人类基因组差异名列榜首
What makes us unique. Changes in the number and order of genes (A-D) add variety to the human genome. CREDIT: COMPOSITE IMAGE: K. KRAUSE/SCIENCE (HUMAN: 3D4MEDICAL.COM; CHROMOSOME: C. BICKEL/SCIENCE)
2007年最令研究人员惊叹的是，从一个人到另一个人的基因组差异程度之大，科学家开始懂得这些差异在疾病和个体特性中的作用。《科学》杂志及其出版者美国科学促进会(AAAS) 将“人类基因组差异”评为2007年首要进展，并在12月21日出版的杂志上列出本年度其他9项最重要的科学成就。
负责评选的《科学》杂志物理类科学新闻副主编Robert Coontz 说，“多年来，我们一直谈人与人如何相像，甚至人与猿如何类似。2007年的几项前沿研究第一次将人与人的DNA存在很大的不同讲透彻了。这是一个巨大的概念性跳跃，将会对所有的事情产生影响：从医生如何治病到我们如何看待自己以及保护我们的隐私。”
2007年，几位个人的基因组被测序。随着技术的提高，我们中的许多人将会了解部分或全部的个人基因组，也将了解自己有患哪些疾病的风险。
自人类基因组序列测出以来，生物学家一直在绘制基因组的一个碱基上的小差异，这种差异被称为单核苷酸多态性(SNPs)。这些差异是2007年十几个研究项目的关键，研究人员在这些被称为基因组范围关联的研究中比较了几千位患病或无病个体的DNA，从而确定哪些小的基因差异带来疾病风险。这种信息能帮助研究人员发现疾病基因，比如近年发现的几个Ⅱ型糖尿病基因。
今年的基因组范围关联研究为许多疾病提供了线索，包括心房颤动、自身免疫疾病、双相障碍、大肠癌、Ⅰ型和Ⅱ型糖尿病、心脏病、高血压、多发性硬化症以及风湿性关节炎。
2007年，生物学家还了解到，在DNA上亿个碱基中，成千到上百万的碱基可能丢失、增加或以某种方式被拷贝，这些变化在几代人内就能改变基因的活性。这些被称为“拷贝数差异”的影响在高淀粉饮食的人群中有表现，这些人群比有狩猎采集传统的人群有更多的消化淀粉DNA的拷贝。研究儿童自闭症的遗传学家发现了导致患自闭症风险增加的一个新的DNA修饰。
进展第一条（原文）
BREAKTHROUGH OF THE YEAR: Human Genetic Variation
Elizabeth Pennisi
Equipped with faster, cheaper technologies for sequencing DNA and assessing variation in genomes on scales ranging from one to millions of bases, researchers are finding out how truly different we are from one another
The unveiling of the human genome almost 7 years ago cast the first faint light on our complete genetic makeup. Since then, each new genome sequenced and each new individual studied has illuminated our genomic landscape in ever more detail. In 2007, researchers came to appreciate the extent to which our genomes differ from person to person and the implications of this variation for deciphering the genetics of complex diseases and personal traits.
Less than a year ago, the big news was triangulating variation between us and our primate cousins to get a better handle on genetic changes along the evolutionary tree that led to humans. Now, we have moved from asking what in our DNA makes us human to striving to know what in my DNA makes me me.
Techniques that scan for hundreds of thousands of genetic differences at once are linking particular variations to particular traits and diseases in ways not possible before. Efforts to catalog and assess the effects of insertions and deletions in our DNA are showing that these changes are more common than expected and play important roles in how our genomes work--or don‘t work. By looking at variations in genes for hair and skin color and in the "speech" gene, we have also gained a better sense of how we are similar to and different from Neandertals.
View a special video presentation on the significance of this year‘s discoveries, featuring interviews with Francis Collins of NIH, Daniel Altshuler of the Broad Institute, and Science News Writer Liz Pennisi.
