Hot off the presses! Oct 08 Nature

The Oct 08 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Genetics without borders
  - Nature 461(7265):697 (2009)
  A UK government scheme to establish nationality through DNA testing is scientifically flawed, ethically dubious and potentially damaging to science.
• Putting DNA to the test
  - Nature 461(7265):697 (2009)
  Genetic-testing companies lack regulation, and a list of guiding principles does not go far enough.
• How to win trust over flu
  - Nature 461(7265):698 (2009)
  Mass-vaccination campaigns for the pandemic H1N1 virus must take public concerns into account.
• Evolution: Boys against girls
  - Nature 461(7265):700 (2009)
  
• Cancer biology: Stem cell–cancer link
  - Nature 461(7265):700 (2009)
  
• Ecology: Wildebeest chain reaction
  - Nature 461(7265):700 (2009)
  
• Geoscience: Earth's magnetic personality
  - Nature 461(7265):700 (2009)
  
• Analytical chemistry: Gloop monitor
  - Nature 461(7265):700 (2009)
  
• Ageing: Live longer, but how?
  - Nature 461(7265):700 (2009)
  
• Stem-cell biology: Rebooting cord blood cells
  - Nature 461(7265):701 (2009)
  
• Microbiology: Bacteria fight back
  - Nature 461(7265):701 (2009)
  
• Chemistry: Microwave magic
  - Nature 461(7265):701 (2009)
  
• Materials science: No gas from glass
  - Nature 461(7265):701 (2009)
  
• Journal club
  - Nature 461(7265):701 (2009)
  
• News briefing: 8 October 2009
  - Nature 461(7265):702 (2009)
  The week in science This article is best viewed as a PDF. Policy|Facilities|Events|Business|Research|Awards|The week ahead|Sound bites|Number crunch Democrats in the US Senate unveiled their climate legislation on 30 September. Based largely on the Waxman–Markey bill passed by the House of Representatives in June, it proposes a cap-and-trade system to reduce greenhouse-gas emissions by 20% by 2020 and 83% by 2050, compared with 2005 levels. An initial committee vote could come later this month. On the same day, the US Environmental Protection Agency proposed a rule that would require major industrial facilities to use "best available" technologies to reduce greenhouse-gas emissions. See go.nature.com/RWjAdj for more. A ¥270-billion (US$3-billion) funding programme in Japan has been put on hold because of a wholesale budget freeze by the country's new government. The Funding Program for World-Leading Innovative R&D on Science and Technology was created this spring by Japan's former ruling party, the Liberal Democratic Party, as part of a supplementary budget. Thirty research groups were quickly chosen to share the money ahead of the 16 September transfer of power to the Democratic Party of Japan, but none is yet assured of the promised funds. The US Environmental Protection Agency (EPA) laid out White House-backed principles for a radical reform of US legislation regulating toxic chemicals, at present controlled by the 1976 Toxic Substances Control Act. EPA administrator Lisa Jackson said the act had proved to be "an inadequate tool" for protecting the public. She wants to strengthen the EPA's authority to clamp down on dangerous chemicals, and for chemical manufacturers routinely to give the agency toxicity data. The American Chemistry Council, which represents US chemical manufacturers, says it welcomes the reform. A congressional bill is expected soon. The US government should grade microorganisms and toxins according to their risk as potential "biothreat" agents, and regulate them accordingly. That was the recommendation of a National Research Council report released last week, entitled Responsible Research with Biological Select Agents and Toxins. Currently, research on 82 human, plant and animal pathogens (called select agents) is monitored under a 1996 law that requires the same security procedures for all of them. The report also called for funding of regular, independent evaluation of the programme governing research into select agents. Control of Europe's research funds should be devolved from the European Commission to agencies with "arms-length" independence, an advisory board has suggested. In a report published on 6 October, the European Research Area Board also said that research's share of the European Union's budget should triple to 12% by 2030, with half of those funds going towards basic research. In the most recent funding round, research was allocated €50 billion (US$74 billion) for 2007–13, of which €7.5 billion went to basic research. See go.nature.com/yVLwT3 for more. After a bitter and lengthy controversy over water management, four hydroelectric dams on the Klamath River in Oregon and California will be removed to restore salmon