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Seminars in Cell & Developmental Biology
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Review
Genomic imprinting: A balance between antagonistic
roles of parental chromosomes
Tetsu Kinoshita ∗ , Yoko Ikeda, Ryo Ishikawa
Plant Reproductive Genetics, GCOE Research Group, Graduate School of Biological Science, Nara Institute of Science and Technology,
8916-5 Takayama, Ikoma, Nara 630-0192, Japan
a r t i c l e
Article history:
Available online xxx
Keywords:
Genomic imprinting
Endosperm
Reproductive barrier
Apomixis
i n f o
a b s t r a c t
Maternally and paternally derived chromosomes might be expected to contribute equally to the various
cellular and developmental processes in placental mammals and flowering plants. However, this is not
true even in the case of the self-pollinated plant, Arabidopsis, which has identical DNA sequences in
both parental genomes. The reason for this is that some genes, called “imprinted genes”, are expressed
exclusively from paternally or maternally inherited chromosomes. As a result, parental chromosomes
express a distinct set of genes and play different roles in biological processes. Here, we review and compare
roles of genomic imprinting in flowering plants and placental mammals.
© 2008 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Control of imprinted genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DNA methylation cycle of imprinted genes in mammals and one-way control of imprinted genes by DNA methylation in flowering plants . . . .
Mechanism of DNA demethylation of imprinted genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of genomic imprinting in parthenogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of genomic imprinting in reproductive barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Genomic imprinting refers to the unequal expression of maternal and paternal alleles of a gene depending on the parent-of-origin,
and is a phenomenon that has evolved in both placental mammals
and flowering plants. In both mammals and plants, the imprinted
genes are differentially marked before fertilization by DNA methylation and histone modifications [1]. As a consequence of the
heritable epigenetic marks on the imprinted genes, the roles of
maternally and paternally inherited chromosomes are not equivalent in cellular and developmental processes. These epigenetic
modifications have been used to explain functional differences
between parental genomes. In mammals, gynogenetic or androgenetic embryos, which have two sets of maternal or paternal
∗ Corresponding author. Tel.: +81 743 72 6210; fax: +81 743 72 6210.
E-mail address: [email protected] (T. Kinoshita).
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chromosomes, respectively, show opposite effects on the development of the placenta; they also display many developmental
abnormalities and do not develop beyond the mid-gestation stage
[2,3]. In flowering plants, an increased dosage of maternal chromosomes usually promotes endosperm development, while an
increased dosage of paternal chromosomes represses endosperm
development [4,5]. Both the placenta and the endosperm are tissues
that provide nutrients to the embryo [6]. One proposed explanation of the evolution of imprinting, the parental conflict theory,
predicts that maternally expressed imprinted genes reduce nutritional flow to the embryo, while paternally expressed imprinted
genes promote nutritional flow [7].
In this review, we focus on the mechanism of genomic imprinting in flowering plants in comparison to that of placental mammals.
Recent studies of Arabidopsis mutants have identified several
imprinted genes [8–12]. Although the life histories of mammals
and plants are very different, the imprinting of genes in plants are
controlled by DNA methylation and histone modification(s) as is
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the case for mammalian genomic imprinting. We also extend our
consideration of genomic imprinting in plants to discussion of its
possible roles in various biological processes. As a consequence of
the nature of epigenetic regulation of parental chromosomes, a balance between parental contributions has been predicted to play
significant roles in endosperm development, reproductive barriers
and apomixis [7].
2. Control of imprinted genes
In mammals, imprinted genes show a parent-of-origin specific
gene expression pattern that relies on differential DNA methylation of the imprinting control regions (ICRs). Deletion of the ICR
located upstream of the imprinted non-coding RNA gene, H19,
results in loss of imprinted gene expression of Igf2 and H19 [13].
Although a variety of molecular mechanisms controlling genomic
imprinting have been identified in mammals, such as chromatin
looping, enhancer blocking, antisense transcripts and small RNAs
[14–16], ICRs are the primary determinants of imprinted gene
expression. Many maternally and paternally expressed imprinted
genes are located in clusters near ICRs. In flowering plants, clusters of imprinted genes have not been identified, however, the
epigenetic control of imprinted genes by DNA methylation and
histone modifications are conserved [8,10,17–21]. In Arabidopsis,
paternally inherited alleles of FWA and FIS2 are silenced by DNA
methylation, while maternally inherited alleles are activated by
the DNA glycosylase, DEMETER (DME) [8,20] (Fig. 1). A different layer of control of imprinted gene expression has also been
reported [18,19,21]: the paternal allele of MEA is silenced by the histone methyltransferase activity of maternal MEA, which forms the
evolutionarily conserved PRC2 Polycomb complex [22,23] (Fig. 1).
