孫博淵, 涂劍波, 李英, 楊明耀

四川農(nóng)業(yè)大學動物遺傳育種研究所, 成都611130

基因及其順式調(diào)控元件在動物表型進化中的作用

孫博淵, 涂劍波, 李英, 楊明耀

四川農(nóng)業(yè)大學動物遺傳育種研究所, 成都611130

順式調(diào)控假說是當前進化發(fā)育生物學中重要的理論之一, 該假說認為順式調(diào)控元件的進化是調(diào)控外表性狀進化的主要遺傳機制。然而越來越多的實驗結(jié)果表明, 僅靠順式調(diào)控假說遠不足以解釋復雜的進化發(fā)育過程, 其他因素也會導致表型的進化, 如：與順式調(diào)控元件相聯(lián)基因的蛋白序列改變; 基因及染色體組復制; 蛋白結(jié)構(gòu)域與順式調(diào)控元件的靈活性等。文章回顧了近年來順式調(diào)控元件以及與順式調(diào)控元件相聯(lián)基因的進化發(fā)育研究, 探討了進化發(fā)育生物學研究的新方法與新思路。

進化發(fā)育生物學; 順式調(diào)控元件; 基因; 外表性狀

成年動物外表形態(tài)的形成是通過一系列發(fā)育基因在胚胎中的表達而實現(xiàn)的,這些基因在時間和空間上精確且有差異的表達, 指導胚胎發(fā)育成形態(tài)各異的個體。進化發(fā)育生物學(Evolutionary developmental biology, 簡稱evo-devo)是進化生物學、發(fā)育生物學以及遺傳學相結(jié)合的交叉新學科[1,2], 旨在探討生物進化過程中基因及其調(diào)控的變化是怎樣通過發(fā)育過程而塑造出特殊的形態(tài)結(jié)構(gòu)。由于發(fā)育基因在時空表達的多樣性通常是被編碼基因附近的多種多樣組織特異性的順式調(diào)控元件(cis-regulatory element, CRE)所調(diào)控, 因此通常認為順式調(diào)控元件的進化才是調(diào)控外表性狀進化的主要遺傳機制, 即順式調(diào)控假說[3～5]。

CRE是能夠影響與之相聯(lián)的目的基因表達的一段DNA序列, 包括啟動子、增強子、沉默子等。一個CRE能夠調(diào)控多個基因的表達, 而一個基因也可被多個CREs調(diào)控。CRE通過其上的轉(zhuǎn)錄因子結(jié)合位點(Transcription factor binding site, TFBS)招募轉(zhuǎn)錄因子, 從而決定基因在何時、何處表達以及表達量的多少[6,7]。因此, CRE在進化中可以增加或減少蛋白結(jié)合位點, 重構(gòu)轉(zhuǎn)錄調(diào)控網(wǎng)絡, 導致發(fā)育相關(guān)的多功能基因在表達時發(fā)生變化, 從而調(diào)控生物的生理功能和外表性狀[3,5,8,9]。CRE的研究對于了解基因表達的調(diào)控機制具有重要意義。

盡管順式調(diào)控假說認為CRE才是造成物種形態(tài)差異的主要原因, 但CRE是如何調(diào)控基因表達？尤其是CRE的進化又是如何影響物種形態(tài)差異？這些問題仍然尚未解決。本綜述回顧了近年來圍繞evo-devo的研究, 討論了在該領(lǐng)域探索中遇到的矛盾及為了解決矛盾而產(chǎn)生的新方法與新思路, 重新思考CRE及其相聯(lián)基因在evo-devo中的作用。

1 順式調(diào)控元件的進化發(fā)育研究

CRE及其在發(fā)育功能上的進化一直是evo-devo研究的熱點。研究CRE的功能通常是通過調(diào)控元件分析(Enhancer assay)來實現(xiàn)的。這是一種將目的CRE與報告基因相連, 在胚胎中觀察報告基因在時空的表達模式, 從而研究CRE功能的方法[10,11]。進化發(fā)育生物學家通過將多個物種的同源CRE在同一模式生物胚胎中表達, 以研究CRE的進化。隨著越來越多物種的基因組被測定, 人們發(fā)現(xiàn)各個物種基因組中都含有一些保守的非編碼序列, 按其序列同源性分為非編碼保守序列(Conserved non-coding elements, CNEs)、超保守元件(Ultra conserved elements, UCEs)以及非保守元件等[12～14]。這些非編碼元件有許多是作為CRE來發(fā)揮作用的。

