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绡悆绔炲僵* :400萬基因開關開啟醫學大突破

篮球竞彩nba www.xvrnl.com   Bits of Mystery DNA, Far From ‘Junk,’ Play Crucial Role

  400萬基因開關開啟醫學大突破

  Among the many mysteries of human biology is why complex diseases like diabetes, high blood pressure and psychiatric disorders are so difficult to predict and, often, to treat. An equally perplexing puzzle is why one individual gets a disease like cancer or depression, while an identical twin remains perfectly healthy.

  有關人類生物學還有許多未解之謎,其中之一是,為什么很多復雜的疾病,如糖尿病、高血壓和精神疾病總是難以預先發現,有時也很難治愈。同樣令人困惑的還有,為什么同卵雙胞胎其中之一患上了像癌癥或抑郁癥這樣的病,而另一個卻安然無恙。

  Now scientists have discovered a vital clue to unraveling these riddles. The human genome is packed with at least four million gene switches that reside in bits of DNA that once were dismissed as “junk” but that turn out to play critical roles in controlling how cells, organs and other tissues behave. The discovery, considered a major medical and scientific breakthrough, has enormous implications for human health because many complex diseases appear to be caused by tiny changes in hundreds of gene switches.

  現在,科學家們發現了一個可以解開謎團的重要線索。人類基因組攜帶著至少400萬個基因開關,這些基因開關位于曾被認為是垃圾的DNA片段上,但后來發現,它們在控制細胞、器官和其他組織的行為上起著關鍵作用。這一發現被認為是醫學界和科學界的重大突破,對人類健康具有重大意義,因為很多復雜的疾病似乎就是由數百個基因開關的微小變化引起的。

  The findings, which are the fruit of an immense federal project involving 440 scientists from 32 laboratories around the world, will have immediate applications for understanding how alterations in the non-gene parts of DNA contribute to human diseases, which may in turn lead to new drugs. They can also help explain how the environment can affect disease risk. In the case of identical twins, small changes in environmental exposure can slightly alter gene switches, with the result that one twin gets a disease and the other does not.

  這些發現是一個大規模美國國家項目的成果。這一項目包括了來自世界上32個實驗室的440名科學家。這些發現可以直接用于研究DNA非基因部分的改變如何引起人類疾病,從而促進新藥的開發;也可以幫助解釋環境如何影響患病風險。在同卵雙胞胎一例中,所處環境的微小變化也會輕微地改變基因開關,從而導致雙胞胎之一患上某種疾病,而另外一個則不會患病。

  As scientists delved into the “junk” — parts of the DNA that are not actual genes containing instructions for proteins — they discovered it is not junk at all. At least 80 percent of it is active and needed. The result is an annotated road map of much of this DNA, noting what it is doing and how. It includes the system of switches that, acting like dimmer switches for lights, control which genes are used in a cell and when they are used, and determine, for instance, whether a cell becomes a liver cell or a neuron.

  這些基因“垃圾”并不是真正的基因,不包含蛋白質指令。但是,當科學家們研究這些“垃圾”的時候,他們發現這部分根本不是“垃圾”,其中至少有80%是有活性和有用的??蒲Ъ頤茄兄瞥雋艘環攵哉獠糠諨NA的帶注解地圖,指出其功能和活動方式。地圖顯示開關系統就如同燈的光線調節開關,能夠控制哪些基因被用于細胞以及何時被用,還能決定一個細胞是成長為肝細胞還是神經細胞。

  “It’s Google Maps,” said Eric Lander, president of the Broad Institute, a joint research endeavor of Harvard and the Massachusetts Institute of Technology. In contrast, the project’s predecessor, the Human Genome Project, which determined the entire sequence of human DNA, “was like getting a picture of Earth from space,” he said. “It doesn’t tell you where the roads are, it doesn’t tell you what traffic is like at what time of the day, it doesn’t tell you where the good restaurants are, or the hospitals or the cities or the rivers.”