Already, the genomes of several individuals have been sequenced, and rapid improvements in sequencing technologies are making the sequencing of "me" a real possibility. The potential to discover what contributes to red hair, freckles, pudginess, or a love of chocolate--let alone quantifying one‘s genetic risk for cancer, asthma, or diabetes--is both exhilarating and terrifying. It comes not only with great promise for improving health through personalized medicine and understanding our individuality but also with risks for discrimination and loss of privacy (see sidebar, p. 1843).
Turning on the flood lamps
Even with most of the 3 billion DNA bases lined up in the right order, there was still much that researchers couldn‘t see in the newly sequenced human genome in 2001. Early comparative studies threw conserved regulatory regions, RNA genes, and other features into relief, bringing meaning to much of our genome, including the 98% that lies outside protein-coding regions. These and other studies, including a pilot study called ENCODE, completed this year, drove home how complex the genome is.
There are an estimated 15 million places along our genomes where one base can differ from one person or population to the next. By mid-2007, more than 3 million such locations, known as single-nucleotide polymorphisms (SNPs), had been charted. Called the HapMap, this catalog has made the use of SNPs to track down genes involved in complex diseases--so-called genome-wide association studies--a reality. More than a dozen such studies were published this year.
Traditionally, geneticists have hunted down genes by tracking the inheritance of a genetic disease through large families or by searching for suspected problematic genes among patients. Genome-wide association studies go much further. They compare the distribution of SNPs--using arrays that can examine some 500,000 SNPs at a time--in hundreds or even thousands of people with and without a particular disease. By tallying which SNPs co-occur with symptoms, researchers can determine how much increased risk is associated with each SNP.
In the past, such links have been hard-won, and most have vanished on further study. This year, however, researchers linked variants of more than 50 genes to increased risk for a dozen diseases. Almost all the variants exert relatively small effects, in concert with many other genetic factors and environmental conditions, and in many cases the variant‘s real role has not yet been pinned down. But the sheer numbers of people studied have made even skeptics hopeful that some of these genetic risk factors will prove real and will help reveal underlying causes.
The Wellcome Trust, the U.K.‘s largest biomedical charity, began to put its weight behind genome-wide association studies in 2005 and recruited 200 researchers to analyze the DNA of 17,000 people from across the United Kingdom. The results are part of an avalanche of genetic information becoming available as more and more geneticists agree to share data and as funding agencies require such exchanges. In June, the consortium published a mammoth analysis of seven diseases, including rheumatoid arthritis, bipolar disorder, and coronary artery disease. It also found several gene variants that predispose individuals to type 1 diabetes and three new genes for Crohn‘s disease.
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At risk. Genomewide association studies are adding to known stretches of DNA connected with type 2 diabetes (colored bars).
CREDIT: K. KRAUSE/SCIENCE (SOURCE: RICHA SAXENA AND DAVID ALTSHULER, BROAD INSTITUTE OF HARVARD AND MIT |
Several large studies have also pinpointed type 2 diabetes genes. One French study involving nonobese diabetics found that a version of a gene for a protein that transports zinc in the pancreas increased the risk of this disease. Three simultaneous reports involving more than 32,000 participants uncovered four new diabetes-associated gene variants, bringing to 10 the number of known non-Mendelian genetic risk factors for type 2 diabetes. These finds strongly point to pancreatic beta cells as the source of this increasingly common chronic disorder.
New gene associations now exist for heart disease, breast cancer, restless leg syndrome, atrial fibrillation, glaucoma, amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, colorectal cancer, ankylosing spondylitis, and autoimmune diseases. One study even identified two genes in which particular variants can slow the onset of AIDS, demonstrating the potential of this approach for understanding why people vary in their susceptibility to infectious diseases.