1.1 保守元件的功能研究

過去對于一些重要的發(fā)育基因及其調(diào)控元件的研究表明, 這些基因的編碼區(qū)非常保守, 與其相鄰的調(diào)控元件也大多為保守元件, 能夠在發(fā)育過程中發(fā)揮較為保守的功能[15,16]。因此通常認為保守元件能夠作為CRE調(diào)控基因表達, 并具有相對保守的功能。如Clarke等[17]測試了在脊椎動物與兩側(cè)對稱動物間均保守的 Bicore1與 Bicore2, 發(fā)現(xiàn)人類(Homo sapiens)、斑馬魚(Danio rerio)、海膽(Strongylocentrotus purpuratus)或者蜱(Amblyomma americanum)的 Bicore1/2均可以在斑馬魚胚胎的相同部位表達; Pauls等[18]發(fā)現(xiàn)有顎脊椎動物中 Sox21(SRY-box containing gene 21)附近的保守元件能夠作為順式調(diào)控元件, 在雞(Gallus gallus)與斑馬魚中均能調(diào)控晶狀體的發(fā)育。Woolfe等[19]鑒定了超過 1400個在人類與河豚(Takifugu rubripes)中均保守的CNEs, 并選取了sox21、pax6 (paired box 6)、hlxb9 (homeo box HB9)與shh (sonic hedgehog)周圍的25個CNEs在斑馬魚上進行調(diào)控元件分析, 發(fā)現(xiàn)超過 90%的河豚CNEs在斑馬魚胚胎發(fā)育中期具有 CRE功能, 且一些CNEs還具有保守的功能。2013年最新的研究發(fā)現(xiàn), 一個保守的CNE能夠作為CRE調(diào)控雌性黑腹果蠅(Drosophila melanogaster)的色素沉積。這一元件上的細小改變導致了不同種的雌果蠅條紋與色斑的差異[20]。這解釋了CNE在調(diào)控外表性狀中的作用, 以及物種間通過CNE形成外表性狀差異的可能的機制。

然而, 也有一些研究發(fā)現(xiàn)保守CRE的功能可能并不像其序列那樣保守。Punnamoottil等[21]通過調(diào)控元件分析, 在斑馬魚胚胎中測試了多個在人類與斑馬魚間保守的Hox4調(diào)控元件, 結(jié)果卻發(fā)現(xiàn)一些人類的同源序列雖具有CRE功能, 但它們在斑馬魚胚胎中的表達卻不具有組織特異性。Ritter等[22]的實驗則更為全面：首先將之前已經(jīng)在小鼠胚胎中測試過的875個人類CNEs與已經(jīng)在斑馬魚胚胎中表達過的151個斑馬魚CNEs進行比對, 從中發(fā)現(xiàn)了41個人類與斑馬魚同源的 CNEs; 然而, 當將人類同源CNEs在小鼠胚胎中的表達模式(HM)與斑馬魚同源CNEs在斑馬魚胚胎中的表達模式(ZZ)進行比較時,發(fā)現(xiàn)只有少數(shù)(約30%)同源CNEs能夠在斑馬魚及小鼠胚胎中具有保守的活性(表 1, 主要內(nèi)容來源于Ritter等[22]); 又將41個人類同源CNEs在斑馬魚胚胎中進行了測試(HZ), 發(fā)現(xiàn)只有4個hCNEs能夠顯示出與斑馬魚CNEs相似的表達模式。盡管這種CRE序列的保守性與其功能間的差異可能由于CNE側(cè)翼序列的影響[23], 但也從側(cè)面說明單純通過傳統(tǒng)的序列比對與進化分析來推測CRE功能上的進化可能并不準確。因此, Ritter等[22]又提出通過鑒定CRE上轉(zhuǎn)錄因子結(jié)合位點的保守性, 能夠更為準確地推測CRE的功能。同時, 在果蠅上進行的CRE研究, 也說明高度保守元件中獲得或丟失轉(zhuǎn)錄因子結(jié)合位點會對CRE的功能產(chǎn)生很大的影響[24～26]。