  “這就像谷歌地圖,”博德研究所(Broad Institute)的所長埃里克·蘭德(Eric Lander)說道。該研究所由哈佛大學(Harvard)和麻省理工大學(Massachusetts Institute of Technology)共同成立。相比之下, 該項目的先驅確定了人類DNA序列的人類基因組計劃(Human Genome Project)則“更像是從太空中拍攝了地球的圖像。那幅畫沒有告訴你路在哪兒,沒有告訴你一天中某個時候的交通如何,沒有告訴你好的餐館在哪兒,也沒有告訴你醫院、城市或河流在哪兒,”蘭德說。

紐約時報中英文網 //www.xvrnl.com

  The new result “is a stunning resource,” said Dr. Lander, who was not involved in the research that produced it but was a leader in the Human Genome Project. “My head explodes at the amount of data.”

  新發現是“驚人的資源”,蘭德說。他沒有參與該研究,但曾負責人類基因組計劃。“看到如此大的數據量,我的頭都快爆炸了。”

  The discoveries were published on Wednesday in six papers in the journal Nature and in 24 papers in Genome Research and Genome Biology. In addition, The Journal of Biological Chemistry is publishing six review articles, and Science is publishing yet another article.

  新發現以六篇論文的形式于周三發表在《自然》雜志(Nature)上,并以24篇論文發表在《基因組研究》(Genome Research)和《基因組生物學》(Genome Biology)上。另外,《生物化學雜志》(The Journal of Biological Chemistry)將會發表六篇評論文章,《科學》也會接著發表一篇文章。

  Human DNA is “a lot more active than we expected, and there are a lot more things happening than we expected,” said Ewan Birney of the European Molecular Biology Laboratory-European Bioinformatics Institute, a lead researcher on the project.

  人類DNA“比我們預期的要活躍得多,還有很多是我們之前沒有想到的,”來自歐洲分子生物實驗室-歐洲生物信息研究所(European Molecular Biology Laboratory-European Bioinformatics Institute)的尤安·伯尼(Ewan Birney)說道,他是該項目的領頭研究人員。

  In one of the Nature papers, researchers link the gene switches to a range of human diseases — multiple sclerosis, lupus, rheumatoid arthritis, Crohn’s disease, celiac disease — and even to traits like height. In large studies over the past decade, scientists found that minor changes in human DNA sequences increase the risk that a person will get those diseases. But those changes were in the junk, now often referred to as the dark matter — they were not changes in genes — and their significance was not clear. The new analysis reveals that a great many of those changes alter gene switches and are highly significant.

  在《自然》雜志的一篇論文中,研究人員指出基因開關與一系列人類疾病有關系——多發性硬化癥、狼瘡、風濕性關節炎、克羅恩病、乳糜瀉等,甚至還包括像身高這樣的體貌特征。在過去10年的大型研究中,科學家們發現人類DNA序列的微小變化會增加人們患上此類疾病的風險。但這些變化是發生在基因“垃圾”(如今被稱為“暗物質”)上,而不是發生在基因上,并且,這些變化究竟有多大意義,也不甚清楚。新的研究表明,很多這類變化會改變基因開關,并且意義重大。

  “Most of the changes that affect disease don’t lie in the genes themselves; they lie in the switches,” said Michael Snyder, a Stanford University researcher for the project, called Encode, for Encyclopedia of DNA Elements.

  “影響疾病的大多數變異不在基因本身,而在基因開關上,”項目的研究員之一,斯坦福大學(Stanford University)的邁克爾·斯奈德(Michael Snyder)說道。該項目稱為“DNA元件百科全書計劃”(Encyclopedia of DNA Elements),簡稱Encode。

紐約時報中英文網 //www.xvrnl.com/

  And that, said Dr. Bradley Bernstein, an Encode researcher at Massachusetts General Hospital, “is a really big deal.” He added, “I don’t think anyone predicted that would be the case.”

  “這是很重要的發現,”Encode研究員、馬薩諸塞州綜合醫院(Massachusetts General Hospital)的布拉德利· 伯恩斯坦博士(Bradley Bernstein)說道。他還補充,“我認為沒有人預見到會是這樣。”

  The discoveries also can reveal which genetic changes are important in cancer, and why. As they began determining the DNA sequences of cancer cells, researchers realized that most of the thousands of DNA changes in cancer cells were not in genes; they were in the dark matter. The challenge is to figure out which of those changes are driving the cancer’s growth.

