人類Y染色體的演化

楊仙榮，王美琴，李少華

1. 內(nèi)蒙古醫(yī)科大學(xué)附屬醫(yī)院眼科，呼和浩特 010050；

2. 內(nèi)蒙古托克托縣人民醫(yī)院，呼和浩特 010200；

3. 內(nèi)蒙古醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院，呼和浩特 010110

人類Y染色體的演化

楊仙榮1，王美琴2，李少華3

1. 內(nèi)蒙古醫(yī)科大學(xué)附屬醫(yī)院眼科，呼和浩特 010050；

2. 內(nèi)蒙古托克托縣人民醫(yī)院，呼和浩特 010200；

3. 內(nèi)蒙古醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院，呼和浩特 010110

人類 Y染色體由于其性別決定的特殊功能和獨(dú)有的進(jìn)化史一直以來(lái)都備受關(guān)注。Y染色體起源于常染色體，經(jīng)歷了嚴(yán)重的退化過(guò)程。由于其缺乏重組，蛋白編碼基因少，重復(fù)序列多所以研究進(jìn)展緩慢。近年來(lái)，隨著比較基因組及測(cè)序技術(shù)的快速發(fā)展，對(duì)人類Y染色體最終命運(yùn)的爭(zhēng)論不斷加劇，Y染色體的研究正逐步成為熱點(diǎn)。文章綜述了人類Y染色體的結(jié)構(gòu)、遺傳特點(diǎn)、起源及進(jìn)化過(guò)程，并根據(jù)目前的研究進(jìn)展對(duì)Y染色體的最終命運(yùn)進(jìn)行了討論，提出了作者的一些看法，以期為從事遺傳及性染色體進(jìn)化的研究者提供參考。

Y染色體退化；重組抑制；進(jìn)化層；轉(zhuǎn)錄組

性別決定是生物界一種形式多樣、原理復(fù)雜的自然現(xiàn)象。目前，研究者普遍認(rèn)為性別決定的原理主要有兩種，即環(huán)境決定和遺傳決定，某些情況下兩種機(jī)制也會(huì)共同發(fā)揮作用[1,2]。如在部分環(huán)境決定性別的蜥蜴和魚(yú)類中，性別決定對(duì)溫度敏感性常常表現(xiàn)出可遺傳的特征[2,3]。性染色體是遺傳決定中一種與特定性別連鎖的染色體[4]，起源于常染色體，而且在不同家系中是多次、獨(dú)立進(jìn)化產(chǎn)生的[5～7]。染色體性別決定主要有3類：雄異配型(Male heterogamety)，如哺乳動(dòng)物中的XY系統(tǒng)；雌異配型(Female herterogamety)，如鳥(niǎo)類、蛇類中的ZW系統(tǒng)；單倍體世代性別決定(Haploid phase determination)，如苔蘚中的UV系統(tǒng)[4]。人類的性別決定屬于雄異配型。

1 人類Y染色體的特點(diǎn)

人類Y染色體基因含量少、功能多，具有男性特異性；存在大量異染色質(zhì)；充滿重復(fù)及擴(kuò)增序列，序列測(cè)定因此難以進(jìn)行[8,9]。

在不同人種間，相較其他染色體來(lái)說(shuō)，Y染色體存在著高度變異，Karafet等[10]根據(jù)這種序列上的差異性將人類Y染色體分成311個(gè)單倍體群。

Y染色體的長(zhǎng)度約為X染色體的1/3，這種Y染色體顯著小于X染色體的現(xiàn)象在自然界中并不是普遍存在，多數(shù)情況是同形的[11～13]，對(duì)木瓜(Chaenomeles sinensis)的研究發(fā)現(xiàn)，Y染色體個(gè)體反而大于X染色體[14]。