1.2 非保守元件的功能研究

與在CNE中的研究類似, 有關(guān)非保守元件的功能進化研究也得到了不同的結(jié)果。通常認為在進化上序列越保守的元件, 它們越可能作為CRE而具有一定的功能, 甚至是保守的功能[27]。然而Fisher等[28]在研究人類與斑馬魚的RET(receptor tyrosine kinase)位點的非編碼元件時發(fā)現(xiàn), 一些元件盡管沒有序列上的保守性, 但仍然可以作為CRE啟動相似的表達模式。有意思的是, Fisher與同事也推測這種與序列保守性相矛盾的結(jié)果是由于側(cè)翼序列發(fā)生改變而CRE上的轉(zhuǎn)錄因子結(jié)合位點仍然保守導致的。這可能是由于轉(zhuǎn)錄因子結(jié)合位點往往只有幾個保守堿基,當它們埋藏在大段的非保守側(cè)翼序列中時很難通過序列比對進行鑒定。

表1 人類與斑馬魚同源CNEs的表達模式比較[22]

Takahashi等[29]于 1999年就發(fā)現(xiàn)玻璃海鞘(Ciona intestinalis)與真海鞘(Halocynthia roretzi)中調(diào)控brachyury基因表達的CREs不具有序列上的相似性, 卻能夠產(chǎn)生相似的表達模式。甚至這兩個CRE的轉(zhuǎn)錄因子結(jié)合位點也不相同：C.intestinalis CRE 除了在激活區(qū)域具有 SuH結(jié)合位點, 還有一個介導負調(diào)控的額外區(qū)域; 而H.roretzi CRE的激活區(qū)域則是一個 T-box結(jié)合位點, 并且沒有抑制作用的負調(diào)控區(qū)域。另外, 一項對于球狀海膽(Strongylocentrotus purpuratus)中基因 spec調(diào)控元件 RSR (Repeat-spacer-repeat)的研究也顯示, 盡管RSR在進化過程中獲得了4個新的不同的轉(zhuǎn)錄因子結(jié)合位點,但它們調(diào)控的基因表達模式依然十分保守[30]。關(guān)于轉(zhuǎn)錄因子結(jié)合位點保守性與CRE功能間矛盾的研究結(jié)果雖然并不多, 但上述研究提示單純通過比較轉(zhuǎn)錄因子結(jié)合位點的保守性推測CRE的功能是不完全可靠的。

1.3 順式調(diào)控元件進化研究的新思路

無論從CRE序列本身, 還是從轉(zhuǎn)錄因子結(jié)合位點入手均無法準確地推測CRE的進化及功能。因此對于CRE進化的研究, 亟需一些新的思路。

首先對于 CRE的定義, 通常認為 CRE大約在100～1000 bp之間[31], 雖然之前有研究發(fā)現(xiàn)了富含TFBS與DNaseⅠ超敏位點的大型調(diào)控區(qū)域, 如IgH增強子(約20 kb)、Th細胞受體(約11.5 kb)、β-球蛋白增強子(約 16 kb)等[32～37], 卻沒有引起足夠的重視。直到2013年, 通過新的算法截取CRE, 并比較轉(zhuǎn)錄因子的富集程度發(fā)現(xiàn)了超級增強子(Superenhancers), 才重新定義了人們對于 CRE大小的認識。幾乎所有有關(guān)細胞特性的重要基因都需要超級增強子調(diào)控。超級增強子在大小上遠大于常規(guī)的CRE, 通常為幾十 kb, 同時超級增強子上富集了遠多于常規(guī)調(diào)控元件的重要轉(zhuǎn)錄因子。超級增強子還與癌癥的發(fā)生密切相關(guān)[38,39]。如果超級增強子確實對細胞的特性具有重要作用, 那么超級增強子的進化必然會影響物種的形態(tài)發(fā)育。這也許能夠為之前CRE進化研究的矛盾提供一個合理的解釋與可行的研究方向。關(guān)于CRE的進化研究總是局限于常規(guī)的CRE大小, 而遺傳工具包基因恰恰有可能受到的是更大范圍的超級增強子的調(diào)控, 那么僅僅對于小范圍CRE的序列變化進行研究顯然是不準確的, 因為一個超級增強子可能包含多個之前認為的CNE。如果能夠?qū)Ω蠓秶鷥?nèi)的超級增強子進行進化分析,或許能夠獲得更準確的結(jié)果。