runs. PacifiCorp, the Portland-based utility in Oregon that owns the dams, announced the draft agreement on 30 September after almost a decade of negotiations with federal agencies, farmers, states, conservation groups and Native American tribes. Removal of the dams will not begin until 2020, and is dependent on government approval as well as full federal and state funding. The image is best viewed as a PDF. Major earthquakes in the Pacific and Indian oceans struck Samoa and Indonesia last week. An earthquake measured by the US Geological Survey as a magnitude 8.0 triggered a tsunami off Tonga and Samoa that killed at least 190 people and left thousands homeless. The death toll for the magnitude-7.6 earthquake that hit just hours later off the Indonesian island of Sumatra may reach thousands. Experts said that the two earthquakes were not related to each other. See go.nature.com/qkxBhD for more. Sequenom, a biotechnology firm in San Diego, California, has cleared out its top executives after an internal investigation found lax oversight of faulty research. The company revealed in April that data supporting a prenatal screen for Down's syndrome were "mishandled" and could not be relied on (see Nature 459, 23; 2009). Last week the company fired chief executive Harry Stylli and Elizabeth Dragon, senior vice-president of research and development. Chief financial officer Paul Hawran and another unnamed executive resigned, and three research scientists also had their contracts ended. In September, French company Arkema became the latest carbon-nanotube manufacturer this year to announce plans for a drastic scaling up of production. Despite the materials' present reliance on the mixed fortunes of the automobile industry, the market for carbon nanotubes as raw materials looks set to grow rapidly. Revenues could reach US$500 million by 2015 (see chart), predicts Jurron Bradley of analysts Lux Research. SOURCE: LUX RESEARCH "In 2009 we have seen a lot of players announce major expansions," Bradley says. Market leader CNano, based in Santa Clara, California, announced in June that its Beijing facility is now producing 500 tonnes of multiwalled nanotubes annually; Arkema's plant in Mont, France, should be turning out 400 tonnes per year by 2011. If companies such as Germany's Bayer MaterialScience, headquartered in Leverkusen, and Tokyo-based Showa Denko follow through with similar plans, global nanotube production will have doubled by 2011 from around 800 tonnes per year at present. Many of these raw nanotubes are multiwalled, and are used to make light, strong, composite materials. But a host of smaller companies — such as Nanocyl, based in Sambreville, Belgium — process them into intermediate products for antistatic coatings, for example, sensors for gas detection and electrode material for batteries — and, on the horizon, for touch-screen displays. China has become the second-largest producer of academic research papers in the world behind the United States, according to a study produced annually for the UK government. Leeds-based analysts Evidence Ltd revised its figures to show that China's output overtook the major European Union states in 2006, although on measures of citation share and research strength (citation share across 10 different fields) it remained lower. The achievement had not been noted until now, and follows an increase in the volume of papers indexed by databases. India and Brazil show signs of following China's rise in the next decade. Developing countries could see crop yields fall dramatically by 2050 if climate change is left unchecked, according to a study released on 30 September by the International Food Policy Research Institute in Washington DC. The report forecasts that wheat yields from irrigated fields might fall by a third or more by 2050, compared to a no-climate-change scenario, and that farmers in southern Asia might see their wheat production almost halve. See go.nature.com/VYzOWl for more. U. GUERUCCI/UPI/NEWSCOM US President Barack Obama visited the National Institutes of Health in Bethesda, Maryland, on 30 September (pictured). Obama toured a National Cancer Institute lab, where he was treated to video images of healthy and cancer-riddled brains, and praised the research made possible by the agency's spending of $5 billion out of the $10.4 billion it got in economic stimulus funds. The agency had raced to disburse the money by that same day, the end of the government's fiscal year. Carbon dioxide emissions could fall by 3% worldwide this year because of the global economic crisis, the International Energy Agency predicted in a teaser from its upcoming World Energy