哺乳類の胎盤と胎生機構の進化におけるLTRレトロトランスポゾン由来の遺伝子の関与

誌名誌名 Journal of mammalian ova research = 日本哺乳動物卵子学会誌

ISSNISSN 13417738

著者著者石野, 知子石野, 史敏

巻/号巻/号 30巻1号

掲載ページ掲載ページ p. 16-23

発行年月発行年月 2013年4月

農林水産省 農林水産技術会議事務局筑波産学連携支援センターTsukuba Business-Academia Cooperation Support Center, Agriculture, Forestry and Fisheries Research CouncilSecretariat

J. Mamm. Ova Res. Vol. 30 (1)， 1ι23，2013 16

-Mini Reviewー

The Evolution of the Placenta and Viviparity is Related to LTR Retrotransposon-derived Genes in Mammals

Tomoko Kaneko聞 Ishino1and Fumitoshi Ishino2*

ISchoolofHeαlth Sciences， Tokai University， K，αnagawa 259-1193， Japαn

2 Medical Reseαrch Institute， Tokyo Medicα1 and Dental University， Tokyo 113-8510， J.αpαn

Abstract: The two L TR retrotransposorトderivedgenes

PEG10 and PEG11/RTL1 play essential roles in placental

formation and its maintenance in the current mammalian

developmental system. The former is a theriarトspecific

and the latter is a eutherian-specific gene， suggesting

that once they had been acquired in common ancestors

of the therian and eutherian mammals， respectively， they

have underwent positive selection during the course of

mammalian evolution due to developmental advantages

they conferred陶 Thus，their exaptation had a profound

impact on the evolution of mammalian viviparity as well

as the emergence of the therians and eutherians， the

infraclass and subclass of mammals， respectively. How

the exaptation of PEG10 and PEG11/RTL1 come to take

place in the mammalian lineage? We propose that the

exaptaion mechanism comprises two subsequent steps

The first follows the pattern of nearly neutral theory of

molecular evolution， where the retrotransposons were

neutralized by ONA methylation and genetic drift fixed

them in the population. At the next step， Oarwinian evo-

lution propagated these genes into all the therian and

eutherian population by natural selection‘In the course

of these processes， the placenta， a mammalian司 specific

extraembyonic tissue， may have been of special impoト

tance as a sort of“natural laboratory" for mammalian

evolution.

Key words: L TR retrotransposon-derived genes， Mam-

malian evolution， Exaptation， Placenta， Viviparity

Introduction

Brosius and Gould coined the term “exaptation" to

describe the evolutionary mechanism by which novel

。2013Japanese Society ofOva Research Received: October 3，2012 Accepted: November 14，2012 * To whom corresponding should be addressed. e-mail: fishino.epgn@mri.tmd.ac.jp

genes are produced from other genetic materials that

have different roles in other organisms [1]. A recent com-

prehensive survey of the mammalian genomes revealed

the presence of 12 newly acquired genes that are de-

rived from a sushi-ichi-related LTR retrotransposon in

eutherians and marsupials， the SIRH(sushHchi-related

retrotransposon homologues) [2， 3]， MART(mammalian-

specific retrotransposon transcripts) [4] or SUSHI fami-

lies of genes [5]. We previously demonstrated that the

Peg10(Sirh1) and Peg11/Rtl1(Sirh2) genes play essential

roles in the formation and maintenance of the placenta

in mice [2， 6]. PEG10 and PEG11 are theriarト andeu-

therian-specific genes， respectively， indicating they have

been positively selected due to their advantageous func-

tions in mammalian development once they were exa-

pted as newly acquired genes in therian and eutherian

ancestors， respectively. Thus， PEG10 and PEG11/RTL1

are very good examples of the exaptation as well as mac-

roevolution that takes place in Oarwinian evolution [7， 8].

In this article， we will discuss what Peg10 and Peg11/

Rtl1 tell us about mammalian evolution and how they

were most probably exapted. We would like to present

one likely scenario of how their exaptation occurred in

the course of mammalian evolution and consider the role

of nearly neutral theory of evolution in the functional ad-

aptation of mammals in the Oarwinian theory of evolu-

tion. We emphasize the placenta as a site in which exap-

tation occurred [7， 8].