Y染色體一般只存在于男性，而與之相對(duì)應(yīng)的X染色體只有1/3時(shí)間存在于男性[4]，這使得Y染色體經(jīng)歷了獨(dú)有的進(jìn)化過(guò)程。同時(shí)，在一夫一妻、一夫多妻的婚姻制度下，很大程度上減少了Y染色體有效群體的大小[5]，即一對(duì)可生育的男女組合中，每存在3條X染色體，與之相對(duì)應(yīng)的Y染色體僅存在1條。

2 人類Y染色體的序列組成

人類Y染色體大約長(zhǎng)60 Mb，根據(jù)在減數(shù)分裂過(guò)程中是否發(fā)生重組劃分為兩類結(jié)構(gòu)：擬常染色體區(qū)(Pseudoautosomal regions，PARs)和男性特異性區(qū)域(Male-specific region of the Y chromosome，MSY)。擬常染色體區(qū)位于Y染色體兩端，在減數(shù)分裂過(guò)程中可與X染色體發(fā)生重組[15～17]，短臂PAR1含13個(gè)基因，長(zhǎng)臂PAR2含 4個(gè)基因[18]；男性特異性區(qū)域約占總長(zhǎng)的95%，由異染色質(zhì)序列以及3類常染色質(zhì)序列拼接而成。異染色質(zhì)序列長(zhǎng)約 40 Mb，至今未被測(cè)序。MSY常染色質(zhì)序列長(zhǎng)約23 Mb，包括156個(gè)轉(zhuǎn)錄單位，78個(gè)蛋白編碼基因，但多是假基因和重復(fù)拷貝，僅編碼27種蛋白。3類常染色質(zhì)區(qū)分別為：X轉(zhuǎn)座區(qū)(X-transposed region)長(zhǎng)約3.4 Mb，僅含兩個(gè)基因；X退化區(qū)(X-degenerate region)含16個(gè)在X染色體上有同源基因的單拷貝基因，包括性別決定因子SRY(Sex-determining region of Y-chromosome)；擴(kuò)增區(qū)(Ampliconic regions)為高度重復(fù)序列，長(zhǎng)約10.2 Mb，約含60個(gè)基因，分屬9個(gè)基因家族，均具有男性特異性功能且多數(shù)位于8個(gè)回文結(jié)構(gòu)中[19～21]。

與其相對(duì)應(yīng)的X染色體含有150 Mb左右的常染色質(zhì)序列，大約800個(gè)蛋白編碼基因[8]，那么XY染色體是否起源于一對(duì)常染色體？如果是同源染色體為什么會(huì)有如此顯著的差異？Y染色體會(huì)一直退化直至消失嗎？下文會(huì)有詳細(xì)論述。

3 人類Y染色體的起源

關(guān)于性染色體起源于常染色體的論斷最早在蛇類性染色體形態(tài)比較中發(fā)現(xiàn)。Z染色體在蛇類各個(gè)屬中具有很高的保守性，而性別特異性的W染色體分化嚴(yán)重[22]。由此，Ohno等[23]在1967年提出蛇類的性染色體源于一對(duì)常染色體，而W染色體是Z的原始同源染色體逐步分化結(jié)果。該理論在隨后的研究中得到進(jìn)一步證實(shí)，在鳥(niǎo)類的研究中發(fā)現(xiàn)鳥(niǎo)類與蛇類的性染色體雖不具同源性，但同樣起源于一對(duì)常染色體[24]。

如前文所述，人類X和Y染色體在形態(tài)和基因組成上都存在顯著差異，但同樣源于一對(duì)同源染色體[25,26]。根據(jù)如下：首先，Y 染色體上多數(shù)具有男性特異性功能的基因在X染色體上都能找到同源基因[26]，甚至包括性別決定基因SRY[27]；其次，它們具有共同的擬常染色體區(qū)[18]。由于Y染色體上基因少且充滿重復(fù)序列，導(dǎo)致研究具有一定困難，所以對(duì)人類Y染色體進(jìn)化的研究多借鑒其同源染色體X及其他物種中新近形成Y染色體的研究成果。