Outlook 2009 report. The excerpt was released on 6 October to coincide with United Nations climate talks in Bangkok. Elizabeth Blackburn, Carol Greider and Jack Szostak shared the 2009 Nobel Prize in Physiology or Medicine, for their discoveries of how chromosomes are protected by telomeres and the enzyme telomerase. The physics prize went to Charles Kao, for his work on how light can be transmitted through optical glass fibres; and to Willard Boyle and George Smith for their invention of the charge-coupled device (CCD) sensor. The chemistry prize was yet to be awarded as Nature went to press. See page 706 and www.nature.com/news for more. NASA's Lunar Crater Remote Observation and Sensing Satellite will crash into a crater near the Moon's south pole, in the hope of disturbing and detecting ice. → http://lcross.arc.nasa.gov 'The ambitions of Europe in space' — European policy-makers, financiers, space scientists and industrial representatives converge on Brussels to discuss the region's space programme. → www.spaceconference.eu Canada's Perimeter Institute for Theoretical Physics (see Nature 461, 462–465; 2009) hosts — and webstreams — the 'Quantum to cosmos' festival in Waterloo, Ontario. → www.q2cfestival.com Francis Collins, the newly minted director of the US National Institutes of Health, tells Nature how he feels about trying to ensure that the agency won't suffer financially when its stimulus money is spent. See go.nature.com/h15ch6 for the full interview. The potential rise in India's nuclear capacity, from 3.8 gigawatts today to 470 gigawatts by 2050, in expansion plans announced by the country's prime minister, Manmohan Singh. (The Times) There are currently no comments.
• Fossil rewrites early human evolution
  - Nature 461(7265):705 (2009)
  A 17-year investigation into a fossilized early human skeleton from Ethiopia culminated last week with 11 papers published in Science. Detailed descriptions of the skeleton, of a fairly complete 4. There are currently no comments.
• Chromosome protection scoops Nobel
  - Nature 461(7265):706 (2009)
  Prize for physiology or medicine awarded for uncovering role of telomeres. Winners in triplicate: Carol Greider, Elizabeth Blackburn and Jack Szostak.Left to right: M. Probst/AP; M. Groll/AP; M. Wilson Three US scientists have won the Nobel Prize in Physiology or Medicine for discovering the structure of molecular caps called telomeres and working out how they protect chromosomes from degradation. Their discoveries in cell biology during the 1980s and 1990s opened new avenues of work, in ageing and in cancer research, which are still highly active today. The prize, announced on 5 October, is shared equally between Elizabeth Blackburn at the University of California, San Francisco, Carol Greider of the Johns Hopkins Medical School in Baltimore, Maryland, and Jack Szostak at Harvard Medical School in Boston, Massachusetts. The three have already won numerous prizes for their work, including sharing one of the 2006 Lasker awards, often considered to be a forerunner of the Nobel prize. Their research revealed a fundamental aspect of how DNA, packed into chromosomes, is copied in its entirety by the DNA polymerase enzyme during cell division. The ends of the chromosomes are capped by telomeres, long thought to have a protective function (see 'Chromosome caps'). Without them, the chromosomes would be shortened during each cell division, because DNA polymerase is unable to copy to the very end of one of the two DNA strands it is replicating. Click for larger image In the early 1980s, after their fortuitous meeting at a Gordon Research Conference in 1980, Blackburn and Szostak discovered that telo­meres include a specific DNA sequence. Fired up by the novelty of each other's work, they devised experiments that seemed crazy at the time, even to themselves. Szostak took the telomere sequences that Blackburn had identified in the protozoan Tetrahymena thermophila and coupled it with mini-chromosomes that he inserted into his own preferred model organism, yeast. Cross-species effect The sequence was able to protect the chromosomes in this different species1. It was soon found that the protection conferred by telomeres is a fundamental biological mechanism present in nearly all animals and plants. Szostak and Blackburn suspected that an unknown enzyme must be involved. On Christmas Day in 1984, Greider — then Blackburn's graduate student — saw the first evidence that this enzyme, which Greider and Blackburn named telomerase, was responsible for constructing telomere DNA2. They worked out that telomerase provides a platform enabling DNA polymerases to copy the entire