Two LTR Retrotransposon-derived Genes， PEG10 and PEG11/RTL1， Play an Essential

Role in Mammalian Development

It is well known that parthenogenetic mouse embryos

having two maternally-derived genomes die around day

9.5 because of poor placental development [9-11]. This

suggests paternally expressed gene (s) plays an impor-

Peg10/Sirh1 Formation of spongiotrophoblast

and labyrinth layers

(extraembryonic ectoderm lineage)

Peg11/Sirh2

κaneko-/shino， et al. 17

de

Maintenance of fetal capillaries probably by regulating interaction of trophoblast

and endothelial cells

(extraembryonic mesoderm lineage)

Fig. 1. Essential placental function of PeglO and Pegll/Rtll PeglO is responsible for formation of spongiotrophoblast and labyrinth layers that are essential for placental function in mice. ln the latter， fetal capillaries are bathed in ma-ternal blood. and exchanσe of gases and nutrients occurs between fetal and maternal D

blood. Pegll/Rtll is essential for maintenance ofth巴fetalcapillaries， the feto-maternal interface. la; a labyrinth layer， sp: a spongiotrophoblast layer， gi: a giant trophoblast layer， de: maternal decidua.

tant role in mammalian development and help determine

the fate of the embryos. Mouse proximal chromosome

6 is the only reported imprinted region in which mater-

nal duplication results in early embryonic lethality [12]

In 2001， we identified human PEG10 on human chromo-

some 7q21， an orthologous region of mouse proximal

chromosome 6， as a candidate gene for this parthenoge-

netic death [13]. We finally demonstrated that Peg10 KO

mice exhibit early embryonic lethality with severe placen-

tal defects similar to the parthenogenetic embryos， and

concluded that Peg10 is one of the major imprinted genes

responsible for the early embryonic lethality caused by

the maternal duplication of proximal chromosome 6 [2].

Peg10 KO embryos exhibited development to at most 9.5

days of postcoitum (dpc) and their placenta lacked two

essential functional parts that support embryonic growth

and development， the labyrinth and spongiotrophoblast

layers， almost completely (Fig. 1).

Mouse distal chromosome 12 and its orthologous

human distal chromosome 14 also harbor critically im-

portant imprinted regions in both mouse and human

development [12， 14， 15]. The maternal duplication of

chromosome 12 in mice causes late embryonic/neonatal

lethality associated with growth retardation， and its pa-

ternal duplication causes late embryonic lethality asso-

ciated with growth and morphological abnormalities. In

humans， similar abnormal phenotypes are observed in

patients with maternal and paternal disomies of human

chromosome 14 (upd (14) mat and upd (14) pat)， respec-

tively [16， 17].

Ovine PEG11 was reported in the course of a study on

callipyge mutations responsible for the onset of muscle

hypertrophy related to this imprinted region [18]. ln 2008，

we demonstrated that Peg11/Rt11 KO mice display late

embryonic/neonatal lethality associated with growth re-

tardation due to placental malfunction [6]. In the placenta，

clogging was observed in fetal capil凶riesin the labyrinth

layer and in addition， phagocytosis of the fetal capillary

endothelial cells by surrounding trophoblast cells was

observed in these regions (Fig. 1). The resulting reduc-

tion of blood flow to the embryos seems to be the direct

cause of the evident late embryonic lethality and growth

retardation. We also reported that overexpression of

Peg11/Rt11 causes a different type of alteration of fetal

capillaries that leads to neonatallethality， like the case of

the mice with the paternal duplication of distal chromo-

some 12 [6]. Thus， it is concluded that Peg11/Rt11 is a

one of the major imprinted genes responsible for the phe-

notypes caused by maternal and paternal duplications of

distal chromosome 12. Similarly， lack and overproduction

of PEG11/RTL1 are attributable to the human upd (14)

mat and upd (14) pat phenotypes， respectively [19].

Interestingly， PEG10 and PEG11/RTL1 have a high

degree of homology with a sushi-ichi retrotransposon.

