'Jumping genes' contribute to uniqueness of individual brains
Brains are marvels of diversity: no two look the same -- not even those of otherwise identical twins. Scientists at the Salk Institute for Biological Studies may have found one explanation for the puzzling variety in brain organization and function: mobile elements, pieces of DNA that can jump from one place in the genome to another, randomly changing the genetic information in single brain cells. If enough of these jumps occur, they could allow individual brains to develop in distinctly different ways.
"This mobility adds an element of variety and flexibility to neurons in a real Darwinian sense of randomness and selection," says Fred H. Gage, Professor and co-head of the Laboratory of Genetics at the Salk Institute and the lead author of the study published in this week's Nature. This process of creating diversity with the help of mobile elements and then selecting for the fittest is restricted to the brain and leaves other organs unaffected. "You wouldn't want that added element of individuality in your heart," he adds.
Precursor cells in the embryonic brain, which mature into neurons, look and act more or less the same. Yet, these precursors ultimately give rise to a panoply of nerve cells that are enormously diverse in form and function and together form the brain. Identifying the mechanisms that lead to this diversification has been a longstanding challenge. "People have speculated that there might be a mechanism to create diversity in brain like there is in the immune system, and the immune system's diversity is perhaps the closest analogy we have," says Gage.
In the immune system, the genes coding for antibodies are shuffled to create a wide variety of antibodies capable of recognizing an infinite number of distinct antigens.
In their study, the researchers closely tracked a single human mobile genetic element, a so-called LINE-1 or L1 element in cultured neuronal precursor cells from rats. Then they introduced it into mice. Every time the engineered L1 element jumped, the affected cell started glowing green [WHY?]. "We were very excited when we saw green cells all over the brain in our mice," says research fellow and co-author M. Carolina N. Marchetto, "because then we knew it happened in vivo and couldn't be dismissed as a tissue culture artifact."
Transposable L1 elements, or "jumping genes" as they are often called, make up 17 percent of our genomic DNA but very little is known about them. Almost all of them are marooned at a permanent spot by mutations rendering them dysfunctional, but in humans a hundred or so are free to move via a "copy and paste" mechanism. Long dismissed as useless gibberish or "junk" DNA, the transposable L1 elements were thought to be intracellular parasites or leftovers from our distant evolutionary past.
It has been known for a long time that L1 elements are active in testis and ovaries, which explains how they potentially play a role in evolution by passing on new insertions to future generations. "But nobody has ever demonstrated mobility convincingly in cells other than germ line cells," says Gage.
Apart from their activity in testis and ovaries, jumping L1 elements are not only unique to the adult brain but appear to happen also during early stages of the development of nerve cells. The Salk team found insertions only in neuronal precursor cells that had already made their initial commitment to becoming a neuron. Other cell types found in the brain, such as oligodendrocytes and astrocytes, were unaffected.
At least in the germ line, copies of L1s appear to plug themselves more or less randomly into the genome of their host cell. "But in neuronal progenitor cells, these mobile elements seem to look for genes expressed in neurons. We think that's because when the cells start to differentiate the cells start to open up genes and expose their DNA to insertions," explains co- author Alysson R. Muotri. "What we have shown for the first time is that a single insertion can mess up gene expression and influence the function of individual cells," he adds.
However, it is too early to tell how often endogenous L1 elements move in human neurons and how tightly this process is regulated or what happens when this process goes awry, cautions Gage. "We only looked at one L1 element with a marker gene and can only say that motility is likely significantly more for endogenous L1 elements," he adds.