其次對于 CRE的鑒定, 過去認為, 當一個細胞完全分化后, 其中維持其細胞特性的CRE將會完全暴露, 以維持該種細胞的特性。然而Ostuni等[40]在2013年發(fā)現(xiàn)已分化的巨噬細胞能夠?qū)Σ煌耐饨绱碳ぎa(chǎn)生反應, 使得一些本沒有增強子活性的“隱蔽的增強子”(Latent enhancer)暴露在染色體上, 從而使巨噬細胞分化為各種亞型以面對不同的環(huán)境。這一發(fā)現(xiàn)不僅說明了在進行 ChIP-seq[41～43]與DNaseⅠ超敏位點[44～47]對 CREs進行鑒定時需要考慮不同刺激對于CREs鑒定的影響, 同時也為evo-devo的研究提供了新的方向。眾所周知, 胚胎的發(fā)育會受到外界環(huán)境的影響[48,49], 然而胚胎應答外界刺激的機制并不清楚。將一個物種的CRE在另一個生殖環(huán)境迥異的物種胚胎中進行表達, 很有可能會導致其活化位點發(fā)生改變, 從而產(chǎn)生矛盾的表達模式。隱蔽增強子的發(fā)現(xiàn)為胚胎應答外界刺激提供了一種新的可能性, 有待該領(lǐng)域的學者進行更深入的研究。

最后是CRE進化標記的選擇。傳統(tǒng)的進化學研究總是以DNA或蛋白質(zhì)序列的改變?yōu)闃擞? 進而研究其結(jié)構(gòu)和功能的變化。然而現(xiàn)在CRE的鑒定是取決于組蛋白上特定的修飾, 因此決定CRE功能的因素除了DNA序列外, 很大程度取決于其上的組蛋白修飾。通過比較人類、恒河猴(Macaca mulatta)以及小鼠(Mus musculus)中影響胚胎四肢發(fā)育的CRE組蛋白 H3K27Ac水平發(fā)現(xiàn), 人類與恒河猴相比, 有13%的啟動子和 11%的增強子獲得了活性, 這些增加的CRE可能是影響人類四肢進化的重要因素[50,51]。這說明組蛋白修飾與表觀遺傳對于CRE功能的進化起著關(guān)鍵性的作用。

2 與順式調(diào)控元件相聯(lián)基因的進化

影響形態(tài)發(fā)育的因素除了CRE的改變以外, 還包括諸多的方面, 例如編碼區(qū)的突變、基因乃至染色體組的復制等, 這些變化都可能對形態(tài)多樣性產(chǎn)生影響[3,52]。但是, 由于順式調(diào)控假說的提出, 大多數(shù)進化發(fā)育學研究都集中在CRE的進化上。這些研究不但證明了 CRE在形態(tài)差異上不可或缺的作用,如scute基因上的DCE增強子的進化導致了不同果蠅后背中部粗剛毛數(shù)量的差異[53]、yellow基因上的調(diào)控元件變化使得雄性 biarmipes果蠅翅膀上帶有斑點[54], 而且在一定程度上解釋了CRE進化的機制,如三刺魚(Gasterosteus aculeatus)背部的棘刺是為了防御大型捕食者, 而這種棘刺的發(fā)育需要大量的鈣質(zhì)。淡水三刺魚背部棘刺數(shù)量比咸水三刺魚有所減少是由于 pitx1(paired-like homeodomain transcription factor 1)鄰近的CRE改變引起的[55,56], 這種進化是由于最近一次冰川消退(約 1～2萬年前)這些魚的祖先有一部分留在了當時形成的湖泊中, 隨著食物中鈣質(zhì)以及大型捕食者的減少所產(chǎn)生的適應性進化[55,57～59]。但是隨著進化發(fā)育生物學的發(fā)展, 越來越多的研究結(jié)果說明形態(tài)上的進化是一個更為復雜的過程。

