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og视讯平台|我们身上的绝大部分DNA都是垃圾吗

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T. Ryan Gregory’s lab at the University of Guelph in Ontario is a sort of genomic menagerie, stocked with creatures, living and dead, waiting to have their DNA laid bare. Scorpions lurk in their terrariums. Tarantulas doze under bowls. Flash-frozen spiders and crustaceans — collected by Gregory, an evolutionary biologist, and his students on expeditions to the Arctic — lie piled in beige metal tanks of liquid nitrogen. A bank of standing freezers holds samples of mollusks, moths and beetles. The cabinets are crammed with slides splashed with the fuchsia-stained genomes of fruit bats, Siamese fighting fish and ostriches.回到安大略省圭尔夫大学(University of Guelph),走出演化生物学家T·瑞安·格雷戈里(T. Ryan Gregory)的实验室,你不会感觉样子走出了一个基因组学的大观园,各种各样死掉或者早已病死的生物正等待着自身的DNA被理解:蝎子潜入在圈养箱里;狼蛛在小盆下面睡觉;格雷戈里和他的学生在北极探险时收集的蜘蛛和甲壳类动物的速冻标本存放在米色金属液氮罐里;软体动物、飞蛾和甲虫标本留存在一排立式冷冻柜中;而橱柜里则塞满了果蝠、暹罗斗鱼和鸵鸟基因组的品红染色涂片标本。Gregory’s investigations into all these genomes has taught him a big lesson about life: At its most fundamental level, it’s a mess. His favorite way to demonstrate this is through what he calls the “onion test,” which involves comparing the size of an onion’s genome to that of a human. To run the test, Gregory’s graduate student Nick Jeffery brought a young onion plant to the lab from the university greenhouse. He handed me a single-edged safety razor, and then the two of us chopped up onion stems in petri dishes. An emerald ooze, weirdly luminous, filled my dish. I was so distracted by the color that I slashed my ring finger with the razor blade, but that saved me the trouble of poking myself with a syringe — I was to supply the human genome. Jeffery raised a vial, and I wiped my bleeding finger across its rim. We poured the onion juice into the vial as well and watched as the green and red combined to produce a fluid with both the tint and viscosity of maple syrup.在对所有这些基因组展开研究的过程中,格雷戈里教给了最重要的一课:从最显然的层面上来说,生命感叹一团乱麻。他很讨厌用“洋葱测试”来回应加以证明。

这个测试的目的是较为洋葱与人类的基因组孰大孰小。为此,格雷戈里的研究生尼克·杰弗里(Nick Jeffery)从大学的温室里采行了一棵小洋葱获得实验室,然后拿着我一把单刃安全性剃须刀,和我一起在培养皿中把洋葱茎磨碎。

不一会儿,我的培养皿里就堆起了一坨带着怪异光泽的翡翠色软泥。这无法解释的颜色让我回头了神,一不小心切到了自己的无名指,不过这样也好,省得我用注射器再行砍自个儿一次了——这次测试中,我是获取人类基因组的志愿者。杰弗里拿走了一个小瓶,让我把手指上的血沾在瓶沿上,随后我们把洋葱汁也放入瓶中,看著绿色和红色的液体混合一起,产生一种从色调和粘度上都跟枫糖浆十分相似的东西。

After adding a fluorescent dye that attaches to DNA, Jeffrey loaded the vial into a boxy device called a flow cytometer, which sprayed the onion juice and blood through a laser beam. Each time a cell was hit, its DNA gave off a bluish glow; bigger genomes glowed more brightly. On a monitor, we watched the data accumulate on a graph. The cells produced two distinct glows, one dim, one bright, which registered on the graph as a pair of peaks.杰弗里向瓶中重新加入了能与DNA结合的荧光染料,然后将小瓶放入一种叫作流式细胞仪的四四方方的装置中。这种仪器可以将洋葱汁和血液喷洒在激光束的光路上,每当一个细胞被打中,其DNA就不会收到蓝色辉光,细胞的基因组越大,收到的光也就就越暗。在我们的身旁下,显示器上图表的数据渐渐累积,它指出两种细胞产生了两种截然不同的光,一种黯淡,一种暗淡,适当地在图表上表明为两个峰。One peak represented my genome, or the entirety of my DNA. Genomes are like biological books, written in genetic letters known as bases; the human genome contains about 3.2 billion bases. Print them out as letters on a page, and they would fill a book a thousand times longer than “War and Peace.” Gregory leaned toward the screen. At 39, with a chestnut-colored goatee and an intense gaze, he somewhat resembles a pre-Heisenberg Walter White. He pointed out the onion’s peak. It showed that the onion’s genome was five times bigger than mine.其中一个峰代表我的基因组,也就是我的全套DNA。

基因组就只不过一本用取名为碱基的遗传学字母写的生物学大书。人类的基因组大约包括32亿个碱基,如果把这些字母打印机在纸上,充足构成一本比《战争与和平》(War and Peace)还宽一千倍的巨作。格雷戈里朝着屏幕一柱上身来,今年39岁的他拔着栗色的山羊胡子,目光盼望,类似于剧集《夺命毒师》中沦为“海森堡(Heisenberg)”之前的主角瓦特·怀特(Walter White)。他用手指着代表洋葱的峰。

它指出,洋葱的基因组是我的五倍大。“The onion wins,” Gregory said. The onion always does.格雷戈里宣告:“洋葱落败。