在與有袋類尤金袋鼠(Macropus eugenii)基因組成比對(duì)時(shí)發(fā)現(xiàn)，人類X染色體是由與袋鼠X染色體同源的一段保守區(qū)(含SRY)和一段與袋鼠5號(hào)染色體短臂部分區(qū)段直系同源的添加區(qū)組成[25,28]，這在Y染色體上也有相同發(fā)現(xiàn)[29]。這表明在147.4 Ma(Million years ago)，從真獸亞綱(Eutheria)分化出有袋類(Marsupials)之后到100 Ma胎盤(pán)類(Placentals)開(kāi)始輻射進(jìn)化前[30]，人類原始 X、Y染色體獲得了一段源于常染色體的添加區(qū)。Veyrunes等[31]發(fā)現(xiàn)，人類X染色體保守區(qū)被檢測(cè)基因，包括與性別決定因子SRY同源的SOX3(SRY-box 3)，在單孔類(Monotremes)鴨嘴獸(Ornithorhynchus anatinus)6號(hào)染色體上均存在直系同源基因。而且鴨嘴獸X染色體與鳥(niǎo)類Z染色體，包括鳥(niǎo)類的性別決定基因 DMRT1(Doublesex and mab-3 related transcription factor 1)，以及人類5號(hào)、9號(hào)染色體的部分區(qū)段同源性顯著[31]。這表明在166.2 Ma，從哺乳動(dòng)物獸亞綱(Theria)分化出單孔類之后到147.4 Ma 有袋類分化產(chǎn)生之前，某對(duì)常染色體獲得了性別決定因子SRY形成了原始的X、Y染色體[31]。此外，人類與原雞(Gallus gallus)基因組成的比對(duì)發(fā)現(xiàn)，人類X、Y染色體添加區(qū)與原雞1號(hào)染色體長(zhǎng)臂部分區(qū)段直系同源，X染色體保守區(qū)與4號(hào)染色體短臂(含SOX3)、12號(hào)染色體部分區(qū)段以及幾條不同的微染色體直系同源[32]。由此，根據(jù)染色體區(qū)段起源可將X染色體保守區(qū)進(jìn)一步分為2個(gè)進(jìn)化層[32](圖1)。Lahn和Page[33]根據(jù)X、Y染色體上同源基因序列相似性將X染色體劃分為4個(gè)進(jìn)化層，并且將含有SOX3的區(qū)段作為第一進(jìn)化層，因此加上擬常染色體區(qū)，可將X染色體劃分為5個(gè)進(jìn)化層[13,32]，但Lahn和Page認(rèn)為第一進(jìn)化層大約形成于310 Ma。作者認(rèn)為L(zhǎng)ahn和Page關(guān)于進(jìn)化層產(chǎn)生時(shí)間的推測(cè)不及Veyrunes等[31]的研究成果可信，這主要是由于其假定的基因退化速率還有待商榷。Lahn和Page[9,33]同時(shí)還發(fā)現(xiàn)Y染色體同樣存在進(jìn)化層的劃分，但是進(jìn)化層發(fā)生了染色體內(nèi)部重排，這在Ross等[26]的研究結(jié)果中得到了驗(yàn)證。

