0.034 0.044 0.041 1.609
Pufferfish 0.041 0.043 0.043 0.039 0.040 0.039 0.042 0.043 0.038 0.061 0.043 0.024
Synonymous substitution rates (dS) are shown above the diagonal (upper right) and the ratios of non-synonymous to synonymous substitution rates
(dN/dS) are shown below the diagonal (lower left).
Human, Homo sapiens; Chimpanzee, Pan troglodytes; Monkey, Macaca mulatta; Mouse, Mus musculus; Rat, Rattus norvegicus; Dog, Canis
familiaris; Cow, Bos taurus; Horse, Equus caballus; Opossum, Monodelphis domestica; Chicken, Gallus gallus; Frog, Xenopus tropicalis; Zebrafish,
Danio rerio; Pufferfish, Takafugu rubripes.





Fig. 8. dN/dS analysis of Smc1 from human, chicken, and mouse
sequences. A, Comparison of SMC1α (Smc1L1) between human and
mouse (diamonds) and between human and chicken (triangles). B,
Comparison of SMC1β (Smc1L2) between human and mouse (dia-
monds) and between human and chicken (triangles).
possible. Furthermore, the nematodes C. elegans and
C. briggsae also have two SMC4 genes and C. elegans
has two SMC6 genes. These copies were the result of
duplication event(s) that occurred before the diver-
gence of two species (Fig. 5). Our results indicate that
SMC2, SMC4, and SMC6 genes are sometimes dupli-
cated due to lineage-specific recent duplications.
2.6 Effect of segmental duplications on SMC gene
copy number
Our phylogenetic analysis showed that in gen-
eral the SMC paralogs have remained stable over
much of eukaryotic history, although a few duplica-
tion events have resulted in two copies for some
paralogs in specific lineages. The chromosomal
positions of the duplicated copies indicate that they
are not likely the result of tandem duplication events.
In plants, it is thought that large segmental (possibly
genome-wide) duplication is the most common dupli-
cation event because most plant species are dip-
loidized polyploids and contain many duplicated
chromosome blocks in the genomes (Adams &
Wendel, 2005). It has been proposed that Arabidopsis
underwent three genome-wide duplication events, of
which the most recent occurred 75±22 million years
ago (Simillion et al., 2002). Similarly, the poplar
genome is believed to have been duplicated more
recently, about 8–13 million years ago (Tuskan et al.,
2006; Jansson & Douglas, 2007). The genome of S.
cerevisiae is also believed to have experienced an
ancient duplication event (Kellis et al., 2004).
Journal of Systematics and Evolution Vol. 46 No. 3 2008 420