This type of self-imprinting, in which a gene is silenced by its
own product, is to date limited to plants, although the Polycomb complex is known to play a role in silencing of imprinted
genes in the mammalian placenta [24]. Thus, DNA methylation and repression by the Polycomb complex are conserved
aspects of genomic imprinting in placental mammals and flowering
plants.
Many transgenic constructs display an imprinted pattern of
gene expression in Arabidopsis and maize suggesting that in plants
the cis-element for controlling imprinted gene expression is most
likely located near the imprinted loci [11,20,25–27]. In Arabidopsis, methylated DNA sequences have been found in the promoter
regions of the maternally expressed imprinted genes MEDEA (MEA),
FERTILIZATION-INDEPENDENT-SEED2 (FIS2) and FWA, and in the
3 -tandem repeats of the paternally expressed imprinted gene
PHERES1 (PHE1). These methylated sequences are included in the
transgenic constructs and, therefore, might confer imprinted gene
expression.
A well-studied example of a cis-element that controls genomic
imprinting in plants is the SINE (short interspersed transposable element)-related tandem repeat structure located in the
5 -region of FWA [28–31]. The methylation status of the tandem
repeats are always correlated with the expression pattern of FWA
[28,32]. When methylation is lost, transcription starts within this
repeat region and causes delayed flowering [32,33]. A transgene
carrying the SINE-related tandem repeats with a GFP reporter
construct showed a similar pattern of imprinted gene expression
to the endogenous FWA gene [28]. Induced methylation of the
hypomethylated allele of FWA, using an RNA-directed de novo DNA
methylation strategy, showed that DNA methylation of SINE-related
tandem repeats determine imprinted gene expression. An analysis
of the evolution of this SINE-related tandem repeat, the region corresponding to this cis-element for imprinting in Arabidopsis species,
has been reported [34]. This study suggested that a SINE-related
sequence, without a tandem repeat structure, is responsible for
the imprinted pattern of FWA expression in A. halleri [34]. Thus,
in A. halleri at least, the tandem repeat structure, but not the
SINE-related sequence, is dispensable for imprinting. The relationship between genomic imprinting and transposon insertion is of
interest because in mammals the paternally expressed imprinted
gene, PEG10, shows similarity to the sushi-ichi retrotransposon.
PEG10 is only found in eutherian mammals, and is not present in
non-mammalian vertebrates that have not evolved a placenta and
genomic imprinting [35].
Due to the absence of evidence on imprinted gene clusters in
flowering plants, it is not yet clear whether a long-distance control
of genomic imprinting occurs. However, a recent report showed
that the DNA methylation status of a 3 -tandem repeat about 2.5 kb
downstream from the PHE1 locus affected the imprinted expression
of the gene [25]. PHE1 encodes a MADS-box transcription factor and,
in Arabidopsis, is a paternally expressed imprinted gene [9]. It was
originally identified as a target gene of the polycomb group protein, MEA [36]. The 3 -tandem repeat of PHE1 is usually methylated
in leaf tissue of wild type plants. However, in methyltransferase1
(met1) mutants, DNA methylation of the 3 -tandem repeat is lost
and expression of the paternal allele is down-regulated. Furthermore, a transgene lacking the 3 -tandem repeat region did not
display imprinted expression of PHE1. Thus, DNA methylation of
the repeat is required for active expression of the paternal PHE1
allele. The authors proposed a hypothesis that DNA methylation
of the 3 -tandem repeat of the maternal allele is erased by DME,
which encodes a DNA glycosylase [18,25]. If this issue were proved,
the epigenetic status of all known imprinted genes in Arabidopsis
might be controlled in the central cell within the female gametophyte by DME. Although the underlying molecular mechanism
is still not clear, the maternal control of imprinted genes in Arabidopsis is reminiscent of the control mechanism of mammalian
imprinted genes. Despite the fact that the number of maternally
and paternally expressed imprinted genes is almost equal in mammals, many of the methylation imprints of ICRs are marked during
female gametogenesis. Only three loci, H19/Igf2, Rasgrf1/A19 and
Dlk1/Gtl2, are known to be methylated in male gametogenesis [37].