4 人類Y染色體的退化

X、Y既是同源染色體，分化為什么會(huì)如此嚴(yán)重，又是什么驅(qū)動(dòng)了Y染色體的退化？

作者認(rèn)為，首先是由于男性特異性區(qū)域的形成。Kazumi等[34,35]構(gòu)建的中華鱉(Pelodiscus sinensis)細(xì)胞遺傳學(xué)圖表明原雞與中華鱉之間的染色體高度保守，其1～6號(hào)較大的染色體幾乎相同。 由此，研究者推測(cè)310 Ma，哺乳類、鳥(niǎo)類和爬行類共同祖先的核型類似于現(xiàn)存的龜類，性別決定系統(tǒng)也是溫度依賴型[13]。在310～166.2 Ma，哺乳類的祖先與鳥(niǎo)類及爬行類分化之后，常染色體發(fā)生融合形成進(jìn)化層 1和2[31]。此后其中1條的進(jìn)化層 1獲得了性別決定基因SRY，形成了原始的同形X、Y染色體，同形性染色體在多種兩棲類、魚(yú)類、爬行類以及無(wú)脊椎動(dòng)物中都有發(fā)現(xiàn)[8]。此后在 SRY附近迅速積累性別對(duì)抗突變(Sexually antagonistic mutations)[36]，它們提高男性的適應(yīng)性而不利于女性[37]，從而抑制了性別決定基因周邊區(qū)域與X染色體同源區(qū)的重組，形成了原始的男性特異性區(qū)域，而且逐步擴(kuò)大。此外，對(duì)東非馬拉維湖麗魚(yú)的研究發(fā)現(xiàn)，性別對(duì)抗性狀甚至?xí)蔀樾滦匀旧w產(chǎn)生的重要因素[38]。此后，多次的臂間倒位導(dǎo)致了大范圍的重組抑制[26,39,40]，致使該區(qū)染色體片段經(jīng)歷了真正意義上的限性遺傳，選擇作用對(duì)象從單個(gè)位點(diǎn)轉(zhuǎn)變?yōu)榉侵亟M區(qū)整個(gè)連鎖群[5]。由此引發(fā)了希爾—羅伯森效應(yīng)(Hill-Robertson effect)[41]，即降低了對(duì)任何單個(gè)位點(diǎn)的選擇效率[42]。同時(shí)在穆勒棘輪效應(yīng)(Muller’s ratchet)[43,44]、搭車效應(yīng) (Genetic hitchhiking)[45]、 背 景 選 擇 效 應(yīng)(Background selection)[46]等作用下，男性特異性區(qū)域出現(xiàn)了大量突變、失活現(xiàn)象，這與多數(shù)新發(fā)現(xiàn)的顯性遺傳病源于Y染色體的現(xiàn)象相一致[47]。另外，相對(duì)其他染色體及其攜帶基因，Y染色體及其基因有效群體明顯較小，顯著加劇了遺傳漂變[37]。而且精原細(xì)胞相比卵原細(xì)胞經(jīng)歷了更多的細(xì)胞分裂，同時(shí)精子所含的遺傳物質(zhì)處于易氧化的環(huán)境且缺乏修復(fù)酶。由于Y染色體、X染色體和常染色體通過(guò)精子傳遞到下一代的概率分別為1、1/2和1/3，所以 Y染色體在這種更易發(fā)生有害突變的環(huán)境中存在的時(shí)間至少是常染色體的2倍，是X染色體的3倍[48]。在上述因素的作用下，Y染色體迅速退化。

5 人類Y染色體的命運(yùn)