Genomic hiccups
Genomes can differ in many other ways. Bits of DNA ranging from a few to many thousands, even millions, of bases can get lost, added, or turned around in an individual‘s genome. Such revisions can change the number of copies of a gene or piece of regulatory DNA or jam two genes together, changing the genes‘products or shutting them down. This year marked a tipping point, as researchers became aware that these changes, which can alter a genome in just a few generations, affect more bases than SNPs.
In one study, geneticists discovered 3600 so-called copy number variants among 95 individuals studied. Quite a few overlapped genes, including some implicated in our individuality--blood type, smell, hearing, taste, and metabolism, for example. Individual genomes differed in size by as many as 9 million bases. This fall, another group performed an extensive analysis using a technique, called paired-end mapping, that can quickly uncover even smaller structural variations.
These differences matter. One survey concluded that in some populations almost 20% of differences in gene activity are due to copy-number variants; SNPs account for the rest. People with high-starch diets--such as in Japan--have extra copies of a gene for a starch-digesting protein compared with members of hunting-gathering societies. By scanning the genomes of autistic and healthy children and their parents for copy-number variation, other geneticists have found that newly appeared DNA alterations pose a risk for autism.
New technologies that are slashing the costs of sequencing and genome analyses will make possible the simultaneous genome-wide search for SNPs and other DNA alterations in individuals. Already, the unexpected variation within one individual‘s published genome has revealed that we have yet to fully comprehend the degree to which our DNA differs from one person to the next. Such structural and genetic variety is truly the spice of our individuality.
进展第二条 重新编程细胞的技术
New program. With the addition of four genes, human skin cells are prompted to act like embryonic stem cells. CREDIT: UNIVERSITY OF WISCONSIN, MADISON
名列《科学》2007年十大进展第二位的是重新编程细胞的技术。日本和美国小组分别在6月宣布他们用小鼠皮肤制造了诱导性多能干(iPS)细胞，这些iPS细胞能产生身体的所有细胞，包括卵子和精子，从而显示iPS细胞具有胚胎干细胞的能力。11月份，两个小组分别报告了用人类皮肤细胞制造iPS细胞的研究。这项研究可能改变干细胞研究的科学与政策。
Coontz说：“与首要进展一样，一旦科学家能清除几个障碍，重新编程细胞可能为生物医学研究开辟新方向。”
进展第二条（原文）
2 REPROGRAMMING CELLS
The riddle of Dolly the Sheep has puzzled biologists for more than a decade: What is it about the oocyte that rejuvenates the nucleus of a differentiated cell, prompting the genome to return to the embryonic state and form a new individual? This year, scientists came closer to solving that riddle. In a series of papers, researchers showed that by adding just a handful of genes to skin cells, they could reprogram those cells to look and act like embryonic stem (ES) cells. ES cells are famous for their potential to become any kind of cell in the body. But because researchers derive them from early embryos, they are also infamous for the political and ethical debates that they have sparked.
The new work is both a scientific and a political breakthrough, shedding light on the molecular basis of reprogramming and, perhaps, promising a way out of the political storm that has surrounded the stem cell field.
The work grows out of a breakthrough a decade ago. In 1997, Dolly, the first mammal cloned from an adult cell, demonstrated that unknown factors in the oocyte can turn back the developmental clock in a differentiated cell, allowing the genome to go back to its embryonic state.
Various experiments have shown how readily this talent is evoked. A few years ago, researchers discovered that fusing ES cells with differentiated cells could also reprogram the nucleus, producing ES-like cells but with twice the normal number of chromosomes. Recently, they also showed that a fertilized mouse egg, or zygote, with its nucleus removed could also reprogram a somatic cell.
Meanwhile, the identity of the reprogramming factors continued to puzzle and tantalize biologists. In 2006, Japanese researchers announced that they were close to at least part of the answer. By adding just four genes to mouse tail cells, they produced what they call induced pluripotent stem (iPS) cells: cells that looked and acted like ES cells.