”一如既往。But why? Why does an onion carry around so much more genetic material than a human? Or why, for that matter, do the broad-footed salamander (65.5 billion bases), the African lungfish (132 billion) and the Paris japonica flower (149 billion)? These organisms don’t appear to be more complex than we are, so Gregory rejects the idea that they’re accomplishing more with all their extra DNA. Instead, he champions an idea first developed in the 1970s but still startling today: that the size of an animal’s or plant’s genome has essentially no relationship to its complexity, because a vast majority of its DNA is — to put it bluntly — junk.只是,为什么不会这样呢?为什么洋葱不会装载比人还多那么多的遗传物质?某种程度的问题也限于于宽足蝾螈(655亿对碱基),非洲肺鱼(1320亿)和衣笠草(又名重楼百合,1490亿)。

这些生物远比我们人类简单,所以格雷戈里不指出这些多出来的DNA的起到是完备它们的机能。忽略,他更加赞成一个在20世纪70年代首次明确提出,但至今听得来依然有些惊世骇俗的学说:动植物基因组的大小与其复杂程度基本牵涉到,因为——说穿了——绝大部分的DNA都是“垃圾”。The human genome contains around 20,000 genes, that is, the stretches of DNA that encode proteins. But these genes account for only about 1.2 percent of the total genome. The other 98.8 percent is known as noncoding DNA. Gregory believes that while some noncoding DNA is essential, most probably does nothing for us at all, and until recently, most biologists agreed with him. Surveying the genome with the best tools at their disposal, they believed that only a small portion of noncoding DNA showed any evidence of having any function.人类基因组大约不含2万个基因,或者说,编码蛋白质的DNA片段。

但这些基因仅有占到整个基因组的1.2%左右。其余的98.8%称作非编码DNA。格雷戈里指出,虽然某些非编码DNA是必不可少的,但大部分很有可能没任何用处。

直到最近,大多数生物学家都表示同意他的意见。他们利用手头最差的工具对基因组展开了调查,找到现有证据指出,只有一小部分非编码DNA具备生物学功能。But in the past few years, the tide has shifted within the field. Recent studies have revealed a wealth of new pieces of noncoding DNA that do seem to be as important to our survival as our more familiar genes. Many of them may encode molecules that help guide our development from a fertilized egg to a healthy adult, for example. If these pieces of noncoding DNA become damaged, we may suffer devastating consequences like brain damage or cancer, depending on what pieces are affected. Large-scale surveys of the genome have led a number of researchers to expect that the human genome will turn out to be even more full of activity than previously thought.然而,在过去的几年中,该领域的风向开始变化。

近期的研究说明了,新发现的众多非编码DNA对我们存活的最重要程度远不如我们更为熟知的那些基因。例如,其中有许多DNA可编码引领我们从受精卵发育为身体健康成年人的类似分子。如果这些非编码DNA片段损毁,因其明确功能的有所不同,我们将有可能遭到脑损伤或癌症之类的灾难性后果。

大规模的基因组研究给大批研究人员带给了这样的希望:也许,人类基因组比以前指出的更为活跃。In January, Francis Collins, the director of the National Institutes of Health, made a comment that revealed just how far the consensus has moved. At a health care conference in San Francisco, an audience member asked him about junk DNA. “We don’t use that term anymore,” Collins replied. “It was pretty much a case of hubris to imagine that we could dispense with any part of the genome — as if we knew enough to say it wasn’t functional.” Most of the DNA that scientists once thought was just taking up space in the genome, Collins said, “turns out to be doing stuff.”今年1月,美国国立公共卫生研究院(National Institutes of Health, N.I.H)主任弗朗西斯·柯林斯(Francis Collins)就目前共识意见的改变公开发表了评论。在旧金山举办的一次公共卫生会议上,一位听众就“垃圾DNA”向他发问。

“我们早已仍然用于这个术语了,”柯林斯问道。“以为我们可以摒弃基因组的某些部分,这觉得是一种十分狂妄自大的点子——就好像我们不敢打包票它们没任何功能似的。

”科林斯认为,在曾多次被科学家们指出只是白占地方的基因组DNA中,大部分“只不过都各有用途”。For Gregory and a group of like-minded biologists, this idea is not just preposterous but also perilous, something that could yield bad science. The turn against the notion of junk DNA, they argue, is based on overinterpretations of wispy evidence and a willful ignorance of years of solid research on the genome. They’ve challenged their opponents face to face at scientific meetings. They’ve written detailed critiques in biology journals. They’ve commented on social media. When the N.I.H.’s official Twitter account relayed Collins’s claim about not using the term “junk DNA” anymore, Michael Eisen, a professor at the University of California, Berkeley, tweeted back with a profanity.这种点子在格雷戈里和一群与他志同道合的生物学家显然不仅可笑而且危险性,很可能会带给“伪科学”。

他们指出,赞成“垃圾DNA”的概念,不过是基于对少数证据的过度理解,以及对多年来坚实的基因组研究的故意忽略。于是,他们在学术会议上面对面地向输掉发动了挑战,还在生物学期刊上编写了详尽的评论文章,并在社交媒体上倾听。当N.I.H.的官方Twitter帐号发送柯林斯有关仍然用于“垃圾DNA”这一术语的声明时,加州大学伯克利分校(University of California, Berkeley)的教授迈克尔·艾森(Michael Eisen)在Twitter上大骂了回来。