3. DNA methylation cycle of imprinted genes in mammals
and one-way control of imprinted genes by DNA
methylation in flowering plants
As the life histories of placental mammals and flowering plants
are very different, it is interesting to understand and compare how
these different groups of organisms control the epigenetic status of their parental genomes. In mammals, the germ line is set
aside during early embryogenesis [38], whereas in plants, male and
female gametophytes form within the floral organs at late stages of
development [39,40]. In addition to this difference in life history,
genomic imprinting is restricted to the endosperm tissue of flowering plants, while imprinted genes are found in both the placenta
and somatic tissues of mammals [6].
During evolution, placental mammals developed a strategy for
the reprogramming of DNA methylation for genomic imprinting in each generation [41] (Fig. 2). In the primordial germ
cells, the DNA methylation imprints marked in the previous
generation are erased by an unknown, but presumably active,
mechanism [42], and de novo DNA methylation imprints are established during gametogenesis. During gametogenesis, the de novo
DNA methyltransferase, DNMT3A, and DNMT3L, which lacks conserved catalytic domain of methyltransferase, play a crucial role
in the establishment of genomic imprinting [43–45]. DNMT3A and
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3
Fig. 1. Control of imprinted genes in Arabidopsis. DNA methylation (asterisks) of imprinted genes, FWA, FIS2 and MEA, is erased by DME in the central cell. In contrast,
the paternal alleles of these maternally expressed imprinted genes retain methylation in the male gametophyte. In the paternally expressed imprinted gene of PHE1, DNA
methylation of the 3 -tandem repeat ensure active expression of the paternal allele, while the maternal allele of PHE1 is silenced by the polycomb complex in the central cell.
After fertilization, the maternally derived alleles of FWA and FIS2 are expressed, while the paternally derived alleles are silenced by DNA methylation. The polycomb complex
represses the paternally derived MEA and maternally derived PHE1 in the endosperm. The depicted outline omits fertilization of the egg cell and embryo as no evidence of
genomic imprinting has yet been found in these tissues.
DNMT3L knock-out mice show disrupted patterns of imprinted
gene expression [43–45]. In contrast, in Arabidopsis, the plant
homologue of the de novo methyltransferase gene, DOMAINREARRANGED-METHYLTRANSFERASE (DRM), has been reported to
be dispensable for genomic imprinting [28,46]. If DNA methylation was erased and re-established in each generation in plants,
then a de novo methyltransferase would be essential for this purpose. Analysis of DNA methylation patterns on the imprinted genes
MEA and FWA in Arabidopsis and ZmFie1 in maize have revealed a
distinct mechanism involving a “one-way” activation of the maternally transmitted allele of these genes [17,18,20,26,27] (Fig. 2).
For maternally expressed imprinted genes, DNA demethylation
of the 5 -promoter region is only observed in the central cell
and endosperm, while paternal alleles retain DNA methylation in
endosperm. In vegetative tissues, both maternal and paternal alleles retain their methylation pattern. Maintenance of methylation
pattern is dependent on METHYLTRANSFERASE1 (MET1), the Arabidopsis homologue of DNMT1. Thus, DNA methylation appears
to be a common epigenetic modification for controlling genomic
imprinting in both plants and mammals, however, the mechanisms that regulate DNA methylation show distinct differences
that reflect the different developmental patterns. Moreover, as
the endosperm is a terminally differentiated tissue and does not
transmit genetic or epigenetic information to the next generation, epigenetic reprogramming is not necessary in this plant
tissue.
4. Mechanism of DNA demethylation of imprinted genes
DNA demethylation is predicted to have a significant role in
the epigenetic programming of imprinted genes in placental mammals and flowering plants. In mammals, methylation imprints
are erased in the primordial germ cells (see above) although the
molecular mechanism is still unclear and controversial. In Arabidopsis, the epigenetic programming of the maternally expressed
imprinted genes, MEA, FWA and FIS2, is established in the central
cell of the female gametophyte by the activity of the DNA glycosylase, DME [8,18,20,26]. DME is a large molecule containing an H1
linker histone domain and a conserved DNA glycosylase domain,
similar to those in a base excision DNA repair protein, and can
excise 5 -methylcytosine in vitro [18]. It is therefore likely that the
base excision DNA repair machinery is involved in the demethylation of imprinted genes. The first step of base excision repair is
removal of a base by DNA glycosylase; this is followed by cleavage of the abasic site by an AP lyase. The resulting nucleotide
gap is filled by a DNA polymerase and completed by DNA ligase [47]. Although DME can catalyze the first two steps of base
excision repair, i.e. can act as a so-called bifunctional DNA glycosylase [18], it is still unclear whether the enzymes for base excision
repair in the remaining steps are involved in DNA demethylation.