2.1 蛋白編碼區(qū)的進化

在順式調(diào)控假說出現(xiàn)之前, 人們通常認為蛋白質(zhì)序列的改變是導致形態(tài)多樣性以及進化的主要原因, 這些改變能夠使蛋白質(zhì)結(jié)構(gòu)發(fā)生變化, 進而產(chǎn)生新的功能[60～62]。然而隨后人們發(fā)現(xiàn), 即使經(jīng)過了10億年的進化, 許多動物的蛋白序列卻進化的十分緩慢, 依然行使著保守的功能。最為著名的兩個實驗是：調(diào)控小鼠眼發(fā)育的 Pax-6能夠在果蠅中調(diào)控昆蟲復眼的發(fā)育, 與果蠅自身的 Pax-6功能一致[63];水螅中的 achaete-scute同源基因能夠誘導果蠅神經(jīng)系統(tǒng)的發(fā)育[64]?；陧樖秸{(diào)控假說的evo-devo認為這種極端的功能保守可能是由于這些蛋白在進化上受到了其功能上的約束。由于蛋白質(zhì)通常具有多效性, 蛋白質(zhì)序列的改變常常會影響到多條通路, 因此為了維持某些重要的功能, 蛋白質(zhì)序列在進化上受到了極大的約束。而順式調(diào)控元件只在蛋白質(zhì)的時空及表達量水平上進行調(diào)控, 受到的選擇約束較小, 更可能發(fā)生突變, 進而促使進化[2,3]。

但是不少研究卻發(fā)現(xiàn), 蛋白質(zhì)序列的改變在進化與形態(tài)多樣性上依然扮演著十分重要的角色。靈長類苦味受體TAS2R16(taste receptor type 2 member 16)上的突變, 改變了靈長類對于苦味化學物質(zhì)的敏感程度, 進而影響了食性[65]; Hemoglobin-B與Duffy抗原基因的突變能夠分別抵抗由 P. falciparum 與 P. vivax瘧原蟲引起的瘧疾[66]; 乳糖酶上的突變能夠使一些成年人消化乳制品中的乳糖[67]。這些被稱為“生理性”[4]的變化, 將最終引起解剖學上的協(xié)同進化[68]?，F(xiàn)代人類EDAR(Ectodysplasin A receptor)具有遺傳多樣性[69,70], EDARV370A(EDAR variant 370A)是產(chǎn)生較粗頭發(fā)與鏟型門牙等亞洲人特征的重要因素[71,72], EDARV370A 可能受到了寒冷干燥環(huán)境的選擇[73]。因此, 在2013年科研人員通過生物信息學手段發(fā)現(xiàn) EDARV370A起源于中國中部, 并將EDARV370A在小鼠模型中表達。研究結(jié)果表明, 表達EDARV370A的轉(zhuǎn)基因小鼠顯示出強烈的中國漢族人特征, 包括較粗的毛發(fā)以及更發(fā)達的乳腺與外泌汗腺[74]。這個結(jié)果強烈的證明了蛋白質(zhì)序列受到自然選擇而發(fā)生進化, 改變了生物的表型。同時也說明盡管 evo-devo認為 CREs在進化上更具優(yōu)勢,但蛋白質(zhì)序列受到的自然選擇還是遠遠超出了人們的預計。

2.2 工具包基因的復制

自20世紀70年代Ohno提出了進化上的基因復制假說以來, 基因復制在進化上的地位就一直飽受爭議。Ohno認為基因復制是物種進化的重要因素,為新基因的出現(xiàn)乃至進化的發(fā)生提供了不可或缺的材料。他認為基因復制后的旁系同源基因?qū)陔S后的進化過程中逐漸獲得新的功能, 從而使物種進化[75]。而Carroll[2,3,5]則認為基因復制所產(chǎn)生的旁系同源基因總是具有相似的功能。同時, 在一些重要的遺傳工具包(Genetic toolkit)基因的進化過程中,工具包中的旁系同源基因也極少獲得新功能。因此,在發(fā)育過程中新功能與新形態(tài)的產(chǎn)生主要依賴于順式調(diào)控元件的進化。如Hox同源框(homeobox), 與原始的 Hox家族相比, 在節(jié)肢動物與脊索動物中均沒有基因復制事件, 甚至還有不同程度基因丟失(圖1),顯示基因復制對于新功能的產(chǎn)生與形態(tài)的多樣性并不是必需的。