length of the chromosome without missing the ends. Greider and Blackburn also showed that telomerase contains a key RNA sequence that acts as a template for the telomere DNA3, which attracts proteins to form a protective cap around the ends of the DNA strands. Telomeres themselves shorten with repeated cell division, making up a key part of the cell's ageing mechanism. Low telomerase activity and telomere shortening speed up ageing, whereas incessantly dividing cancer cells often have high telomerase activity and maintain their telo­mere length. Cancer therapies directed against telomerase are now being tested in clinical trials. But there is still a lot of basic biology to discover — such as how telomerase activity is regulated at individual telomeres, and how telomeres manage to avoid the attentions of DNA repair enzymes which seek out breaks in DNA and restitch the torn ends. Blackburn and Greider become only the ninth and tenth female scientists to win the physiology or medicine prize since it was first awarded in 1901, and it is the first time that two women have been recognized in a single prize. Indeed, telomere research is unusually dominated by women. "It is hard to find a male among us," says David Shore, a cell biologist at the University of Geneva, Switzerland. "And two main reasons are Liz and Carol — they created the field and have been role models." ADVERTISEMENT Blackburn has also been involved in the politics of science, serving on the US President's Council on Bioethics from 2002 until she was dropped in 2004 after criticizing the restrictions on human embryonic stem-cell research imposed by then President George W. Bush. Lea Harrington, Greider's first graduate student, who is now at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, UK, says that her four years in Greider's laboratory at Cold Spring Harbor, New York, were "electric. We all realized what an exciting time it was — so many questions being answered about the composition of telomerase, how it worked and its relevance to human biology." * References * Szostak, J. W. & Blackburn, E. H. Cell29, 245-255 (1982). | Article | PubMed | ISI | ChemPort | * Greider, C. W. & Blackburn, E. H. Cell43, 405-413 (1985). | Article | PubMed | ISI | ChemPort | * Greider, C. W. & Blackburn, E. H. Nature337, 331-337 (1989). | Article | PubMed | ISI | ChemPort |
• Nobel Prize in Physics awarded to light pioneers
  - Nature 461(7265):707 (2009)
  Advances in fibre optics and digital imaging are rewarded. Two technologies that revolutionized science, computing and communication have secured their developers a share of the Nobel Prize in Physics. Charles Kao: fibre-optic cables.REUTERS Charles Kao of the Chinese University of Hong Kong has won half the prize for his role in developing fibre-optic cables. The other half is shared by Willard Boyle and George Smith of Bell Laboratories in Murray Hill, New Jersey, for their development of the charge-coupled device (CCD), an electronic chip that converts light into a digital signal. In 1969, Boyle and Smith developed a chip that could transform light into an electronic signal. The duo used newly discovered metal oxide semiconductors that could convert photons into a flow of electrons, which could be read from the edges of the chip and used to recreate the image. The ability to digitally capture light has found application in nearly every field of science — particularly astronomy. "Basically, they revolutionized optical astronomy," says Mark Casali, head of instrumentation at the European Southern Observatory in Garching, Germany. Before the advent of CCDs, astronomers were imaging stars using photographic plates, which were less sensitive and less precise than their digital successors, Casali says. Using CCD cameras, astronomers have been able to discover faint galaxies and even see fluctuations in a star's light created by an orbiting planet. Willard Boyle and George Smith developed charge-coupled devices.Alcatel-Lucent/Bell Labs The detectors also made space-based astronomy a reality, says Matt Mountain, director of the Space Telescope Science Institute in Baltimore, Maryland, which coordinates science for the Hubble Space Telescope. "It made telescopes like the Hubble possible," he says. "You could now put large electronic detectors in space that could beam down digital pictures of some of the faintest objects human beings have ever seen." Fibre optics has had an equally impressive impact on science, not least by facilitating collaboration on a global scale. But the transmission of data over thousands of kilometres seemed a distant dream when Kao first began his work on fibre-optic