18 J. Mamm. Ova Res. Vol. 30 (1)，2013

PEG10

。決F2

CCHC : RNA binding motif DSG : protease active site YLDD : reverse transcripta舘。AS : RNase highly conserved motif トiHCC: integrase DNA binding mot汗DDE : strongly conserved integrase

Sushi-Ichi (Ty3/gypsy type retrotransposon from Fugυfish)

Pol

PEG11/RTL1

Fig.2. PEGIO and PEGll/RTLl proteins display significant homology to Gag and Pol proteins of a suchi-ichi retrotransposon. Several features ofLTR retrotransposons are retained in PEGlO and PEGIl/RTLl proteins， such as a CCHC RNA binding motif in Gag， a DSG protease active site in Pol and a -1 frameshift mechanism to produce a Gag-Pol fusion protein in the former and the DSG protease active site in the latter. Overall amino acid sequence of both PEGIO and PEGll/RTLl proteins display 20-30% homology to Gag and Pol proteins.

PEG10 has two open reading frames (ORF1 and ORF2)，

which display 20-30% homology to the Gag and Pol

proteins of the sushi-ichi retrotransposon， respectively

[13] (Fig. 2). The PEG10 ORF1 has a CCHC RNA bind-

ing motif in the Gag protein and the PEG10 ORF2 has a

DSG protease active site in the Pol protein. Importantly，

a -1 frameshift mechanism that produces a Ga十Pol

fusion protein unique to the LTR retrotransposons and

retroviruses is also conserved in PEG10， and a PEG10

ORF1-2 fusion protein has been demonstrated in the

placenta [2， 20， 21]. The ovine PEG11 protein was also

reported to show an overall homology with the sushi幽

ichi retrotransposon Gag and Pol proteins [18， 22] (Fig.

2)， and thus PEG11 subsequently came to be called

RTL1(retrotransposon-like 1). The DSG protease active

site is also conserved in the PEG11 protein. AII of these

features together provide strong evidence that PEG10

and PEG11/RTL1 are derived from a sushトichトrelated

LTR retrotransposon.

The Contributions of PEG10 and PEG11/RTL1

to the Evolution of Mammalian Viviparity as

Therian閉 andEutherian-specific Genes， Respectively

revealed that PEG10 is only conserved in the therian

mam円1als.Its presence has been confirmed in more

than 20 eutherian species and 3 marsupial species， in幽

cluding both Australian and South American marsupials，

while no PEG10 orthologue was found in the platypus，

an Australian monotreme species as well as birds， rep同

tiles， amphibians and fish [23] (unpublished data). There欄

fore， it is evident that the insertion of the original PEG10

retrotransposon occurred in a common therian ances・

tor and its exaptation was completed before the spilt of

the marsupials and eutherians [7， 23] (Fig. 3)闘 Boththe

eutherians and marsupials are viviparous mammals us-

ing a placenta in support of embryonic development and

growth during the gestation period. Thus， it may be said，

as far as PEG10's function is concerned， the exaptation

of PEG10 is a critical milestone in the history of mam-

malian viviparity.

In contrast， PEG11/RTL1 is a eutherian-specific gene，

that is， it is conserved in only the eutherians and not the

marsupials (Fig. 3). Interestingly， the eutherians and mar-

supials have different types of placenta， a chorioallan-

toic placenta and choriovitellin placenta (i.e. a yolk sac

placenta)， respectively， and adopt different reproductive

strategies. The marsupials give birth to relatively tiny and

altricial young after a short gestation and the pups keep

A comparative genome analysis of eutherians， mar- developing in the mother's pouch for long time by means

supials， monotremes and non-mammalian vertebrates of lactation， while the eutherians give birth to more ma-

κaneko-Ishino， et al. 19

Chicken ヤoVlparous

叩叩-1315MYA Monotren司esPlatypus

oviparous

186 MYA ~

Marsupiaぬふ¥.，_¥f醐問問畑 Wallaby 期切必 ド，L-̂'''-

静岡欄..160MYA

民xaptationof PEG10

Exaptation of PEG11/RTL1

Eutherians

Mouse

Human

ι型投1lt'‘尊属姐灘縦、

vi.viparous Chorio泌総llineplacen鎗

ζ〉一

，vMparous Chorioallantoic placenta

w Fig.3. Exaptation of PEGlO and PEGll/RTLl in mammalian evolution.

