'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
据scienceblog网6月15日报道,人的大脑具有惊人的多样性:世界上没有任何人的大脑是相同的,即使那些双胞胎也是如此。美国Salk生物研究中心的科学家有可能解释这个令人迷惑的生物大脑多样性之谜。"跳跃基因"是指基因组中有些基因会从一个地方转移到另一个地方,这样就可以在单个大脑细胞中改变其基因结构。如果这种跳跃基因足够多,那么大脑细胞基因的多样性也就不足为奇。
美国Salk生物研究中心遗传学实验室负责人Fred H. Gage指出,此项新发现正好印证了达尔文的生物随机进化和选择进化的有关理论。跳跃基因会改变生物体的大脑细胞基因结构,经过自然选择使生物体慢慢进化,但是这种“跳跃基因”仅仅存在于生物体大脑中。比如说生物体的心脏细胞就不具备这种能力。
生物体胚胎大脑细胞的基因同样具有与跳跃基因类似的能力,这些细胞最终会成长为大脑神经细胞。这种细胞在生长的过程中不断生成不同种类的神经细胞,而这些神经细胞最终组成了人类的大脑。但是这种说法也受到人们的怀疑。Gage解释说,有些科学家推测大脑细胞多样性同免疫系统细胞多样性具有相似的产生机制,并且这是目前找到的唯一具有类比性的解释。
在生物体免疫系统中,基因会控制不同种类免疫细胞的生成,这些细胞再分别对应不同种类的抗原,这样,免疫系统就可以对付不同种类的病毒入侵。
在他们的研究中,科学家仔细观察人类大脑中一种名叫LINE- 1的跳跃基因在老鼠大脑细胞中的行为。当科学家把具有LINE- 1的细胞植入老鼠大脑中时,每当这种跳跃基因发生跳跃,这种细胞就会产生变化。参与此次研究的科学家M. Carolina N. Marchetto说,当他们观察到此现象时十分兴奋,因为他们知道这确实是由于跳跃基因而不是生物体控制了这种细胞的变化。
跳跃基因LINE- 1占到人类DNA总数的17%,但是科学家对它们知之甚少。几乎所有的跳跃基因都受到限制无法跳跃,但是它们可以通过"复制和粘贴"机制对细胞产生作用。以往科学家认为LINE- 1是DNA中的无用基因片断,他们只不过是人类进化过程中存留下来的无用信息。
但是很早以前科学家就发现LINE- 1在人类卵巢中有活动迹象,这就使得科学家怀疑LINE- 1在生物体的进化过程中起到了一定的作用。但是人们一直没有证实LINE- 1在其它细胞中也有活动迹象。
LINE- 1除了在人类卵巢中活跃外,还在人类大脑中和和神经细胞成长初期起到一定的作用。当生物细胞进行复制的时候,LINE- 1就会随机插入到新细胞的DNA片断中去。但是在生物体神经细胞中的LINE- 1似乎专门寻找并插入控制神经细胞种类的基因片断。参加此次研究的科学家Alysson R. Muotri认为,这或许是因为当神经细胞开始分裂和复制时,其DNA会自动留出某些空位来让LINE- 1插入。此次的研究成果显示出仅仅一个LINE- 1插入到细胞基因中就可能影响一个细胞的功能。
然而Gage说道,科学家还不能确定LINE- 1在生物体神经细胞中的跳跃频率以及这种跳跃失败后会对生物体细胞产生什么样的变化。他们目前只是研究了单个跳跃基因对生物体细胞产生的变化,并且只能肯定这种跳跃基因确实会对细胞产生影响。
正如世界上没有两片树叶是完全一样的,大脑也存在着这种惊人的多样性。来自Salk Institute的生物学研究人员找到了这种大脑组织和功能性差异的可能解释:能够从基因组的一个位置跳跃到其他位置的DNA机动成分和单个脑细胞中遗传信息的随机变化造就了个性化的大脑。如果这种跳跃发生的够多,那么它们可能促使个体大脑以完全不同的方式发育。这项研究的结果公布在6月16日的《自然》杂志上。
胚胎大脑中的前体细胞(最终发育成神经元)最终产生出在形式和功能上有巨大差异的一套神经细胞,而确定出这种多样化的机制则是一大科学挑战。有人推测大脑中必然存在一种类似免疫系统中的机制以创造出大脑的多样性。
在新的研究中,研究人员密切跟踪了培养的大鼠神经元前体中的一种叫做LINE-1或L1成分的人类机动遗传成分。他们将这种成分引入小鼠,而且当这种经加工的L1成分在每次跳跃时,受其影响的细胞就会开始闪烁绿色光芒。
这种跳跃基因构成了17%的人类基因组DNA,但是人们对它们却知之甚少。人们早都已经知道L1成分在睾丸和卵巢中很活跃,但是却没有人能有力地证明除生殖细胞外的其他细胞中的这种机动性。
Salk研究组只在神经元前体细胞中发现了这种跳跃成分的插入,而大脑中其他细胞类型则不受影响。
但是,目前还不能确定这种内生的L1成分在人类神经元中如何运动以及这种过程的调节和这个过程出错时发生的事。因此,目前的这项研究只是万里长征的第一步。
在谈到脊椎动物大脑和思想的组织时,我们说“差异万岁”似乎是很公平的。基本的构成部分在不同个体之间能实现很大的差异。神经基因组中可变性的一个来源也许可以解释本期Nature上报告的一些差别:由LINE-1调节要素造成的逆转录移位。研究表明,在成年大鼠的神经干细胞中和在转基因小鼠的活体大脑中, 一种由基因工程方法做成的人类LINE-1能够通过逆转录从RNA生成DNA。以前,在生殖细胞中或在早期胚胎形成过程中曾看到类似的逆转录移位,这是在这些细胞成为某一具体类别的细胞(比如说神经细胞)之前看到的。但本期《自然》上发表的这项新工作表明,移动遗传要素也许能改变神经基因组,而在非常靠后的某个阶段也许还能改变神经回路。