The junk DNA wars are being waged at the frontiers of biology, but they’re really just the latest skirmish in an intellectual struggle that has played out over the past 200 years. Before Charles Darwin articulated his theory of evolution, most naturalists saw phenomena in nature, from an orchid’s petal to the hook of a vulture’s beak, as things literally designed by God. After Darwin, they began to see them as designs produced, instead, by natural selection. But some of our greatest biologists pushed back against the idea that everything we discover in an organism had to be an exquisite adaptation. To these biologists, a fully efficient genome would be inconsistent with the arbitrariness of our genesis, with the fact that every species emerged through pure happenstance, over eons of false starts. Where some look at all those billions of bases and see a finely tuned machine, others, like Gregory, see a disorganized, glorious mess.如今,“垃圾DNA”之战正在生物学的前沿上打响,但它们事实上不过是将近200年来知识界纷争中最近的几场小战役罢了。在查尔斯·达尔文(Charles Darwin)公开发表知名的进化论之前,大多数博物学家都指出自然界中的现象——从兰花的花瓣到秃鹫喙上的钩——都是上帝设计出来的杰作。在达尔文的理论获得普遍拒绝接受之后,他们又开始将其视作自然选择的产物,指出生物的方方面面都是准确适应环境的结果。

然而,一些最最出色的生物学家却明确提出了赞成意见。在这些生物学家显然,充份高效的基因组与我们起源的政治性相符,事实上,每一个物种都是在无数次错误的尝试中无意间问世的。有些人从这数十亿碱基里看见一架调控精巧的机器,而在格雷戈里等其他人眼里,那只是一片狼藉。

In 1953, Francis Crick and James Watson published a short paper in the journal Nature setting out the double-helix structure of DNA. That brief note sent biologists into a frenzy of discovery, leading eventually to multiple Nobel Prizes and to an unprecedented depth of understanding about how living things grow and reproduce. To make a protein from DNA, they learned, a cell makes a single-stranded copy of the relevant gene, using a molecule called RNA. It then builds a corresponding protein using the RNA as a guide.1953年,弗朗西斯·克里克(Francis Crick)和詹姆斯·沃森(James Watson)在《大自然》杂志(Nature)上公开发表了一篇短文,展出了DNA的双螺旋结构。这篇短文让生物学家们投放了探寻的狂潮之中,最后还产生了多个诺贝尔奖,人们对生物的生长和交配的理解超过了前所未有的深度。

他们找到,要根据DNA来生产蛋白质,细胞要用于一种叫作RNA的分子来制作涉及基因的单链拷贝,然后再行利用该RNA来指导适当蛋白质的制备。This research led scientists to assume that the genome was mostly made up of protein-coding DNA. But eventually scientists found this assumption hard to square with reality. In 1964, the German biologist Friedrich Vogel did a rough calculation of how many genes a typical human must carry. Scientists had already discovered how big the human genome was by staining the DNA in cells, looking at the cells through microscopes and measuring its size. If the human genome was made of nothing but genes, Vogel found, it would need to have an awful lot of them — 6.7 million genes by his estimate, a number that, when he published it in Nature, he admitted was “disturbingly high.” There was no evidence that our cells made 6.7 million proteins or anything close to that figure.这项研究促成科学家们庞加莱基因组的绝大部分应当是编码蛋白质的DNA,但后来他们找到,这种假设与现实相去甚远。科学家们通过对细胞中的DNA展开染色,并以显微镜仔细观察和测量,估计出有了人类基因组的大小。

1964年,德国生物学家弗里德里希·福格尔(Friedrich Vogel)在《大自然》杂志上公开发表了一篇文章,粗略计算出来了如果人类基因组几乎由基因构成,一般来说,一个人应当装载的基因数目是670万个基因。这个数字真是难以置信地大,福格尔自己也否认它“低得令人不安”。没任何证据指出,我们的细胞可以产生670万种或相似这一数字的蛋白质。Vogel speculated that a lot of the genome was made up of essential noncoding DNA — possibly operating as something like switches, for example, to turn genes on and off. But other scientists recognized that even this idea couldn’t make sense mathematically. On average, each baby is born with roughly 100 new mutations. If every piece of the genome were essential, then many of those mutations would lead to significant birth defects, with the defects only multiplying over the course of generations; in less than a century, the species would become extinct.于是福格尔推断基因组大部分是由必须的非编码DNA构成——举例来说,它们有可能是充分发挥了类似于电源的起到,管理着基因的活跃与重开。

但其他的科学家们意识到,即使按照这个点子,在数学角度上还是不合理。平均值而言,每个婴儿出生于时约具有100个新的基因突变。

如果基因组中的所有片段都是必不可少的,那么这些变异中有很多都会造成根本性的天生缺失,即使这些缺失只有在传代过程中才不会成倍增加,该物种也不会在一个世纪内绝种。Faced with this paradox, Crick and other scientists developed a new vision of the genome during the 1970s. Instead of being overwhelmingly packed with coding DNA, the genome was made up mostly of noncoding DNA. And, what’s more, most of that noncoding DNA was junk — that is, pieces of DNA that do nothing for us. These biologists argued that some pieces of junk started out as genes, but were later disabled by mutations. Other pieces, called transposable elements, were like parasites, simply making new copies of themselves that were usually inserted harmlessly back in the genome.面临这一悖论,克里克和其他科学家在20世纪70年代明确提出了关于基因组的新观点:基因组并没塞满编码DNA,事实上,基因组绝大部分所谓编码DNA。更加最重要的是,大多数非编码DNA都是“垃圾”——也就是说,这些DNA片段对我们来说一无所用。这些生物学家指出,某些“垃圾DNA”片段最初也是基因,只是后来因为变异的缘故失活了。

