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.
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.
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.
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.
“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.”
“这就像谷歌地图，”博德研究所(Broad Institute)的所长埃里克·兰德(Eric Lander)说道。该研究所由哈佛大学(Harvard)和麻省理工大学(Massachusetts Institute of Technology)共同成立。相比之下， 该项目的先驱确定了人类DNA序列的人类基因组计划(Human Genome Project)则“更像是从太空中拍摄了地球的图像。那幅画没有告诉你路在哪儿，没有告诉你一天中某个时候的交通如何，没有告诉你好的餐馆在哪儿，也没有告诉你医院、城市或河流在哪儿，”兰德说。
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.”
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.
新发现以六篇论文的形式于周三发表在《自然》杂志(Nature)上，并以24篇论文发表在《基因组研究》(Genome Research)和《基因组生物学》(Genome Biology)上。另外，《生物化学杂志》(The Journal of Biological Chemistry)将会发表六篇评论文章，《科学》也会接着发表一篇文章。
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.
人类DNA“比我们预期的要活跃得多，还有很多是我们之前没有想到的，”来自欧洲分子生物实验室-欧洲生物信息研究所(European Molecular Biology Laboratory-European Bioinformatics Institute)的尤安·伯尼(Ewan Birney)说道，他是该项目的领头研究人员。
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.
“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.
“影响疾病的大多数变异不在基因本身，而在基因开关上，”项目的研究员之一，斯坦福大学(Stanford University)的迈克尔·斯奈德(Michael Snyder)说道。该项目称为“DNA元件百科全书计划”(Encyclopedia of DNA Elements)，简称Encode。
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.”
“这是很重要的发现，”Encode研究员、马萨诸塞州综合医院(Massachusetts General Hospital)的布拉德利· 伯恩斯坦博士(Bradley Bernstein)说道。他还补充，“我认为没有人预见到会是这样。”
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.
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.
Dr. Bernstein said, “This is a resource, like the human genome, that will drive science forward.”
The system, though, is stunningly complex, with many redundancies. Just the idea of so many switches was almost incomprehensible, Dr. Bernstein said.
There also is a sort of DNA wiring system that is almost inconceivably intricate.
“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.”
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.
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研究员、冷泉港实验室(Cold Spring Harbor Laboratory)的托马斯·金格拉斯(Thomas Gingeras)称，计划开始之前，大家认为，仅有5%到10%的人类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.
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.
当美国国家国家卫生研究院(National Institutes of Health)的分支机构国家人类基因组研究所(National Human Genome Research Institute)启动Encode计划的时候，DNA测序和计算生物学的重大进展已经使人类DNA暗物质变得比较容易理解了。尽管如此，数据分析仍令人望而却步。研究人员得到的原始数据有15万亿字节之巨。分析这些数据需要相当于一台计算机运算300多年的时间。
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.