In the Xenopus oocyte, it has been shown that Gadd45a (Growth
arrest and DNA damage inducible) can act synergistically with
the repair endonuclease, XPG, to demethylate Oct4 [48]. Thus, a
Please cite this article in press as: Kinoshita T, et al. Genomic imprinting: A balance between antagonistic roles of parental chromosomes. Semin
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Fig. 2. Patterns of DNA methylation of imprinted genes in placental mammals and flowering plants. In mammals, the pattern of DNA methylation marked in the previous
generation (asterisks) is erased in PGCs (primordial germ cells). During gametogenesis, allele specific de novo methylation establishes genomic imprinting. Thus, the DNA
methylation imprints on chromosomes are erased and established in each generation. In plants, the epigenetic asymmetry of parental chromosomes that is essential for
genomic imprinting is only observed in the endosperm. Establishment of genomic imprinting occurs in the central cell by demethylation of methylated imprinted genes
(see text). In contrast, the DNA methylation status of the paternal allele in the male gametophyte and endosperm, and those of the both alleles in vegetative tissues remains
unchanged.
functioning DNA demethylation mechanism through the base excision DNA repair pathway might be conserved in many organisms.
In mammals, MBD4, which contains a methyl cytosine binding
domain and a DNA glycosylase domain, has been implicated in DNA
demethylation via the GT mismatch repair pathway [49]. Deamination of 5-methylcytosine induces a mismatched uracil that may
be recognized by MBD4 or the GT mismatch repair enzyme. Interestingly, the 5-methylcytosine deaminase genes, Aid and Apobec1,
are located in a cluster of pluripotency genes, including Nanog and
PGC7/Stella, and co-expressed with these genes in the oocyte, the
cell type in which genome-wide demethylation is observed [50].
5. Role of genomic imprinting in parthenogenesis
Parthenogenesis, the development of an unfertilized gamete
into an embryo, is usually blocked by genetic mechanisms in placental mammals and flowering plants. One such mechanism was
predicted from the results of nuclear transplantation experiments
[2,3,7]. Formation of gynogenetic and androgenetic embryos by
nuclear transplantation showed that the embryos displayed opposite phenotypes during development, especially in the placenta
[2,3]. The most likely explanation for this opposite phenotype was
that the maternally and paternally inherited genomes played different roles during embryonic development due to differences
in epigenetic modification, such as genomic imprinting. Therefore, successful reproduction requires both maternal and paternal
genomes, which enables the respective parental imprints to complement one another.
This predicted role of genomic imprinting in parthenogenetic
development was confirmed by the birth of a parthenogenetic
mouse, KAGUYA [51,52]. KAGUYA had two sets of chromosomes of
maternal origin. One chromosome set had been genetically manipulated with a large deletion of the differentially methylated domain
and H19 so that the downstream enhancers could activate Igf2
expression. Thus, although KAGUYA has bi-maternal chromosome
sets, epigenetic status of one of the chromosomes sets mimics
that of paternally derived chromosomes and allows completion of
embryonic development and birth.
In flowering plants, genomic imprinting has been suggested to
be a means to prevent asexual reproduction by allowing only successful seed production after fertilization of parental genomes that
have complementary imprinted genes [7]. Since genomic imprinting is restricted to the endosperm tissue of flowering plants, sexual
reproduction is essential to the parental genomes at least in the
endosperm. Indeed, many apomictic species are psuedogamous:
although the embryo develops from an unfertilized egg cell, the
endosperm requires fertilization by the paternal genome [7]. In Arabidopsis, a combination of mutants of imprinted genes and CDKA;1,
a homologue of Cdc2, demonstrated the role of genomic imprinting in preventing asexual development [53]. In the cdka;1 mutant,
a cell cycle defect occurs in the second round of pollen mitosis and
results in the formation of a single sperm pollen. This single sperm
pollen preferentially fertilizes the egg cell and therefore the central
cell is left unfertilized. The embryo develops after a single fertilization event, instead of the double fertilization that usually occurs in
normal plant reproduction, but aborts at an early stage of embryo
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development with only a few rounds of proliferation of the central cell [54]. Strikingly, a combination of cdc2a and mea, fis2 or fie,
which are mutants of the FIS-class complex and show autonomous
endosperm development without fertilization [55,56], overcomes
the seed lethality of the single fertilization described above. One
interpretation is that the maternally expressed imprinted gene
counterbalances the action of the paternal genome. Therefore,
deletion of the maternally expressed imprinted gene allows seed
development without a paternal contribution to the endosperm,
which is related to the predicted role of genomic imprinting to
apomixes.