PEGIO is conserved only in the therian mammals and PEGll/RTLl is a eutherian-specific gene Thus， their exaptation must have occurred in ancestors of the therian and eutherian mammals， respectively. MYA: million years ago.

ture， precocial young after a long gestation [24]. It is high四

Iy likely that the placental type was one important factors

in the reproductive strategy followed. It should be noted

that PEG11/RTL1's function is essential for the long ges-

tation that takes place in the eutherians， suggesting that

PEG11/RTL is also a key contributor to the establishment of the eutherian reproductive system [6].

A Possible Scenario for Retrotransposon Exaptation in Mammals

As described， PEG10 and PEG11/RTL1 are instances of exaptation from an L TR retrotransposon as well as

positively selected genes in Darwinian evolution after

their exaptation [7]. It is in accord with evolutionary theo-

ry to think that they propagated in the therian and euthe-

rian population under natural selection due to the devel-opmental advantages they conferred. A question arises:

what happened to the inserted original retrotransposons

in the ancestors' genomes before exaptation? Given that

inserted retrotransposons and retroviruses are totally in-

activated by heavy DNA methylation on their promoter regions in the host mammalian species because they are

harmful， it is highly likely that the inserted retrotranspo量

sons in the common therian ancestor would also have

been repressed by such DNA methylation. In such con-

ditions they would have been neutral genes. According

to the neutral theory of molecular evolution proposed by

Kimura [25]， such neutral genes be transmitted to the next generations and became fixed in a given popula四

tion by chance， a process known as“genetic drift". In the

case of PEG1O， the exaptaion must have occurred within

a period of approximately 26 million years， from the diveト

sification of the therians from the monotremes which took

place 186 million years ago (MYA) to the split of the two

therian groups in 160 MYA (Fig. 3). Because， the amino

acid homology of PEG10 and the sushi-ichi retrotrans-

poson is only 20-30%， the inserted original sushi-ichi

related retrotransposon must have been subjected to a

number of mutations in this period that finally resulted

in the PEG10 prototype that conferred some slight ad-

vantage. Then， Darwin evolution took over and PEG10

became more advantageous by positive selection and，

after that， came to be conserved in all of the therian spe-

cies as a result of purifying selection [4， 22] (Fig. 4).

20 J. Mamm. Ova Res. Vol. 30 (1)，2013

Nearly-neutral evolution

Mutated sushi-ichi retrotransposon

↓M叫 D…討

Placenta harmful

less harmful

Mutated sushi-ichi retrotransposon slightly advantageous

↓… e selection

Darwinian evolution -・::a司Z司 ~'J ・U・il.~'::{C:量". advantageous

↓ 向何M川r吋岬i均 附旬

(negative selection)

.0fTTii当日・m・P-Iril.oI.::{C1ill. advantageous

Fig.4. Two subsequent steps in exaptation from LTR retrotransposons in placenta In this sc巴nario，both nearly neutral evolution and Darwinian evolution contribute to the exaptation mechanism from LTR retrotransposons. We assume that placenta has been providing an unusually suitable place for exaptation due to its lower DNA methylation level， and served as a sort of natural laboratory for mammalian evolution in which a numbers ofnew genes were acquired for certain mammalian-specific traits.

The Placenta as a Laboratory for genes were acquired that were of special importance for

Mammalian Evolution certain mammalian-specific traits [7， 8].