  這些發現還能揭示,哪些基因變異對癌癥比較重要,以及為什么重要。當研究人員開始繪制癌細胞的DNA序列時,他們意識到,癌細胞中的幾千個DNA變異中的大多數并不在基因中,而是在暗物質中。困難的是找出這些變異中究竟哪些造成了癌癥的生長。

  In prostate cancer, for example, mutations have been found in important genes that are not readily attacked by drugs. But Encode, by showing which regions of the dark matter control those genes, gives another way to attack them: target those controlling switches.

  比如,在前列腺癌中已經發現了重要基因上的一些突變,但藥物不易對它們起作用。但是,Encode能展示暗物質的哪些具體區域控制著這些基因,從而給出了解決它們的新途徑:針對那些控制開關實施治療。

  Dr. Bernstein said, “This is a resource, like the human genome, that will drive science forward.”

  伯恩斯坦博士稱,“就像人類基因組一樣,這是一種會推動科學進步的資源。”

  The system, though, is stunningly complex, with many redundancies. Just the idea of so many switches was almost incomprehensible, Dr. Bernstein said.

  不過,這個系統的復雜性令人咋舌,帶有許多冗余。伯恩斯坦博士稱,開關數量之多,到了難以想象的程度。

  There also is a sort of DNA wiring system that is almost inconceivably intricate.

  DNA網絡系統也錯綜復雜幾乎令人難以置信。

  “It is like opening a wiring closet and seeing a hairball of wires,” said Mark Gerstein, an Encode researcher from Yale. “We tried to unravel this hairball and make it interpretable.”

  “這就像是打開一個配線室,結果看到一團亂麻,”Encode研究員、耶魯大學的馬克·格斯坦(Mark Gerstein)說道。“我們試圖解開這團麻,使之能夠被理解。”

  The project began in 2003, as researchers began to appreciate how little they knew about human DNA. In recent years, some began to find switches in the 99 percent of human DNA that is not genes, but they could not fully characterize or explain what a vast majority of it was doing.

  Encode計劃始于2003年,當時研究人員開始意識到,他們對人類DNA知之甚少。前幾年,一些人開始發現人類DNA中99%的非基因部分存在基因開關,但他們未能充分描述或解釋其中大部分的功能。

  The thought before the start of the project, said Thomas Gingeras, an Encode researcher from Cold Spring Harbor Laboratory, was that only 5 to 10 percent of the DNA in a human being was actually being used.

  Encode研究員、冷泉港實驗室(Cold Spring Harbor Laboratory)的托馬斯·金格拉斯(Thomas Gingeras)稱,計劃開始之前,大家認為,僅有5%到10%的人類DNA真正被用到。

  The big surprise was not only that almost all of the DNA is used but also that a large proportion of it is gene switches.

  結果卻大大出乎預料。不僅幾乎全部的DNA都有用,而且其中的大部分是基因開關。

  By the time the National Human Genome Research Institute, part of the National Institutes of Health, embarked on Encode, major advances in DNA sequencing and computational biology had made it conceivable to try to understand the dark matter of human DNA. Even so, the data analysis was daunting — the researchers generated 15 trillion bytes of raw data. Analyzing the data required the equivalent of more than 300 years of computer time.

  當美國國家國家衛生研究院(National Institutes of Health)的分支機構國家人類基因組研究所(National Human Genome Research Institute)啟動Encode計劃的時候,DNA測序和計算生物學的重大進展已經使人類DNA暗物質變得比較容易理解了。盡管如此,數據分析仍令人望而卻步。研究人員得到的原始數據有15萬億字節之巨。分析這些數據需要相當于一臺計算機運算300多年的時間。

  Just organizing the researchers and coordinating the work was an enormous undertaking. Dr. Gerstein, who was one of the project’s leaders, has produced a diagram of the authors with their connections to one another. It looks nearly as complicated as the wiring diagram for the human DNA switches.

  僅僅組織這些研究者并協調彼此的工作就是一項巨大的工程。格斯坦博士是項目的負責人之一,他畫出了一張論文作者圖,標出了他們之間彼此的聯系。圖的復雜程度,看起來與人類DNA開關網絡圖差不了多少。

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