cables. Back then, fibres could carry light only a few metres by total internal reflection before the signal faded. Kao and his colleagues at Standard Telecommunication Laboratories in Harlow, UK, worked out that impurities, mainly iron ions, were causing the loss. Kao identified an alternative material — fused silica — that could carry light over much greater distances without significant loss. The work ultimately led to the billion-kilometre-long network of fibre-optic cables that span the globe today. ADVERTISEMENT Fibre optics will also have a pivotal role in the world's largest science experiment, the Large Hadron Collider (LHC) at CERN, Europe's particle-physics centre near Geneva, Switzerland. The LHC's largest detectors create around a million gigabytes of raw data every second. The cables then shepherd the data to nearby servers and on to thousands of scientists in 33 countries through an ultrafast computer grid. "The whole infrastructure is based on optical fibre," says Ian Bird, the grid's project leader. "There's no way that our data rates could be sustained without it."
• X-ray free-electron lasers fire up
  - Nature 461(7265):708 (2009)
  Heinz Graafsma is tired of the "pretty, but useless" images of proteins that regularly adorn the pages of journals such as Nature. "Chemistry depends on changes," says Graafsma, the head of detectors for photon science at DESY, Germany's high-energy physics laboratory in Hamburg. There are currently no comments.
• From plant to power
  - Nature 461(7265):710 (2009)
  Petrol might yet survive the green revolution. Some investors are taking seriously the concept of 'green gasoline' — transforming the woody remains of plants into exact replicas of today's transportation fuels. There are currently no comments.
• Correction
  - Nature 461(7265):711 (2009)
  The News story 'Climate burden of refrigerants rockets' (see Nature 459, 1040–1041; 2009) cited an incorrect year for when hydrofluorocarbon emissions were predicted to reach between 5.5 billion and 8.8 billion tonnes of carbon dioxide equivalent annually. The year is 2050, not 2010. There are currently no comments.
• Human genetics: Hit or miss?
  - Nature 461(7265):712 (2009)
  Genome-wide association studies have identified hundreds of genetic clues to disease. Kelly Rae Chi looks at three to see just how on-target the approach seems to be. Download a PDF of this story Five years ago human geneticists rallied around an emerging concept. Technology had granted the ability to compare the genomes of individuals by looking at tens of thousands of known single-letter differences scattered across them. These differences, called single nucleotide polymorphisms or SNPs, served as reference points or signposts of common variation between individuals. The idea was that common variants in the genome might contribute to the genetics of common diseases. Genome-wide association studies (GWAS) could scan SNPs in thousands of people, with and without a disease. When a DNA variant can be associated with the risk of developing a disease, it signals that something in that area of the genome might be partly responsible. With such 'hits' would presumably flow a better mechanistic understanding of disease, genetic-testing abilities and even treatment. "Many researchers really grabbed on to the common variant hypothesis, and in some cases it worked," says Jonathan Haines, director of the Vanderbilt University Medical Center's Center for Human Genetics Research in Nashville, Tennessee. But, he adds, "it hasn't panned out to be as pervasive an explanation as we thought". Here are the stories of three hits. One provides a near perfect example of the positive outcome that this sort of unbiased approach can have. One reveals that without biological context the findings can be hard to interpret. And the third demonstrates that GWAS in their current form can't cope well with some common traits. A direct hit in haemoglobin In 2007, researchers reported on genome-wide scans of healthy adults looking for SNPs associated with very high or very low levels of fetal haemoglobin. Among several hits were variants of a gene on chromosome 2 called BCL11A (ref. 1). This finding, quickly replicated in multiple populations, generated a lot of excitement. Fetal haemoglobin is a remnant of embryonic development. For most people, the fetal version of this crucial oxygen-carrying protein drops off after birth as the adult version kicks in. Some people retain relatively high expression, which seems to have no effect in healthy adults. But for patients with blood disorders such as sickle-cell disease and β-thalassaemia, those expressing high