Fig. 9. Phylogenetic analysis of SMC genes from plants and other
selected taxa. (top) An NJ tree of SMC1 and SMC4; (middle) An NJ
tree for SMC2 and SMC3; (bottom) An NJ tree of SMC5 and SMC6.
Bootstrap supports are from NJ/ML/MP analyses.
To examine the possible mechanism for the du-
plication history of the SMC genes in Arabidopsis
and poplar, we looked first for evidence of segmen-
tal duplications. Initially, we looked for evidence of
genome/segmental duplications in yeast where
massive gene loss and specialization took place. Our
literature search identified duplicated sister regions
in the budding yeast genome that had a 2:1 mapping
with a related yeast species, Kluyveromyces waltii,
which diverged before the ancient genome duplica-
tion in budding yeast (Kellis et al., 2004). We found
that for SMC2, SMC5, and SMC6, there are three K.
waltii tiles (genomic regions), tile 117, tile 1, and
tile 56, respectively, that each matches to two re-
gions in the budding yeast genome. For each set of
three matching regions, K. waltii and one of the two
budding yeast regions contained an SMC gene. The
remaining region of the budding yeast genome only
contained genes flanking the SMC gene, indicating
that one of the duplicated SMC genes had been lost.
Because the yeast genome has undergone frequent
and massive chromosome rearrangements, the
genome duplication evidence for the other three
yeast SMCs—SMC1, SMC3 and SMC4—was not
clear.
In addition, to test whether segmental duplica-
tion was responsible for the duplicated plant SMC
genes, we performed dot-matrix analyses to compare
the genomic regions 50k upstream and downstream
of the duplicated SMC2 and SMC6 genes, or with
chromosomal regions containing genes similar to the
genes flanking one of the other SMC genes. As
shown in Fig. 10, we can see clearly that except for
AtSMC1, all other SMC genes are associated with
segmental duplications. Even for regions related to
AtSMC1, there are also some conserved regions, but
with different orientations, suggesting chromosomal
rearrangements. Whereas the duplicated copies of
AtSMC2, AtSMC6, and PtSMC2 were retained, the
one copy of the other SMC genes was lost, along
with a region of approximately 30 kb adjacent to the
SMC genes. Therefore, following the most recently
genome-wide duplication in both Arabidopsis and
poplar, most duplicated copies were lost, resulting in
the retention of a single copy. The retention of
duplicate copies of AtSMC2, AtSMC6 and PtSMC2
suggests that these genes provide a selective advan-
tage, and that the retention of additional copies of
the other paralogs might be deleterious. This suppo-
sition is buttressed by the fact that regions that
contain AtSMC1 and ScSMC1 seem to have more
frequent gene loss and genome rearrangement,
SURCEL et al.: Evolution of the eukaryotic SMC family

421

Fig. 10. Comparisons of the flanking genomic regions (50 kb on both upstream and downstream) of AtSMC and PtSMC genes. A, AtSMC1 vs.
AtSMC1*; B, AtSMC2a vs. AtSMC2b; C, AtSMC3 vs. AtSMC3*; D, AtSMC4 vs. AtSM4*; E, AtSMC5 vs. AtSMC5*; F, AtSMC6a vs. AtSMC6b; G,
PtSMC1 vs. PtSMC1*; H, PtSMC2a vs. PtSMC2b; I, PtSMC3 vs. PtSMC3*; J, PtSMC4 vs. PtSMC4*; K, PtSMC5 vs. PtSMC5*; L, PtSMC6 vs.
PtSMC6*. All Arabidopsis and poplar SMCs can be explained by segmental duplication and gene loss events. * The hypothesized SMC genes that
were lost during evolution.
Journal of Systematics and Evolution Vol. 46 No. 3 2008 422
exhibited by losses of long segments flanking SMC1
and apparent chromosome rearrangements. The
specific loss of SMC1 and SMC3, both members of
the cohesin complex, implies that sister chromatid
cohesion may be a more tightly regulated process than
either chromosome condensation (with SMC2 and
SMC4) or DNA repair (with SMC5 and SMC6).
3 Conclusions
The SMC family is an excellent example of how
the ever-growing body of genome sequence informa-
tion can add to our understanding of the evolution of a
family of proteins. We demonstrate that the origin of
the meiotic isoform of SMC1 is likely in the most
recent common ancestor of vertebrates and that it has
experienced divergence under relaxed selection.
Additionally, we have shown that most of the dupli-
cate copies of SMC genes in plants and yeast due to
genome-wide duplication events were lost, with
preferential retention of SMC2, SMC4, and SMC6.
These results suggest that the condensin and DNA
repair pathways are more flexible and able to accom-
modate multiple copies of their respective SMC
proteins, whereas sister chromatid cohesion does not
tolerate higher doses of SMC1 and SMC3.
Acknowledgements A.S. was supported by the
Huck Institutes of the Life Sciences and the
Department of Biochemistry and Molecular Biology
at the Pennsylvania State University. X.Z. was
supported by the Huck Institutes of the Life
Sciences. L.Q. was supported by the Department of
Biology and by funds from Rijk Zwaan, the Nether-
lands. This work was supported by a grant from the
US Department of Energy (DE-FG02-03ER15-448),
and by funds from the Huck Institutes of the Life
Sciences and from the Department of Biology, The
Pennsylvania State University.
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