From Salk Institute
據(jù)scienceblog網(wǎng)6月15日?qǐng)?bào)道,，人的大腦具有驚人的多樣性：世界上沒(méi)有任何人的大腦是相同的，即使那些雙胞胎也是如此,。美國(guó)Salk生物研究中心的科學(xué)家有可能解釋這個(gè)令人迷惑的生物大腦多樣性之謎,。"跳躍基因"是指基因組中有些基因會(huì)從一個(gè)地方轉(zhuǎn)移到另一個(gè)地方，這樣就可以在單個(gè)大腦細(xì)胞中改變其基因結(jié)構(gòu),。如果這種跳躍基因足夠多,，那么大腦細(xì)胞基因的多樣性也就不足為奇。
美國(guó)Salk生物研究中心遺傳學(xué)實(shí)驗(yàn)室負(fù)責(zé)人Fred H. Gage指出,，此項(xiàng)新發(fā)現(xiàn)正好印證了達(dá)爾文的生物隨機(jī)進(jìn)化和選擇進(jìn)化的有關(guān)理論,。跳躍基因會(huì)改變生物體的大腦細(xì)胞基因結(jié)構(gòu),，經(jīng)過(guò)自然選擇使生物體慢慢進(jìn)化,，但是這種“跳躍基因”僅僅存在于生物體大腦中。比如說(shuō)生物體的心臟細(xì)胞就不具備這種能力,。
生物體胚胎大腦細(xì)胞的基因同樣具有與跳躍基因類似的能力,，這些細(xì)胞最終會(huì)成長(zhǎng)為大腦神經(jīng)細(xì)胞,。這種細(xì)胞在生長(zhǎng)的過(guò)程中不斷生成不同種類的神經(jīng)細(xì)胞,，而這些神經(jīng)細(xì)胞最終組成了人類的大腦。但是這種說(shuō)法也受到人們的懷疑,。Gage解釋說(shuō),有些科學(xué)家推測(cè)大腦細(xì)胞多樣性同免疫系統(tǒng)細(xì)胞多樣性具有相似的產(chǎn)生機(jī)制，并且這是目前找到的唯一具有類比性的解釋,。
在生物體免疫系統(tǒng)中,，基因會(huì)控制不同種類免疫細(xì)胞的生成,，這些細(xì)胞再分別對(duì)應(yīng)不同種類的抗原,，這樣,，免疫系統(tǒng)就可以對(duì)付不同種類的病毒入侵,。
在他們的研究中,，科學(xué)家仔細(xì)觀察人類大腦中一種名叫LINE- 1的跳躍基因在老鼠大腦細(xì)胞中的行為,。當(dāng)科學(xué)家把具有LINE- 1的細(xì)胞植入老鼠大腦中時(shí),，每當(dāng)這種跳躍基因發(fā)生跳躍，這種細(xì)胞就會(huì)產(chǎn)生變化,。參與此次研究的科學(xué)家M. Carolina N. Marchetto說(shuō),，當(dāng)他們觀察到此現(xiàn)象時(shí)十分興奮,，因?yàn)樗麄冎肋@確實(shí)是由于跳躍基因而不是生物體控制了這種細(xì)胞的變化,。
跳躍基因LINE- 1占到人類DNA總數(shù)的17%,，但是科學(xué)家對(duì)它們知之甚少,。幾乎所有的跳躍基因都受到限制無(wú)法跳躍,，但是它們可以通過(guò)"復(fù)制和粘貼"機(jī)制對(duì)細(xì)胞產(chǎn)生作用,。以往科學(xué)家認(rèn)為L(zhǎng)INE- 1是DNA中的無(wú)用基因片斷,，他們只不過(guò)是人類進(jìn)化過(guò)程中存留下來(lái)的無(wú)用信息。
但是很早以前科學(xué)家就發(fā)現(xiàn)LINE- 1在人類卵巢中有活動(dòng)跡象,，這就使得科學(xué)家懷疑LINE- 1在生物體的進(jìn)化過(guò)程中起到了一定的作用,。但是人們一直沒(méi)有證實(shí)LINE- 1在其它細(xì)胞中也有活動(dòng)跡象。
LINE- 1除了在人類卵巢中活躍外,，還在人類大腦中和和神經(jīng)細(xì)胞成長(zhǎng)初期起到一定的作用,。當(dāng)生物細(xì)胞進(jìn)行復(fù)制的時(shí)候，LINE- 1就會(huì)隨機(jī)插入到新細(xì)胞的DNA片斷中去,。但是在生物體神經(jīng)細(xì)胞中的LINE- 1似乎專門尋找并插入控制神經(jīng)細(xì)胞種類的基因片斷,。參加此次研究的科學(xué)家Alysson R. Muotri認(rèn)為，這或許是因?yàn)楫?dāng)神經(jīng)細(xì)胞開始分裂和復(fù)制時(shí),，其DNA會(huì)自動(dòng)留出某些空位來(lái)讓LINE- 1插入。此次的研究成果顯示出僅僅一個(gè)LINE- 1插入到細(xì)胞基因中就可能影響一個(gè)細(xì)胞的功能,。