Ohta extended Kimura's neutral theory of molecular Discussion

evolution to her own“nearly neutral" theory， and predict-

ed that less harmful as well as strictly “neutral" mutations Dozens of newly acquired genes have been shown to could become fixed in a population provided the popu- be derived from LTR retrotranspsons and retroviruses in lation size were small enough [26]. It is known that the mammals. As described in this article， the SIRH family of

DNA methylation levels in extraembryonic tissues， such genes comprises 12 genes， and another LTR retrotrans-as the yolk sac and placenta， are lower than those in oth- poson-derived gene family， the PNMA(paraneoplastic

er embryonic and adult tissues， so the retrotransposons Ma antigen) family， comprises 19 and 15 genes in hu-and retroviruses in these tissues are not completely re- mans and mice， respectively [27， 28 and unpublished pressed. In this situation， the integrated retrotransposons data]. The SASPase gene is a single mammalian-spe-

would be less harmful in terms of leaky expression (Fig. cific gene encoding skin aspartic protease (SASPase)，

4). Importantly， placental c創Iswould have retained the which is known to be a retroviral-like aspartic protease function of retrotransposon-derived genes from the time that plays a key role in determining the texture of skin by their integration and benefit when the function conferred modulating the degree of hydration via the processing of

some slight advantage. At this point， a swift transition profilaggrin [29-31]. The SCAN-family is not a mamma-from the state of nearly neutral evolution to that of Dar- lian-specific gene family， because its ancestral form ex-winian evolution would take place. Thus， we assume that ists in non-mammalian vertebrates， but its expansion has

the placenta was an unusually suitable site for exapta- been confirmed in the eutherians. Approximately 60 and tion， or， in other words， it served as a sort of naturallabo- 40 genes are known in humans and mice， respectively，

ratory for mammalian evolution in which a number of new and some of them are involved， as transcription factors，

in development and differentiation [28]. The SYNCY7二

YIN genes were exapted independently in many euthe-

rian species and are derived from retroviral Env genes

[32-34]. We propose that the placenta has been a site

of retrotransposon exaptation during the course of mam闇

malian evolution. which is consistent with the fact that

Peg10 and Peg11/RtI1， as well as the retrovirus-derived

Syncytin A and B genes [2， 6， 35， 36]， play essential

roles in the normal， healthy placenta [7]. However， this

does not necessarily mean that independent exaptation

events have happened as for each occurrence of these

genes. Some might have been produced by the duplica-

tion of a single originally exapted gene， such as in the

case of the SCAN family genes. Approximately 8% of the

human genome is composed of some 450，000 copies

of LTR retrotransposons and endogenous retroviruses

(ERVs)， although thus far none have been shown to have

transposable activity. Therefore， we can say that ret-

rotransposon exaptation is evidently quite a rare event，

but once it takes place， its impact is enormous. PEG10/

SIRH1 is common to both the marsupials and eutherians，

while PEG11/SIRH2 and SIRH3-11 are only found in the

eutherians， and SIRH12 was derived from a marsupial-

specific retrotransposition event [13]. Therefore， the eu同

therians and marsupials have completely different sets

of SIH尺genes，except for PEG10. The same is also true

for the PNMA genes: most are eutherian-specific and a

few are marsupiaトspecific(in preparation). Therefore，

the functions of other SIRH genes and PNMA genes are

of special interest to elucidate mammalian evolution. It

is possible that each SIRH and PNMA gene plays some

mammalian-specific functional role in gestation， delivery

and maternal nursing behavior， including lactation， thus

contributing to the establishment and the diversification

of the marsupial and eutherian reproductive systems.

It is highly likely that DNA methylation played an es-

sential role in the exaptation of retrotransposons in the

evolution of the therian mammals. We assume that the

evidence indicates that nearly neutral evolution played

an essential background role in the exaptation mecha“

nism by both inactivating and neutralizing integrated ret-

rot旧 nsposons.Neutral evolution is widely accepted to

play an important role in the molecular evolution that is

related to changes at the DNA level. However， its contrト

bution to evolutionary changes at morphological， func-

tional and behaviorallevels is still under debate. It seems

logical to think that the exaptation mechanism comprises

two subsequent steps: the first step is in accord with the

processes of nearly neutral evolution， while the second

step depends upon natural selection. Therefore， it ap-

pears there is good evidence that nearly neutral evo-

Kaneko-Ishino， et a/. 21

lution makes a contribution to phenotypic (functional)

changes via the exaptation mechanism as well as by the

diversification of new genes occurring after gene dupli-

cation originally proposed by Kimura [37]