fetal-haemoglobin levels can be protected from some of the nastier ravages of the disease, such as leg ulcers, severe pain and even death. GWAS findings often just provide the signpost, a rough coordinate for a causal gene. The SNP signal is often outside gene sequences. The variants in BCL11A were a direct hit in a gene, however, and a surprising gene at that. The protein it codes for, which controls the expression of other genes, had been associated with cancer progression, but never with haemoglobin production. A mouse model had even been made in which the gene had been knocked out, but until the GWAS no one had looked at its regulation of blood. "Nobody would have ever dreamed that a gene like this would have any regulatory role in fetal haemoglobin," says Martin Steinberg, a haematologist at the Boston University School of Medicine in Massachusetts. Last year, he and his colleagues replicated the BCL11A finding in three different populations with haemoglobin disorders2. Of course, there was functional work to be done. Stuart Orkin's lab at Harvard Medical School in Boston reduced expression of BCL11A in cultured blood progenitor cells from humans. Fetal haemoglobin expression went up, suggesting that the gene normally acts as a repressor3. In a follow-up study4, the group showed that the gene controls the silencing of fetal haemoglobin during development in mice. But the exact switch mechanism has not been solved, says Orkin. His group has gone on to look for proteins and other genes that the product of BCL11A binds to or influences. Results from these studies will inform research that looks for molecules that would interfere with the gene's expression or function and thus serve as potential therapies to activate synthesis of fetal haemoglobin in people with blood disorders. Steinberg, for his part, hopes to use these and other GWAS findings to refine a computational tool that predicts disease severity or death in people with sickle-cell disease. The hope is to intervene earlier and with more specific treatments. even those who have been generally pessimistic about the outcomes of GWAS consider the BCL11A find a win for science. "It's a tour de force illustration of the value of GWAS," says David Goldstein, a geneticist at the Duke Institute for Genome Sciences & Policy in Durham, North Carolina. "You learn something new, you understand the mechanism, and it's biologically and clinically important." As winners go, however, Goldstein says it is on a short list. In some ways, says Steinberg, the GWAS provided a lucky hit. The researchers built on years of evidence that fetal haemoglobin has a powerful effect on the severity of sickle-cell disease and β-thalassaemia. It was the clear physiological signal — quantity of fetal haemoglobin — that helped researchers to design the GWAS. Other genes and pathways will be found to affect the severity of the disorders, but probably none with the same force as fetal haemoglobin. "We're not going to find another fetal haemoglobin," Steinberg says. Scoping schizophrenia Schizophrenia genetics has been a mire of false starts. Scores of candidate gene association studies had identified promising targets, but few held up to further scrutiny. So the excitement around approaching the disease in an unbiased genome-wide study was high. But the first four schizophrenia GWAS reported no statistically significant associations. Then, in research published last year, researchers performed scans in roughly 500 people with the disorder and 3,000 healthy controls. When 12 of the hits that turned up were examined in 16,000 more individuals, a signal started to emerge. Three variants were significant, but only one of them was in a gene, ZNF804A, which encodes a protein with unknown function5. Having a potential candidate gave researchers something concrete to work with. One group took 115 healthy people, a little less than half of whom had two copies of the high-risk ZNF804A variant, and compared their brain activity using functional magnetic resonance imaging (fMRI), a method that reveals local blood oxygenation and presumably electrical activity in the brain in real time. Those with the variant, they found, had abnormal connectivity between certain brain areas, impairing "the degree in which they talk to one another", says Andreas Meyer-Lindenberg, the director of the Central Institute of Mental Health in Mannheim, Germany, who led the study6. Healthy adults with the variant were showing schizophrenia-like brain activity even though they showed no outward signs of disease. Combining genetic and brain-imaging data to study psychiatric disease is not new. Since 2001, researchers