然而Gage說(shuō)道,，科學(xué)家還不能確定LINE- 1在生物體神經(jīng)細(xì)胞中的跳躍頻率以及這種跳躍失敗后會(huì)對(duì)生物體細(xì)胞產(chǎn)生什么樣的變化。他們目前只是研究了單個(gè)跳躍基因?qū)ι矬w細(xì)胞產(chǎn)生的變化,，并且只能肯定這種跳躍基因確實(shí)會(huì)對(duì)細(xì)胞產(chǎn)生影響,。
正如世界上沒(méi)有兩片樹葉是完全一樣的，大腦也存在著這種驚人的多樣性,。來(lái)自Salk Institute的生物學(xué)研究人員找到了這種大腦組織和功能性差異的可能解釋：能夠從基因組的一個(gè)位置跳躍到其他位置的DNA機(jī)動(dòng)成分和單個(gè)腦細(xì)胞中遺傳信息的隨機(jī)變化造就了個(gè)性化的大腦,。如果這種跳躍發(fā)生的夠多，那么它們可能促使個(gè)體大腦以完全不同的方式發(fā)育,。這項(xiàng)研究的結(jié)果公布在6月16日的《自然》雜志上,。
胚胎大腦中的前體細(xì)胞（最終發(fā)育成神經(jīng)元）最終產(chǎn)生出在形式和功能上有巨大差異的一套神經(jīng)細(xì)胞，而確定出這種多樣化的機(jī)制則是一大科學(xué)挑戰(zhàn),。有人推測(cè)大腦中必然存在一種類似免疫系統(tǒng)中的機(jī)制以創(chuàng)造出大腦的多樣性,。
在新的研究中，研究人員密切跟蹤了培養(yǎng)的大鼠神經(jīng)元前體中的一種叫做LINE-1或L1成分的人類機(jī)動(dòng)遺傳成分,。他們將這種成分引入小鼠,，而且當(dāng)這種經(jīng)加工的L1成分在每次跳躍時(shí)，受其影響的細(xì)胞就會(huì)開始閃爍綠色光芒,。
這種跳躍基因構(gòu)成了17％的人類基因組DNA,，但是人們對(duì)它們卻知之甚少。人們?cè)缍家呀?jīng)知道L1成分在睪丸和卵巢中很活躍,，但是卻沒(méi)有人能有力地證明除生殖細(xì)胞外的其他細(xì)胞中的這種機(jī)動(dòng)性,。
Salk研究組只在神經(jīng)元前體細(xì)胞中發(fā)現(xiàn)了這種跳躍成分的插入，而大腦中其他細(xì)胞類型則不受影響,。
但是,，目前還不能確定這種內(nèi)生的L1成分在人類神經(jīng)元中如何運(yùn)動(dòng)以及這種過(guò)程的調(diào)節(jié)和這個(gè)過(guò)程出錯(cuò)時(shí)發(fā)生的事,。因此，目前的這項(xiàng)研究只是萬(wàn)里長(zhǎng)征的第一步,。
在談到脊椎動(dòng)物大腦和思想的組織時(shí),，我們說(shuō)“差異萬(wàn)歲”似乎是很公平的?；镜臉?gòu)成部分在不同個(gè)體之間能實(shí)現(xiàn)很大的差異,。神經(jīng)基因組中可變性的一個(gè)來(lái)源也許可以解釋本期Nature上報(bào)告的一些差別：由LINE-1調(diào)節(jié)要素造成的逆轉(zhuǎn)錄移位。研究表明,，在成年大鼠的神經(jīng)干細(xì)胞中和在轉(zhuǎn)基因小鼠的活體大腦中,， 一種由基因工程方法做成的人類LINE-1能夠通過(guò)逆轉(zhuǎn)錄從RNA生成DNA。以前,，在生殖細(xì)胞中或在早期胚胎形成過(guò)程中曾看到類似的逆轉(zhuǎn)錄移位,，這是在這些細(xì)胞成為某一具體類別的細(xì)胞（比如說(shuō)神經(jīng)細(xì)胞）之前看到的。但本期《自然》上發(fā)表的這項(xiàng)新工作表明,，移動(dòng)遺傳要素也許能改變神經(jīng)基因組,，而在非常靠后的某個(gè)階段也許還能改變神經(jīng)回路,。