How did the mammalian viviparous reproductive sys-

tem originally start using the retrotransposon司 derived

PEG10 gene? If the viviparous reproductive system in四

deed first happened in a single individual， it is very dif-

ficult to imagine that such an individual would survive and

propagate offspring. Kimura first advance the notion that

the neutral theory of molecular evolution helped explain

how new species originated from a population subset

[37]. Because preadaptive mutations were already dis-

tributed， albeit in a neutral manner， adaptive functions

could emerge in such a group at the same time when the

selective pressures came to be changed by the inhabita-

tion of a new environment. In this regards， it might be

useful to say that the neutral evolution process acts as a

“capacitor" for evolutionary changes at the morphologト

cal， functional and behavioral levels [38， 39]

Acknowledgements

We thank all the collaborators and laboratory mem-

bers， especially Ryuichi Ono， Yoich Sekita and Shun-

suke Suzuki for analyzing Peg10 and Peg11 KO mice

and marsupial PEG10， respectively. The work has long

been supported by a number of grants， Grants-in・Aidfor

Scientific Research (S) from the Ministry of Education， Culture， Sports， Science， and Technology (MEXT) of Ja-

pan (FI)， Funding Program for Next Generation World幽

Leading Researchers (NEXT Program)(TK-I) and Bilat-

eral Program on Joint Research Project (FI)， Creative

Science Research (FI and TK-りfromthe Japan Society

for the Promotion of Science (JSPS)， Asahi Glass Foun-

dation (TK-I)， The Mitsubishi Foundation and the Uehara

Memorial Foundation (FI).

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46 英文論文和文要 約

匪の着床と遺伝子発現の変化.・・・…・…・・・・・…・…・・・・・…・・・・…・・・・司・・開・....・ H ・-…..…・・…・・・・・・・・・開開・…・・..........2-10今川和彦 1 安田二朗 2 小林剛 3，4・宮沢孝幸 3 1東京大学大学院農学生命科学研究科，文京区 干 113-8657，

2長崎大学熱帯医学研究所，長崎市 干 852-8523，3京都大学ウイルス研究所，京都市 〒 606-8507，

4現所属:大阪大学微生物病研究所・感染症国際研究センター，吹田市 〒 565同 0871

日南乳(真獣)類は，次世代を子宮内で育てるという生殖戦略をとっ

た.このことは受精卵一個一個の生存率を格段に増すことになった

が，遺伝的に異なる胎仔を体内に共存させることから，新たな問題に直面することにもなった.胎仔と母親の間に存在するのが胎盤で

あり，その胎仔側の構成部分が栄養膜(卜口ホブラスト)細胞であるー

そして，受精卵.Jff盤胞のトロホブラスト細胞が最初に母親の子宮内膜細胞に直面するのが着床である かつて，晴乳動物の着床過程

は動物種によって異なると考えられてきた ところが，着床過程で

起きている接着，浸潤や細胞分化などの様々な現象に関わっている

ホルモン，サイトカイン，タンパク質分解酵素，細胞外基質，細胞

接着因子や細胞分化に関わる転写因子などの遺伝子群を解析すればするほど，それらの遺伝子群の種類と発現動態にはそれほどの差が

ないことが分かつてきたー最近では，着床から胎盤形成にかけて上

皮問葉系転換 (EMT)，関連遺伝子群のエピジヱネテック制御や内在性レト口ウイルス (ERV)の存在とその機能などが関わっている

ことが明らかになってきた このことは，いままでの要因に加えて，

EMT，工ピジェネテック制御や ERVを検証し，これまでの知見と合わせ総合的に個々の現象を解析するだけではなく，一連の現象を

再構築する・できる実験系の開発の必要性を示唆している.そのこ

とがヒ卜や家畜動物の生殖機構の理解を深め，着床から胎盤形成過

程を明らかにしていくだけではなく，その改善へ向けての臨床応用も可能にしていくに違いない

キーワード着床，日甫乳動物，遺伝子発現，上皮間葉系転換 (EMT)，内在性レトロウイルス (ERV)

胎盤形成のエピジェネティクス....・ H ・....・ H ・-…………....・ H ・....…・圃・ H ・H ・....……・…....・ H ・....・H ・...11-15