This year, in two announcements that electrified the stem cell field, scientists closed the deal. In a series of papers in June, the same Japanese group, along with two American groups, showed that the iPS cells made from mouse skin could, like ES cells, contribute to chimeric embryos and produce all the body‘s cells, including eggs and sperm. The work convinced most observers that iPS cells were indeed equivalent to ES cells, at least in mice.
Then in November came a triumph no one had expected this soon: Not one, but two teams repeated the feat in human cells. The Japanese team showed that their mouse recipe could work in human cells, and an American team found that a slightly different recipe would do the job as well.
The advance seems set to transform both the science and the politics of stem cell research. Scientists say the work demonstrates that the riddle of Dolly may be simpler than they had dared to hope: Just four genes can make all the difference. Now they can get down to the business of understanding how to guide the development of these high-potential cells in the laboratory. In December, scientists reported that they had already used mouse iPS cells to successfully treat a mouse model of sickle cell anemia. The next big challenge will be finding a way to reprogram human cells without using possible cancer-causing viruses to insert the genes.
Politicians and ethicists on both sides of the debate about embryo research are jubilant. Supporters hope the new technique will enable them to conduct research without political restrictions, and opponents hope it will eventually render embryo research unnecessary. Indeed, several scientists said the new work prompted them to abandon their plans for further research on human cloning.
Officials at the National Institutes of Health said there was no reason work with iPS cells would not be eligible for federal funding, enabling scientists in the United States to sidestep restrictions imposed by the Bush Administration. And President George W. Bush himself greeted the announcement by saying that he welcomed the scientific solution to the ethical problem.
But it‘s much too early to predict an end to the political controversies about stem cell research. Some researchers say they still need to be able to do research cloning to find out just what proteins the egg uses for its reprogramming magic. And now that science has come a step closer to the long-term goal of stem cell therapy, mouse models won‘t be adequate for animal studies. Rather, researchers will need to test cell transplantation approaches with primates, a move that will inevitably stir up resistance from animal-rights activists.
《科学》评选出的其他8项进展包括：
跟踪宇宙射线
来自阿根廷Pierre Auger天文台的研究人员报告说，进入地球大气的宇宙线可能来自天空中存在着许多活跃星系核的区域。这些宇宙线可能是经过黑洞附近的磁场时获得加速度的。
受体结构
研究人员确定了人类Beta2-肾上腺素能受体的结构，这是一个重要的G蛋白偶联受体，它通过传递体内的激素、血清素以及其他分子的信息管理人体内部系统。从抗组胺剂到beta阻滞剂的一系列药物以这些受体为靶标。结构知识可能带来新的药物。
超越硅电子器件
过渡金属氧化物研究的进展也许预示了下一个材料革命，2007年，几个研究小组将两种氧化物结合在一起，制造了带有各种有用的电子和磁性性能潜力的界面。
量子霍尔效应
理论和实验物理学家制造了预测的量子霍尔效应，这是电子从某些材料中流过时在外加电场作用下的奇怪行为。如果这一效应在室温下工作，它可能导致新的低功率的“自旋电子学”计算的设备。
分而治之
研究揭示，与病毒和肿瘤作战的T细胞有立刻保护和长期保护的分工，改进的疫苗也许使这项研究成果得到应用。研究人员发现，当他们捕捉到刚刚分化的T细胞时，在T细胞相反的两极有两类蛋白质被生成，一边的蛋白带有“战士”的分子标记，另一边的显示“记忆细胞”的特征，记忆T细胞能潜伏多年以防备未来的入侵。
以少胜多
合成化学家研制了一个高效低成本的制造药物和电子化合物的技术。
返回未来
用人和大鼠作的研究提出，记忆和想象扎根于大脑的海马区，该区是记忆的一个关键中心。研究人员推测，大脑的记忆也许能通过重新整理过去的经历来产生未来的情景。
游戏结束
一个人工智能编程的精心杰作使双陆棋成为迄今为止计算机解决了的最复杂的游戏。研究人员发现，如果竞技双方不犯任何错误，双陆棋将以平局结束。
2008年应该注意的领域包括microRNA、人工制造的微生物、新的计算机芯片材料、人类细菌以及尼安德特人的基因组、人类神经回路以及来自CERN的大型强子对撞机的数据。（图片均来自《科学》杂志网站）
《科学》社论
Breakthrough of the Year
Donald Kennedy*
The breakthrough of this year has to do with humans, genomes, and genetics. But it is not about THE human genome (as if there were only one!). Instead, it is about your particular genome, or mine, and what it can tell us about our backgrounds and the quality of our futures.