其他的DNA片段称作转座因子,它们就样子寄生虫一样,全然地拷贝自己并放入到基因组的新方位上去(这种放入一般来说是有害的)。Junk DNA’s recognition was part of a bigger trend in biology at the time. A number of scientists were questioning the assumption that biological systems are invariably “well designed” by evolution. In a 1979 paper in The Proceedings of the Royal Society of London, Stephen Jay Gould and Richard Lewontin, both of Harvard, groused that too many scientists indulged in breezy storytelling to explain every trait, from antlers to jealousy, as an adaptation honed by natural selection for some essential function. Gould and Lewontin refer to this habit as the Panglossian paradigm, a reference to Voltaire’s “Candide,” in which the foolish Professor Pangloss keeps insisting, in the face of death and disaster, that we live in “the best of all possible worlds.” Gould and Lewontin did not deny that natural selection was a powerful force, but they stressed that it was not the only explanation for why species are the way they are. Male nipples are not adaptations, for example; they’re just along for the ride.当时,辨识“垃圾DNA”是生物学研究的大趋势之一。

许多科学家都开始批评所有生物体系都是演化“精心设计而来”的这一假设。1979年,哈佛大学(Harvard)的史蒂芬·杰伊·古尔德(Stephen Jay Gould)和理查德·列万廷(Richard Lewontin)在《伦敦皇家学会会刊》(The Proceedings of the Royal Society of London)上公开发表了一篇文章,责怪有过于多的科学家纵容自己讲故事般精彩热情地将每一个性状——从鹿角到嫉妒心——都说明沦为了构建什么必不可少的功能而自然选择出来的适应性。古尔德和列万廷称之为这种习惯是“盲目乐观”(Panglossian)的典范——这个字眼来自伏尔泰(Voltaire)的小说《憨第德》(Candide)中那位再三坚决,即使面临丧生和灾难,人们的处境依然是“在所有有可能的情况中最理想”的可笑教授潘格罗士(Professor Pangloss)。

古尔德和列万廷并不坚称自然选择是一种强劲的力量,但他们特别强调,它并不是说明物种为何不会演化成现在这个模样的唯一答案。例如,雄性的乳头就不是一种适应性,它们不过是在演化中凑凑热闹罢了。Gould and Lewontin called instead for a broader vision of evolution, with room for other forces, for flukes and historical contingencies, for processes unfolding at different levels of life — what Gould often called “pluralism.” At the time, geneticists were getting their first glimpses of the molecular secrets of the human genome, and Gould and Lewontin saw more evidence for pluralism and against the Panglosses. Any two people may have millions of differences in their genomes. Most of those differences aren’t a result of natural selection’s guiding force; they just arise through random mutations, without any effect for good or ill.古尔德和列万廷敦促人们以更加广阔的眼光来看来演化,为其他的演化力量,如车祸和历史突发事件,以及在生命的有所不同层面上进行的过程留给空间——也就是古尔德经常说道的“多元主义”。

当时正值遗传学家们第一次看清人类基因组的分子秘密之时,古尔德和列万廷找到了更好反对多元主义,赞成盲目乐观的证据。任何两个人的基因组之间都有可能不存在数百万个差异,其中大多数都不是自然选择引领下的结果,它们只是些随机变异,无所谓优劣。

When Crick and others began to argue for junk DNA, they were guided by a similar vision of nature as slipshod. Just as male nipples are a useless vestige of evolution, so, in their theory, is a majority of our genome. Far from the height of machine-like perfection, the genome is largely a palimpsest of worthless instructions, a den of harmless parasites. Crick and his colleagues argued that transposable elements were common in our genome not because they did something essential for us, but because they could exploit us for their own replication. Gould delighted at this good intellectual company, arguing that transposable elements behaved like miniature organisms, evolving to become better at adding new copies to their host genomes. Our genomes were their ocean, their savanna. “They are merely playing Darwin’s game, but at the ‘wrong level,’” Gould wrote in 1981.当克里克等人开始为“垃圾DNA”而辩时,他们也抱持着类似于的观点:大大自然是个漫不经心的家伙。他们指出,雄性的乳头只是演化中的一个多余的痕迹,我们的绝大部分基因组也是如此。基因组预想超过机械般的准确和极致,在相当大程度上,它更加看起来一本被重复擦去又改写的抄本,又看起来有害的寄生虫们的巢穴。

克里克和他的同事们认为,转座因子之所以在我们的基因组中十分少见,不是因为它们有什么必不可少的功能,而是因为它们可以利用我们来已完成它们自身的拷贝。这种学术上的志同道合令其古尔德十分伤心,他也主张转座因子的不道德与微生物相近,在演化过程中,它们更加擅长于在宿主基因组中减少新的自身DNA拷贝。