6. Role of genomic imprinting in reproductive barriers
As described above, a balance between the maternal and paternal contributions, repression and promotion of nutritional flow
to the embryo, is required for post-zygotic development. This
idea may also be applicable to the reproductive barrier between
species in placental mammals and flowering plants. In mammals,
inter-specific crosses between Peromyscus manicuatus (BW) and
Peromyscus polionotus (PO) can produce viable progeny, although
miscarriage of embryos is frequently observed when PO females
are used [57]. When BW females are mated to PO males, abnormal placentas, approximately half-size of the parental species,
and growth-retarded embryos are produced; the reciprocal cross
results in overgrowth of placentas. This parent-of-origin dependent
phenotype in inter-species breeding and the observed phenotype
of loss-of-function of imprinted genes in mouse might explain the
molecular basis of the post-zygotic reproductive barrier between
these rodent species. In the hybrid Peromyscus mice, expression of
many imprinted genes and X-linked loci are mis-regulated [57].
A backcross of the hybrid to the PO parental strain demonstrated
a correlation between Peg3 expression, a paternally expressed
imprinted gene, and placental weight [58]. This correlation is not
conserved in Mus hybrids, however, suggesting that the underlying
molecular mechanisms for the post-zygotic barrier vary [59]. Nevertheless, the mechanism of genomic imprinting is still relevant
when considering experimental hypotheses for the post-zygotic
barrier. Abnormal expression of imprinted genes has also been
found in hybrids between flowering plant species [60]. Interestingly, hybrid seeds of A. thaliana and A. arenosa show increased
viability when a mutation of the paternally expressed imprinted
gene, PHE1, is present [60].
In flowering plants, endosperm breakdown in inter-specific
hybrids has regularly been observed [61–63]. In this phenomenon,
endosperm sizes are affected in a parent-of-origin dependent manner, which is also demonstrated in inter-ploidy crosses [64]. The
endosperm abnormality caused by inter-specific and inter-ploidy
crosses emerges at an early stage of endosperm development. After
fertilization, the central cell undergoes several rounds of mitosis without cytokinesis and forms a syncytium. The syncytium
then cellularizes [65], and the timing of cellularization is often
altered in inter-specific and inter-ploidy crosses [4,66]; this timing alteration can be critical to phase transition during endosperm
development [67]. In general, precocious cellularization results in a
smaller endosperm, while delayed cellularization induces a larger
endosperm. Based on analyses of many inter-specific crosses, several hypotheses have been proposed: “Endosperm balance number”
in Solanum; “Polar nuclei activation” in Avena; and, “Ploidy barrier” in maize [64,68–70]. All of these proposals can be applied to
other plant species. Although the molecular mechanism is still controversial [64,66,71], there is a general agreement that the degree
of interaction of maternally and paternally contributed genomes
determines this phenomenon [64].
5
7. Conclusions
In placental mammals and flowering plants, maternal nutritional flow to the embryo is provided from specialized tissues,
namely the placenta and endosperm [6]. According to the parental
conflict theory, maternally expressed imprinted genes repress
nutritional flow to the embryo, and paternally expressed imprinted
genes promote it [7,72]. Although there are exceptions, many of
the imprinted genes in mammals and plants control development
of the placenta and endosperm. They affect, therefore, nutritional
flow to the embryo. In many studies, it has been shown that
a proper balance between maternal and paternal contributions,
determined by an epigenetic mechanism, is required for successful
reproduction. Hence, mutation in imprinted genes induces abnormal development of placenta and endosperm, and consequently
the embryos abort. This epigenetic mechanism may also be essential for reproductive barriers in placental organisms. Maternal and
paternal contributions usually differ between species. If the regulatory mechanisms, copy number, activity of encoded proteins
or affinity of protein–protein interactions were not equivalent in
their genomic imprinting between these related species, then the
developmental processes of the placenta and endosperm might
be adversely affected. Uncovering the mechanism of genomic
imprinting in different species will provide greater insights into
the molecular frameworks of the reproductive barriers in the placenta and endosperm. Thus, the epigenetic mechanisms that we
have described here might serve as an indicator of compatibility
between species. Although no molecular mechanism was identified, a similar idea was proposed previously by both Nishiyama and
Cooper [62,70].
Acknowledgements
Funding on this topic is provided by a grant from the Ministry
of Agriculture, Forestry and Fisheries of Japan (molecular cloning
and characterization of agronomically important genes of rice,
IPG0017) and by Grant-in-Aid for Scientific Research on Priority
Areas (18075010) from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan.
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