盡管工具包基因復制在形態(tài)進化上的作用仍有爭議, 但是基因復制的另一種形式——染色體組復制, 隨著越來越多物種的基因組被測定, 現(xiàn)在被認為對于脊椎動物的起源具有關(guān)鍵性的作用[76～80]。Ohno認為在脊椎動物出現(xiàn)早期, 染色體組曾經(jīng)經(jīng)歷了兩次完整的復制過程, 為脊椎動物的出現(xiàn)提供了重要的物質(zhì)基礎(chǔ), 被稱為2R假說(2 rounds of whole genome duplication, 2R WGD)[75,81]。仍以Hox同源框為例, 節(jié)肢動物只有一個 Hox基因座, 而經(jīng)過兩次全染色體組復制之后, 脊索動物的 Hox基因座增加到4個(圖1)。最近, 對于這些旁系同源Hox的研究則說明這種基因復制的重要性。Soshnikova等[82]采用全基因座敲除的方法, 分別在轉(zhuǎn)基因小鼠上敲除了 HoxA與 HoxB基因座, 發(fā)現(xiàn)盡管旁系同源的Hox基因在表達上有很多相似的地方, 但是如果完全敲除整個旁系同源基因座, 則會對胚胎的發(fā)育產(chǎn)生很大的影響。而Goode等[23]的研究將CNE與WGD聯(lián)系在一起, 發(fā)現(xiàn)由WGD得到的大量CNE通過其側(cè)翼序列的改變而獲得了新的功能, 繼而使復制的旁系同源基因得以在進化中保留。這說明在脊椎動物的起源上, 染色體組的大規(guī)模復制對于形成脊椎動物特有的形態(tài)特征具有關(guān)鍵性的作用。

2.3 蛋白結(jié)構(gòu)域與順式調(diào)控元件的靈活性

雖然 2R假說證明了基因復制在進化中的重要地位, 為新功能的產(chǎn)生提供了充足的遺傳基礎(chǔ)[75]。但是它無法解釋眾多由基因復制產(chǎn)生的同源基因是如何進化, 并在進化中獲得新功能而免于被淘汰的。最近, 有關(guān)節(jié)肢動物fushi tarazu(ftz)基因的研究為同源基因的進化機制提供了證據(jù)。節(jié)肢動物中ftz作為 Hox基因家族一員調(diào)控昆蟲的體節(jié)發(fā)育, 它的表達模式與功能和相鄰的Hox基因Antp、Scr重疊[83]。因此ftz中的Hox同源結(jié)構(gòu)域?qū)τ谒l(fā)揮專屬功能是不必要的, 這種冗余的功能并不能使它避免被淘汰。但是它在中樞神經(jīng)系統(tǒng)(Central nervous system, CNS)中的表達卻十分的特殊且保守[84]。在隨后的研究中發(fā)現(xiàn)ftz在CNS發(fā)育上的功能依賴于其蛋白上的 Antennapedia(Antp)同源結(jié)構(gòu)域, 敲除 Antp蛋白結(jié)構(gòu)域?qū)е?CNS發(fā)育缺陷, 同時表達全長Antennapedia蛋白無法挽救ftz缺失帶來的CNS發(fā)育缺陷。由于蛋白結(jié)構(gòu)域與CRE的靈活性, ftz基因獲得了一個原神經(jīng)性的CRE從而獲得了獨有的功能而在進化中保留了下來[85]。這說明蛋白結(jié)構(gòu)域與CRE是以一種靈活的方式相互組合, 從而在進化中使得原有的蛋白不斷獲得新的功能。因此單純研究蛋白序列或CRE對于形態(tài)差異的影響無疑是片面的。