我们的基因组就只不过它们存活的海洋和草原。古尔德在1981年写到:“它们不过是在‘错误的层面上’玩游戏达尔文的游戏罢了。”Soon after Gould wrote those words, scientists set out to decipher the precise sequence of the entire human genome. It wasn’t until 2001, shortly before Gould’s death, that they published their first draft. They identified thousands of segments that had the hallmarks of dead genes. They found transposable elements by the millions. The Human Genome Project team declared that our DNA consisted of isolated oases of protein-coding genes surrounded by “vast expanses of unpopulated desert where only noncoding ‘junk’ DNA can be found.” Junk DNA had started out as a theoretical argument, but now the messiness of our evolution was laid bare for all to see.就在古尔德写上面那番话后旋即,科学家们开始著手破解整个人类基因组的准确序列。

但直到2001年,古尔德去世前不久,他们才公开发表了第一稿研究结果。他们辨识出有了具有“杀基因”标志的数千个DNA片段,还找到了数以百万计的转座因子。“人类基因组计划(Human Genome Project)”团队声称,我们的DNA就像“一大片由‘垃圾DNA’构成的荒漠”,其中星星点点散播着编码蛋白质的基因“绿洲”。“垃圾DNA”最初只是一个理论上的争辩,但现在我们在演化上的杂乱无章早已是有目共睹。

If you want to see the genome in a fundamentally different way, the best place to go is the third floor of Harvard’s Department of Stem Cell and Regenerative Biology, in a maze of cluttered benches, sequencing machines and microscopes. This is the lab of John Rinn, a 38-year-old former competitive snowboarder who likes to ponder biological questions on top of a skateboard, which he rides from one wall of his office to the other and back. Rinn is overseeing more than a dozen research projects looking for pieces of noncoding DNA that might once have been classified as junk but actually are essential for life.如果你想用一种迥然不同的方式去实地考察基因组,哈佛大学干细胞与再造生物学系(Department of Stem Cell and Regenerative Biology)乱糟糟地摆放了试验台、测序仪和显微镜的迷宫般的三楼是一个绝佳场所。这里是约翰·里恩(John Rinn)的实验室,他今年38岁,曾是一名竞技雪板滑雪运动员,现在仍然讨厌匹敌着雪板从办公室的一面墙滑到另一面墙,同时思维生物学问题。

里恩负责管理着十几个项目,目的是研究一些曾多次被视作“垃圾”,只不过却为生命所必须的非编码DNA片段。Rinn studies RNA, but not the RNA that our cells use as a template for making proteins. Scientists have long known that the human genome contains some genes for other types of RNA: strands of bases that carry out other jobs in the cell, like helping to weld together the building blocks of proteins. In the early 2000s, Rinn and other scientists discovered that human cells were reading thousands of segments of their DNA, not just the coding parts, and producing RNA molecules in the process. They wondered whether these RNA molecules could be serving some vital function.里恩的研究对象是RNA,但不是我们的细胞借以作为生产蛋白质的模板的那种RNA。

科学家们早就告诉,人类基因组中包括着一些其他类型的RNA的基因:这些碱基组成的长链在细胞内继续执行着其他任务,比如帮助蛋白质装配等。21世纪初,里恩和其他科学家找到,人类细胞可以读者数千个自身DNA片段(不仅包括编码区),并在此过程中生产RNA分子。他们想要告诉这些RNA分子否具备什么生死攸关的功能。

As a postdoctoral fellow at Stanford University, Rinn decided he would try to show that one of these new RNA molecules had some important role. After a couple years of searching, he and a professor there, Howard Chang, settled on an RNA molecule that, somewhat bizarrely, was produced widely by skin cells below the waist but not above. Rinn and Chang were well aware that this pattern might be meaningless, but they set out to investigate it nevertheless. They had to give their enigmatic molecule a name, so they picked one that was a joke at their own expense: hotair. (“If it ends up being hot air, at least we tried,” Rinn said.)里恩在斯坦福大学(Stanford University)做到博士后时就要求要尝试证明这些新的RNA分子具备最重要的起到。经过几年的检索,他与该大学的教授张元豪(Howard Chang)指定了一种类似的RNA分子,这种分子十分怪异,它在腰部以下的皮肤细胞中普遍不存在,但在腰部以上却几乎不知踪迹。

里恩和张都确切地告诉,这种模式有可能毫无意义,但他们依然开始了研究。他们给自己的谜样分子所取了个极具调侃意味的名字:“hotair”。“如果最后证明它什么也不是(hot air有“吹牛”、“空话”之意——学术著作),起码我们曾多次希望过,”里恩说道。

Rinn ran a series of experiments on skin cells to figure out what, if anything, hotair was doing. He carefully pulled hotair molecules out of the cells and examined them to see if they had attached to any other molecules. They had, in fact: they were stuck to a protein called Polycomb.里恩对皮肤细胞展开了一系列的实验,想要想到hotair有什么功能(就是说,如果有的话)。他小心翼翼地将hotair分子从细胞中萃取出来,并检查它们否曾与任何其他分子相连接。事实上,是的:它们可与一种取名为Polycomb的蛋白质紧密结合。