Y染色體會(huì)不斷退化直至消失嗎？該問(wèn)題引起了研究者的激烈討論。

在一些哺乳動(dòng)物中確實(shí)存在Y染色體完全消失的實(shí)例，如在鼴形田鼠(Ellobius lutescens)以及日本發(fā)現(xiàn)的兩種刺鼠 Tokudaia osimensis和 Tokudaia muenninki中，性別決定系統(tǒng)均為 XO[49,50]。到目前為止，在其各自基因組中均未發(fā)現(xiàn)胎盤(pán)類保守的性別決定因子 SRY，這表明其性別決定功能已經(jīng)被其他基因取代，其載體—Y 染色體已完全消失[51]。Graves等[13]認(rèn)為在SRY的功能被取代后，Y 染色體會(huì)完全消失。但是Hughes等[21]通過(guò)對(duì)人類及遠(yuǎn)親恒河猴(Rhesus macaque，親緣關(guān)系遠(yuǎn)于黑猩猩及大猩猩)MSY的基因比對(duì)發(fā)現(xiàn)，在最近的0.25億年里，人類MSY的基因丟失僅限于最新形成的第5進(jìn)化層，其他4個(gè)進(jìn)化層盡管主要結(jié)構(gòu)差異顯著但在這期間沒(méi)有丟失一個(gè)基因，表明基因丟失已經(jīng)停滯了 0.25億年[21]。在與人類現(xiàn)存親緣關(guān)系最近的黑猩猩以及親緣關(guān)系較遠(yuǎn)的大猩猩的MSY比較中發(fā)現(xiàn)，人類與大猩猩的MSY相對(duì)保守，而黑猩猩的MSY退化嚴(yán)重，這可能是由于黑猩猩特有的婚配制度所致[52,53]。那么這種非編碼序列結(jié)構(gòu)差異顯著，而基因丟失速度放緩甚至停滯該如何解釋？首先，部分研究者認(rèn)為Y染色體退化不是不可避免，在其他物種中也有古老的同形性染色體發(fā)現(xiàn)[5,54,55]。其次，研究者發(fā)現(xiàn)人類及靈長(zhǎng)類的染色體內(nèi)存在大量回文結(jié)構(gòu)，這種結(jié)構(gòu)導(dǎo)致基因轉(zhuǎn)換，在染色體內(nèi)部發(fā)生重組，修復(fù)突變，這種結(jié)構(gòu)可能會(huì)阻滯 Y染色體退化[20,56]。但是也有研究者認(rèn)為這種基因轉(zhuǎn)換作用是雙向的，該過(guò)程不但可能使正?；蜣D(zhuǎn)換為突變基因，同時(shí)提高突變率[8,13]，而且臨床上確有重復(fù)結(jié)構(gòu)內(nèi)部重組造成的男性不育[57]。Hughes等[52]研究表明，黑猩猩Y染色體的回文結(jié)構(gòu)數(shù)量是人類的兩倍，但黑猩猩卻丟失了大部分Y染色體連鎖基因，所以基因轉(zhuǎn)換的效用還有待商榷。再有，Y染色體上所?；蚨际艿綇?qiáng)烈的負(fù)向選擇的保護(hù)[13,58]，近來(lái)關(guān)于轉(zhuǎn)錄組及基因譜的研究表明現(xiàn)存胎盤(pán)類及有袋類Y染色體上的基因并不是隨機(jī)保留下來(lái)的，其功能多與蛋白轉(zhuǎn)錄、翻譯及其穩(wěn)定性相關(guān)，是重要的劑量敏感性調(diào)控因子，因此今后Y染色體的基因內(nèi)容不會(huì)輕易發(fā)生變化[59,60]。在對(duì)雞 W 染色體轉(zhuǎn)錄組的研究發(fā)現(xiàn)，雌性特異性選擇對(duì)W染色體基因的表達(dá)模式有顯著影響，該作用會(huì)保護(hù) W染色體免于退化。由于 W與Y染色體共同的限性遺傳特點(diǎn)，Y染色體會(huì)經(jīng)歷類似的進(jìn)化壓力，研究者由此推測(cè)人類Y染色體也不會(huì)消失[61]。此外，Y染色體可能會(huì)通過(guò)轉(zhuǎn)座或染色體融合獲得新基因以維持其基因數(shù)目及形態(tài)大小。研究發(fā)現(xiàn)，許多種類的果蠅性染色體在進(jìn)化過(guò)程中都與常染色體發(fā)生了融合，前文關(guān)于人類Y染色體進(jìn)化層的論述中也有大量染色體融合的事實(shí)[8]。在與其他靈長(zhǎng)類Y染色體序列的比對(duì)中發(fā)現(xiàn)，有3.4 Mb的序列是人類Y染色體所特有，研究者認(rèn)為其大概是在3～4 Ma 從X染色體轉(zhuǎn)座而來(lái)[8,19]。