A number of studies in the past year have led to a new appreciation of human genetic diversity. As soon as genomes are looked at individually, important differences appear: Different single-nucleotide polymorphisms are scattered throughout, and singular combinations of particular genes forming haplotypes emerge. A flood of scans for these variations across the genome has pointed to genes involved in behavioral traits as well as to those that may foretell deferred disease liability. And more extensive structural variations, such as additions, deletions, repeat sequences, and stretches of "backwards" DNA, turn out to be more prevalent than had been recognized. These too are increasingly being associated with disease risks.
High-throughput sequencing techniques are bringing the cost of genomics down. The few "celebrity genomes" (e.g., Watson‘s and Venter‘s) will soon be followed by others, we hope in an order not determined by wealth but by scientific need or personal medical circumstance. Our natural interest in personal genealogy, accompanied by worries about our health, will create an incentive structure that even now is creating a sometimes dubious niche market for having one‘s genome "done."
A strong Breakthrough runner-up arrived at this year‘s finish line just in time. Two new studies, one published in Science, showed how adult human epithelial cells could be reprogrammed, through the virally mediated introduction of just four genes, to behave like pluripotent cells; that is, able to act as embryonic stem cells do, to produce every descendent cell type. This breakthrough has produced some relief, but it also comes with some reservations. James Thompson of the University of Wisconsin, who did the first research with embryonic stem cells, has now taken a major step toward ending the "ethical" controversy over their use. But hold on: That controversy was generated by specific objections from one religion, not some universal ethic. There is every reason to continue research along the old path, with embryo-derived cells: The new methods may carry unknown liabilities, so making the case for changing Bush‘s 2001 presidential order should continue.
Finally, readers will notice that we usually have a "Breakdown" of the year. That custom produced ambivalence this time around. On the strictly scientific front, progress in climate change research was spectacular. There was new information about the dynamics of the major ice sheets in Greenland and Antarctica, analyses of paleoclimates, new estimates of sea-level rise, and studies of the impacts of global warming on high-latitude ecosystems and sea ice. The Intergovernmental Panel on Climate Change delivered a summary report at year‘s end emphasizing the seriousness of the risks. But on the breakdown side, continual denial by the Bush Administration added to its long history of failing to mitigate the emission of greenhouse gases.
A specimen case of the Administration‘s reluctance to acknowledge climate change was added just recently when Julie Gerberding, head of the U.S. Centers for Disease Control and Prevention, was asked to present congressional testimony on the potential impacts of climate change on public health. It is surely no secret that heat spells are a health hazard, or that drought and excess rainfall can influence human susceptibility to pathogen-borne disease--just the kind of thing Congress wanted to know. Gerberding‘s testimony was reviewed at the White House and soon made to disappear: Virtually all of what she said about climate change--six pages of it--was blacked out of the document filed with the Senate Environment and Public Works Committee (see http://alt.coxnewsweb.com/ajc/pdf/gerberding.pdf). There‘s an odd behind-the-scenes story here, involving two offices that report to the president. The Office of Science and Technology Policy raised questions about particular statements and made suggestions, but then the Office of Management and Budget, apparently unwilling to work on the suggestions, simply eliminated every section about which questions had been raised. It‘s worth a look just to understand what these people don‘t want you to know.