Polycomb belongs to a group of proteins that are essential to the development of animals from a fertilized egg. They turn genes on and off in different patterns, so that a uniform clump of cells can give rise to bone, muscle and brain. Polycomb latches onto a number of genes and muzzles them, preventing them from making proteins. Rinn’s research revealed that hotair acts as a kind of guide for Polycomb, attaching to it and escorting it through the jungle of the cell to the precise spots on our DNA where it needs to silence genes.Polycomb隶属于一组对于从受精卵到动物成体的发育过程必不可少的蛋白质。它们可在有所不同的模式下转录或重开基因,从而使一群细胞统一地发育成骨骼、肌肉或脑。Polycomb蛋白可以与多种基因结合并使其失活,无法再生产蛋白质。里恩的研究表明,hotair的起到就看起来Polycomb蛋白的一行,当它融合在Polycomb上后,就可以随行该蛋白穿越乱七八糟的细胞内环境,精确地融合到必须被绝望的基因位点上。

When Rinn announced this result in 2007, other geneticists were stunned. Cell, the journal that released it, hailed it as a breakthrough, calling Rinn’s paper one of the most important they had ever published. In the years since, Chang and other researchers have continued to examine hotair, using even more sophisticated tools. They bred engineered mice that lack the hotair gene, for example, and found that the mice developed a constellation of deformities, like stunted wrists and jumbled vertebrae. It appears very likely that hotair performs important jobs throughout the body, not just in the skin but in the skeleton and in other tissues too.2007年,里恩在《细胞》(Cell)杂志上公开发表了自己的研究结果,愤慨了遗传学界。《细胞》杂志称之为其为极大的突破,并回应里恩的这项研究是他们曾多次公开发表过的最重要的论文之一。

在随后的几年中,张和其他研究人员用于更加简单的工具之后对hotair深入研究。例如,他们利用基因工程,培育出了缺少hotair基因的小鼠,并找到这些小鼠经常出现了一系列畸形,如腕部发育功能障碍、椎骨夹杂等。似乎hotair很有可能在皮肤、骨骼以及全身的其他的组织中也充分发挥着最重要的起到。In 2008, having been lured to Harvard, Rinn set up his new lab entirely in hopes of finding more hotair-like molecules. The first day I visited, a research associate named Diana Sanchez was dissecting mouse embryos the size of pinto beans. In a bowl of ice next to her were tubes for the parts she delicately removed — liver, leg, kidney, lung — that would be searched for cells making RNA molecules. After Rinn and I left Sanchez to her dissections, we ran into Martin Sauvageau, a blue-eyed Quebecer carrying a case of slides, each affixed with a slice of a mouse’s brain, with stains revealing cells making different RNA molecules. I tagged along with Sauvageau as he headed to a darkened microscope room to look at the slides with a pink-haired grad student named Abbie Groff. On one slide, a mouse’s brain looked as if it wore a cerulean mustache. To Groff, every pattern comes as a surprise. She once discovered an RNA molecule that created thousands of tiny rings on a mouse’s body, each encircling a hair follicle. “You come in in the morning, and it’s like Christmas,” she said.2008年,里恩受邀回到哈佛大学,并在此创建了自己的新实验室,一心一意期望能寻找更加多类似于hotair的分子。

我去参观的第一天,正赶上他的研究助理戴安娜·桑切斯(Diana Sanchez)在解剖学只有斑豆大小的小鼠胚胎。她旁边的冰浴槽中挂着好些个试管,里面鲜花着她精心挤压的各种器官和身体部件——肝脏、腿、肾脏、肺等,用作从其中搜索生产RNA分子的细胞。为了不睡觉桑切斯的解剖学工作,里恩和我离开了,然后我们遇到了马丁·索瓦若(Martin Sauvageau),这个蓝眼睛的魁北克人拿着一盒玻片,每片玻片上都相同着一片小鼠大脑切片,并以染色表明了生产有所不同RNA分子的细胞。

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我随同索瓦若前往黑暗的显微镜室,和一个具有粉红色头发的研究生阿比·格罗夫(Abbie Groff)一起查阅了这些切片。有一张切片上的小鼠脑部就像拔了一簇天蓝色的小胡子。

在格罗夫显然,每种模式都是一个惊艳。她曾多次找到了一种RNA分子可以在小鼠体内产生数千个微小的环状物,每个环都包在绕着一个毛囊。

“每天早上进去的时候,感觉都像在过圣诞节,”她这样形容道。In December 2013, Rinn and his colleagues published the first results of their search: three potential new genes for RNA that appear to be essential for a mouse’s survival. To investigate each potential gene, the scientists removed one of the two copies in mice. When the mice mated, some of their embryos ended up with two copies of the gene, some with one and some with none. If these mice lacked any of these three pieces of DNA, they died in utero or shortly after birth. “You take away a piece of junk DNA, and the mouse dies,” Rinn said. “If you can come up with a criticism of that, go ahead. But I’m pretty satisfied. I’ve found a new piece of the genome that’s required for life.”2013年12月,里恩和同事们公开发表了第一批搜寻结果:有三个新的潜在的RNA基因有可能对小鼠的存活至关重要。