久 須 美 真 紀 1，2・秦健一郎 1 1独立行政法人国立成育医療研究センター研究所周産期病態研究部，世田谷区

〒 157-8535，2東京大学医学部産婦人科，文京区 〒 113四 0033

エピジェネティックな遺伝子発現制御は，細胞や組織分化に必須の機構である日甫乳類の正常な胎盤形成には，ゲノムインプリンティ

ングが必須であることが明らかになっており，同現象は DNAのメ

チル化によって制御されている. DNAメチル化に加え，ヒストン

の修飾やノンコーデインク RNAなども，胎盤形成に関与しているーヒト疾患との関連では，最近，胎児発育不全症例や妊娠高血圧症候

群と工ビジ、ェネティックな異常との関連も示唆されているーこれら，

発生に関わるエピジェネティクスの研究は，新たな疾患概念の提唱

や，新たな治療法の開発へと展開する事が期待される.

キーワード.エピジェネティクス， DNAメチル化，ヒストンメチ

ル化，ノンコーディング RNA，胎児発育不全，妊娠高血圧症候群

晴乳類の胎盤と胎生機構の進化における LTRレトロトランスポゾン由来の遺伝子の関与.........16-23

金児一石野知子・石野史敏 東京医科歯科大学難治疾患研究所，干 113-8510 文京区

PEG10， PEG11/RTL 1は胎盤形成に必須の機能を果たす遺伝子である.どちらも LTRレトロトランスポゾンに由来しており，

PEG10は胎生の晴乳類(有袋類と真獣類)， PEG11/RTL1は真獣類にのみ保存されている.すなわちこれらの遺伝子はレ卜口トランス

ポゾンが祖先のゲノムに挿入後，内在遺伝子化し，自然選択を受けたものであることが、分かる 遺伝子機能を考えあわせると，これら

の遭伝子獲得が

真獣類というそれぞれ日晴甫李乳L類の亜綱，下綱の形成に重要な寄与をは

たしたことも確かであろう. LTRレト口トランスポゾンが内在遺伝

子化するイグザプテーション機構は， 1ほぼ中立説jに従うプロセスと自然選択による「ダーウィン進化jの2段階のステップから構成されると考えられる.また イグザプテーションの起きる場所と

して， DNAメチル化レベルが比較的低い胎盤は好条件下にある目「胎

盤は日甫乳類進化の実験場として機能した」という仮説を提唱したい.

キーワード:LTRレトロトランスポソン由来の遺伝子群，日南乳類の

進化，イグザプテーション，胎盤，胎生

卵巣および排卵後の卵子，卵丘細胞での Sirtuin遺 伝 子 発 現の 母 性工イジングへの影響…… …24-29

岡本直樹・河村和弘・河村七美・西島千絵・石塚文平・鈴木 直・平田和明

聖マリアンナ医科大学，川崎市干 216-8512

SirtuinはNAD+依存性脱アセチル化酵素familyで agingや細胞代謝，細胞や組織に対する酸化ダメージを制御すると考えられて

いる.卵巣の agingはミ卜コンドリア機能不全 agingに伴う活性

酸素種の蓄積による DNAダメージなどの影響で，質の低下した卵子を増加させる，我々は卵巣および卵子，卵E細胞における Sirtuin

遺伝子ファミリー (Sirt1-7) の発現を， リアルタイム PCRを用い

て調べた卵巣において，各 Sirtuin遺伝子の発現が確認され，中でも Sirt2遺伝子が高発現していた. youngとagedマウスの比較

検討では，卵子における Sirtuins遺伝子発現に変化はなかった.一

方で， agedマウスの卵丘細胞で，Sirt2および Sirt6の遺伝子発現

がyoungに比べ減少していた これらの結果は， agedマウスにおける卵子の質の低下と卵丘細胞における Sirt2および Sirt6遺伝子発

現が関与している可能性を示した.卵子および卵丘細胞における，

これら Sirtuin遺伝子の更なる機能解析は，卵子の antトagingに新

たな strategyを示すことができるかもしれない.

キーワード:サーチュイン，エイジンク，卵巣，卵丘細胞，卵子