圖1 Hox家族在節(jié)肢動物與脊索動物中演化[3]A：節(jié)肢動物Hox基因簇的演化; B：脊索動物Hox基因簇的演化。

無獨有偶, 蛋白質(zhì)結(jié)構(gòu)域與CRE間的靈活組合不但能夠使相似的基因獲得新的功能, 還可以使分化差異較大的基因保持原始的功能。通過對比抑制果蠅足發(fā)育的Hox基因Ultrabithorax(Ubx)、AbdominalA (AbdA)、AbdominalB(AbdB)的功能發(fā)現(xiàn), 這3種Hox基因是通過不同的 DNA結(jié)合結(jié)構(gòu)域以及與不同的TALE輔因子結(jié)合來行使相同的功能[86]。

然而, 即使是蛋白結(jié)構(gòu)域相似、CRE的表達模式也相似的同一基因在不同物種中也可能發(fā)揮不同的作用。在昆蟲中Antp基因的表達能夠促使胸部足的發(fā)育[87～90], 相反Ubx、AbdA/B在腹部的表達會抑制腹部形成足[91]。而 Khadjeh等[92]發(fā)現(xiàn)在蜘蛛(Achaearanea tepidariorum)中 Antp卻在胸部表達,抑制足的形成。抑制 Antp的表達使蜘蛛形成了 10只腳的極端形態(tài)。而將蜘蛛的Antp在果蠅中進行表達, 卻發(fā)現(xiàn)蜘蛛的Antp在果蠅的胸部依然行使促進足發(fā)育的角色。這說明既不是蛋白質(zhì)序列的改變,也不是 CRE時空表達模式的改變導致了 Antp在Achaearanea tepidariorum中的特殊作用。有意思的是, 盡管Antp在Achaearanea tepidariorum中行使不同的功能, 這種蜘蛛在其形態(tài)發(fā)育上與其他蜘蛛以及昆蟲比較, 腿的發(fā)育依然被限制在胸部, 顯示了趨同性。這種由不同機制導致的進化趨同性說明了形態(tài)發(fā)育上的復雜性, 所有參與這一發(fā)育網(wǎng)絡的輔因子、Hox基因的協(xié)作基因或靶基因的進化[92]、甚至蛋白質(zhì)修飾的改變[93], 都有可能對形態(tài)發(fā)育產(chǎn)生影響。

3 結(jié)語與展望

順式調(diào)控假說的提出使evo-devo得到了迅速的發(fā)展, 使人們了解了曾經(jīng)被稱為“垃圾DNA”的無數(shù)非編碼元件對于物種形態(tài)多樣性的貢獻, 同時也豐富了進化學的理論。但是隨著 evo-devo的發(fā)展,得到了越來越多不同的研究結(jié)果。為了解釋這些結(jié)果, 必須不斷地完善 evo-devo的研究方法與研究思路。未來的evo-devo不應僅局限在CRE的研究, 而應更加全面地研究形態(tài)發(fā)育網(wǎng)絡中的每一個因素,才能更加接近進化發(fā)育的真相。

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(責任編委: 王義權(quán))

Role of genes and their cis-regulatory elements during animal morphological evolution

Boyuan Sun, Jianbo Tu, Ying Li, Mingyao Yang

Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China

Cis-regulatory hypothesis is one of the most important theories in evolutionary developmental biology (evo-devo), which claims that evolution of cis-regulatory elements (CREs) plays a key role during evolution of morphology. However, an increasing number of experimental results show that cis-regulatory hypothesis alone is not far enough to explain the complexity of evo-devo processes. Other modifications, including mutations of protein coding, gene and genome duplications, and flexibility of homeodomains and CREs, also cause the morphological changes in animals. In this review, we retrospect the recent results of evolution of CREs and genes associated with CREs and discuss new methods and trends for research in evo-devo.

evo-devo; cis-regulatory element; gene; morphology

2013-10-07;

2013-12-06

四川農(nóng)業(yè)大學“雙支”計劃基金(編號2920200)和四川省教育廳“科研創(chuàng)新團隊”基金資助

孫博淵, 在讀碩士研究生, 專業(yè)方向：動物遺傳與進化。E-mail: sunboy0415@foxmail.com

楊明耀, 博士, 教授, 博士生導師, 研究方向：動物遺傳與進化。E-mail: yangmingyao@sicau.edu.cn

10.3724/SP.J.1005.2014.0525

時間: 2014-5-20 11:05:57

URL: http://www.cnki.net/kcms/doi/10.3724/SP.J.1005.2014..html