为了调查每个潜在基因,科学家设法移除了小鼠体内该基因两个拷贝中的一个。当这些小鼠交配时,一部分胚胎将具有两个基因拷贝,有的具有一个,有的则一个也没。

不论是缺乏这三种DNA片段中的哪一个,小鼠都会胎死宫中或在出生于后旋即丧生。“敲打除了一个‘垃圾DNA’片段,小鼠就无法存活,”里恩说道。

“如果你要提出批评意见,尽管谈谈了。但我早已很失望了。

我又找到了一个新的生命必须的基因组片段。”As the scientists find new RNA molecules that look to be important, they are picking out a few to examine in close molecular detail. “I’m totally in love with this one,” Rinn said, standing at a whiteboard wall and drawing a looping line to illustrate yet another RNA molecule, one that he calls “firre.” The experiments that Rinn’s team has run on firre suggest that it performs a spectacular lasso act, grabbing onto three different chromosomes at once and drawing them together. Rinn suspects that there are thousands of RNA molecules encoded in our genomes that perform similar feats: bending DNA, unspooling it, bringing it in contact with certain proteins and otherwise endowing it with a versatility it would lack on its own.在找寻新的具备最重要功能的RNA分子的同时,科学家们也借此投票决定了几个来展开分子层面上的详尽研究。

里恩车站在白板前,用循环线图示向我阐述另一种被他命名为“firre”的RNA分子,“我想要我早已深深爱上它了,”他说道。里恩的团队目前对firre展开的实验指出,它的功能像一个极大的套索,可以同时逃跑三个有所不同的染色体并把它们纳到一块儿来。里恩猜测我们的基因组编码了成千上万个可以展开类似于伟业的RNA分子,它们可以倾斜DNA、找出DNA螺旋,使其与某些特定的蛋白质认识或者彰显其本身没的普遍功用。

“It’s genomic origami,” Rinn said about this theory. “In every cell, you have the same piece of paper. Stem cell, brain cell, liver cell, it’s all made from the same piece of paper. How you fold that paper determines if you get a paper airplane or a duck. It’s the shape that you fold it into that matters. This has to be the 3-D code of biology.”“这就只不过在基因组层面上做到折纸手工,”里恩这样说明他的理论。“每个细胞都享有一张某种程度的纸。

干细胞、脑细胞、肝脏细胞……全都就是指某种程度的纸上问世的,是你的折法要求了最后不会获得一架飞机还是一只鸭子。你拉链出来的形状才是最重要的。这是生物学的三维代码。

”To some biologists, discoveries like Rinn’s hint at a hidden treasure house in our genome. Because a few of these RNA molecules have turned out to be so crucial, they think, the rest of the noncoding genome must be crammed with riches. But to Gregory and others, that is a blinkered optimism worthy of Dr. Pangloss. They, by contrast, are deeply pessimistic about where this research will lead. Most of the RNA molecules that our cells make will probably not turn out to perform the sort of essential functions that hotair and firre do. Instead, they are nothing more than what happens when RNA-making proteins bump into junk DNA from time to time.一些生物学家指出,里恩这类新发现提醒我们的基因组中隐蔽着一座大宝库。由于有数研究证明,有几种这样的RNA分子至关重要,他们指出,基因组其余的非编码片段一定也蕴含着非常丰富的宝藏。但是格雷戈里和其他人回应这种点子不过是潘格罗士博士那样的盲目乐观罢了。

相比之下,他们倒是对这项研究的前景感到乐观。事实上,我们的细胞生产的大多数RNA分子很有可能并没像hotair或firre那样的最重要功能。忽略,在大部分情况下,不过是生产RNA的蛋白质有时候撞上了“垃圾DNA”而已。

“You say, ‘I found it — America!’” says Alex Palazzo, a biochemist at the University of Toronto who co-wrote a spirited defense of junk DNA with Gregory last year in the journal PLOS Genetics. “But probably what you found is a little bit of noise.”“你激动地声称:‘我找到了美洲新大陆!’”多伦多大学(University of Toronto)的生化学家,与格雷戈里协力在《公共科学图书馆:遗传学》杂志(PLOS Genetics)上撰文为“垃圾DNA”极力申辩的亚历克斯·帕拉佐(Alex Palazzo)说道,“但你找到的很有可能只是一点点噪音罢了。”Palazzo and his colleagues also roll their eyes at the triumphant declarations being made about recent large-scale surveys of the human genome. One news release from an N.I.H. project declared, “Much of what has been called ‘junk DNA’ in the human genome is actually a massive control panel with millions of switches regulating the activity of our genes.” Researchers like Gregory consider this sort of rhetoric to be leaping far beyond the actual evidence. Gregory likens the search for useful pieces of noncoding DNA to using a metal detector to find gold buried at the beach. “The idea of combing the beach is a great idea,” he says. But you have to make sure your metal detector doesn’t go off when it responds to any metal. “You’re going to find bottle caps and nails,” Gregory says.帕拉佐和同事们还将目光改向了近期的一次大规模人类基因组调查的胜利宣言。一项N.I.H.项目最近发布新闻称之为:“人类基因组中之前被称作‘垃圾DNA’的片段只不过大多是极大的控制面板,含有数以百万计的电源,调节着我们的基因活性。”格雷戈里等研究人员指出这是相比之下远超过了实际证据的夸张之言。

格雷戈里将找寻简单的非编码DNA片段比作用于金属探测器搜寻挖出在沙滩里的黄金。“把海滩彻底搜查一番是个好主意,”他说道。但你必需保证你的金属探测器会遇上任何金属都警铃大作。“不然你寻找的绝大部分都将是瓶盖和钉子。