圖1 哺乳動(dòng)物主要類群的性染色體系統(tǒng)進(jìn)化(參考文獻(xiàn)[31]并修改)同一紋理表示不同基因組之間的同源性；表示參與哺乳類性染色體形成的主要染色體；染色體間的叉狀符號(hào)表示可以發(fā)生自由重組；表示DMRT1、SOX3或SRY在染色體上的相對(duì)位置；X染色體旁的3種線型表示3個(gè)主要進(jìn)化層的覆蓋范圍。

作者認(rèn)為，目前為止有大量證據(jù)表明人類Y染色體退化停滯，但人類Y染色體命運(yùn)依舊難以預(yù)測(cè)。這一方面是由于外部因素多變，導(dǎo)致Y染色體所經(jīng)受進(jìn)化力方向的不可預(yù)知，這些改變包括人類生存環(huán)境的改變，人類文明發(fā)展帶來(lái)的性別選擇或是擇偶偏向性以及婚配制度的改變。另一方面是由于基因以及染色體突變的方向不可預(yù)知，會(huì)不會(huì)發(fā)生新的染色體融合，Y染色體序列結(jié)構(gòu)中回文序列在對(duì)抗退化過(guò)程中到底能發(fā)揮多大作用，這一切都使得Y染色體的命運(yùn)難以預(yù)測(cè)。那么，如果發(fā)生了Y染色體退化消失，會(huì)不會(huì)帶來(lái)人類滅絕？作者樂(lè)觀認(rèn)為不會(huì)，在其他哺乳動(dòng)物中存在缺乏Y染色體物種存活的例子，而且隨著人類科技的進(jìn)步，這一問(wèn)題一定會(huì)得到進(jìn)一步解決，如 Yasuhiro等[62,63]對(duì)小鼠的研究發(fā)現(xiàn)，在輔助生殖技術(shù)的幫助下，僅需兩個(gè)基因就可取代整條Y染色體產(chǎn)生可育后代。這一實(shí)例為未來(lái)人類輔助生殖技術(shù)提供了無(wú)限的想象空間。

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(責(zé)任編委: 盧大儒)

The evolution of human Y chromosome

Xianrong Yang1, Meiqin Wang2, Shaohua Li3

1. Ophthalmology Department, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China;
2. Tuketuo County People's Hospital, Hohhot 010200, China;
3. College of Basic Medicine, Inner Mongolia Medical University, Hohhot 010110, China

The human Y chromosome is always intriguing for researchers, because of its role in gender determination and its unusual evolutionary history. The Y chromosome evolves from an autosome, and its evolution has been characterized by massive gene decay. The lack of recombination and protein-coding genes and high content of repetitive sequences have hindered the progress in our understanding of the Y chromosome biology. Recently, with the advances in comparative genomics and sequencing technology, the research on Y chromosome has become a hotspot, with an intensified debate about Y-chromosome final destination resulting from degeneration. This review focuses on the structure, inheritance characteristics, gene content, and the origin and evolution of Y chromosome. We also discuss the long-term destiny of Y chromosome.

Y-chromosome degeneration; recombination suppression; evolutionary strata; transcriptome

2014-04-03;

2014-07-21

秦惠莙 與李政道中國(guó)大學(xué)生見(jiàn)習(xí)進(jìn)修基金和國(guó)家基金委人才培養(yǎng)基金和國(guó)家拔尖人才培養(yǎng)計(jì)劃資助

楊仙榮，副主任護(hù)師。E-mail:15049165177@163.com

李少華，助教，研究方向：遺傳學(xué)。E-mail:bisimai2008@163.com

10.3724/SP.J.1005.2014.0849

時(shí)間: 2014-7-30 11:26:14

URL: http://www.cnki.net/kcms/detail/11.1913.R.20140730.1126.002.html