”格雷戈里说道;He expects that as we examine the genome more closely, we’ll find many bottle caps and nails. It’s a prediction based, he and others argue, on the deep evolutionary history of our genome. Over millions of years, essential genes haven’t changed very much, while junk DNA has picked up many harmless mutations. Scientists at the University of Oxford have measured evolutionary change over the past 100 million years at every spot in the human genome. “I can today say, hand on my heart, that 8 percent, plus or minus 1 percent, is what I would consider functional,” Chris Ponting, an author of the study, says. And the other 92 percent? “It doesn’t seem to matter that much,” he says.他预计,随着我们更加细心地检查基因组,还不会找到许多瓶盖和钉子。他和其他人回应,这个预测是基于我们基因组很深的进化史作出的。

数百万年来,必须基因并没有再次发生多少变化,而“垃圾DNA”却拿着了很多有害的变异。牛津大学(University of Oxford)的科学家们取决于了过去一亿年来人类基因组的每个位点在演化上的转变。该研究的作者之一,克里斯·庞廷(Chris Ponting)说道:“现在我不敢拍着胸脯说道,我指出其中只有8%(上下波动范围会多达1%)具备生物学功能。”那其他的92%呢?“或许就没有那么最重要了,”他说道。

It’s no coincidence, researchers like Gregory argue, that bona fide creationists have used recent changes in the thinking about junk DNA to try to turn back the clock to the days before Darwin. (The recent studies on noncoding DNA “clearly demonstrate we are ‘fearfully and wonderfully made’ by our Creator God,” declared the Institute for Creation Research.) In a sense, this debate stretches back to Darwin himself, whose 1859 book, “On the Origin of Species,” set the course for our understanding natural selection as a natural “designer.” Later in his life, Darwin took pains to stress that there was more to evolution than natural selection. He was frustrated to see how many of his readers thought he was arguing that natural selection was the only force behind life’s diversity. “Great is the power of steady misrepresentation,” Darwin grumbled when he updated the book for its sixth edition in 1872. In fact, he wrote, he was quite open-minded about other forces that might drive evolution, like “variations that seem to us in our ignorance to arise spontaneously.”格雷戈里等研究人员指出,笃信的创世纪论者不约而同地利用“垃圾DNA”观念中的近期变化,这毕竟无意间,他们这是企图让时间衰退返达尔文时代之前。(创世纪论研究学会[Institute for Creation Research]称之为:近期关于非编码DNA的研究“确切地指出我们是造物主‘建构的不可思议又可怕的作品’”。

)从某种程度上说道,这场辩论可以追溯到达尔文本人,他在1859年出版发行的著作《物种起源》(“On the Origin of Species”)中将我们对自然选择的解读定位为天然的“设计师”。晚年时期的达尔文也曾煞费苦心地特别强调,自然选择只是演化的一个方面。

看见许多读者误以为他主张自然选择是产生生物多样性的唯一动力,令其他十分失望。“接连不断的错误阐述的力量真为大。”达尔文在1872年改版该书第六版时责怪道。

事实上,他对有可能推展演化的其他力量,比如“在我们从不知情的情况下自发性产生的变异”等持有人非常专制的态度。Darwin was certainly ignorant about genomes, as scientists would continue to be for decades after his death. But Gregory argues that genomes embody the very mix of adaptation and arbitrariness that Darwin had in mind. Over millions of years, the human genome has spontaneously gotten bigger, swelling with useless copies of genes and new transposable elements. Our ancestors tolerated all that extra baggage because it wasn’t actually all that heavy. It didn’t make them inordinately sick. Copying all that extra DNA didn’t require them to draw off energy required for other tasks. They couldn’t add an infinite amount of junk to the genome, but they could accept an awful lot. To subtract junk, meanwhile, would require swarms of proteins to chop out every single dead gene or transposable element — without chopping out an essential gene. A genome evolving away its junk would lose the race to sloppier genomes, which left more resources for fighting diseases or having children.达尔文认同对基因组一无所知,因为直到他去世几十年后,科学家们才开始孜孜不倦地研究这一课题。但格雷戈里指出,基因组刚好反映了达尔文的想法:适应性和政治性的混合体。

数百万年来,人类基因组自发性减小了不少,其中弥漫着多余的基因拷贝和新的转座因子。我们的祖先尊重地将所有这些额外的行李带在了身上,因为它们本来也远比多重的开销。这些额外的DNA既会造成重病,拷贝所需的能量也很少,会影响其他长时间工作的已完成。当然,基因组不有可能无限制地采纳垃圾,但其垃圾容量显然非常极大。

另一方面,要清理垃圾则很困难,必须大批的蛋白质来移除每一个“杀基因”或转座因子——同时还得确保会伤到必须基因。一个校验的基因组可以保有更好的资源来展开交配或与疾病斗争,而遗失“垃圾DNA”的基因组则将沦落演化中的输家。The blood-drenched slides that pack Gregory’s lab with their giant genomes only make sense, he argues, if we give up thinking about life as always evolving to perfection. To him, junk DNA isn’t a sign of evolution’s failure. It is, instead, evidence of its slow and slovenly triumph.格雷戈里指出,只有当我们仍然指出生命总是朝着更加完备的方向发展,才能解读塞满他实验室的那些血淋淋的切片中展出的极大基因组。在他显然,“垃圾DNA”并不是演化告终的标志,忽略,它指出演化是个较慢的过程,其顺利往往是不经意间的妙手偶得。

:og视讯平台。

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