have used the strategy to link imaging data to candidate gene findings in schizophrenia, depression and autism. Meyer-Lindenberg's study is the first to use a genetic loci identified through GWAS for follow-up with fMRI. "We've now applied [the technique] to a variant that has definitive support as being a schizophrenia risk gene. That wasn't available before," says Meyer-Lindenberg. Part of the problem when seeking schizophrenia-related genes is that, unlike fetal haemoglobin levels for example, the definition of the trait both within and between studies can differ. Also the spectrum and severity of schizophrenia symptoms varies between individuals and are sometimes subjective from a clinical perspective. That's why fMRI is attractive. The researchers hope to get closer to quantitative measures of psychiatric disorders. "It makes sense to have a biological level of analysis on which these genetic associations can be studied," says Daniel Weinberger, the director of the genes, cognition and psychosis programme at the National Institute of Mental Health in Bethesda, Maryland, who pioneered the method in the 1990s. The ZNF804A association from GWAS has been replicated in some studies but not others. And there are few clues to the mechanism by which this gene might contribute to brain connectivity. It was the group of Michael O'Donovan, a professor of psychological medicine at Cardiff University, UK, that made the initial discovery using GWAS. The team is now carrying out a series of experiments to determine which DNA sequences and other proteins it binds, and how variants might alter gene expression. some have doubts about the combined assault of GWAS and fMRI on psychiatric illness. Imaging data itself isn't the best quantitative trait, says Goldstein, because one three-dimensional fMRI image can contain more than 50,000 picture elements of data, a single trait can be defined in multiple ways. "There hasn't been a sufficient consistency in how those phenotypes are defined," he says. Weinberger and others contend that the imaging paradigms are well established before they are used in imaging genetics research. "I think it's very important that the phenotypes are well validated — that they are themselves heritable, and that they're related in some way to the underlying neural circuitry," says Weinberger. Reviews from others studying schizophrenia are somewhat lukewarm. Kári Stefánsson, chief executive of the Icelandic biopharmaceutical company deCODE Genetics in Reykjavik, says he's not completely convinced. "In schizophrenia, the imaging differences are subtle," he says. Nevertheless, he plans to study differences in brain morphology using imaging and GWAS, in people with and without the disorder. Given the shortage of standout GWAS hits, should researchers continue to use the candidate-gene approach to form the basis for hypothesis-driven imaging genetics work? "It is still a point of debate," Meyer-Lindenberg says. Sight set on height Height has produced clearer hits than schizophrenia, but with a less than satisfying punch. In 2007, by analysing the genomes of nearly 5,000 people, researchers were able to see that a variant in a gene called HMGA2 explains some of height's variability — about 0.3% (ref. 7). Since then, additional GWAS have revealed more than 40 loci involved in height. Added together, these variants account for 5% of the trait's variation. Even a clear quantitative trait doesn't necessarily provide simple answers. Genes are thought to contribute to roughly 60–80% of the variation in stature, leaving much of the heritability of height unaccounted for by GWAS findings. This 'missing heritability' has been a thorn in the side of the common-disease-common-variant hypothesis (see page 747). "In the field of height," says Haines, "obviously that hypothesis is not completely correct." But the news isn't all bad. "Optimistic people like me say we didn't know anything about the genetics of height before 2007," says Guillaume Lettre, a geneticist at the Montreal Heart Institute in Quebec, Canada. "Now we have more than 40 loci." Researchers may have loci, but they have little idea how these contribute to height. As with other traits, many of the associated SNPs fall within the vast regions between genes or within genes whose function is unknown. And with little funding for understanding height variation and scant biological footholds, the field sees very little follow-up of its GWAS leads. Lettre is collaborating with others with the hope of tying mystery SNPs to genes through animal models. "Basically what we are doing is taking the genes near these markers and looking at the expression of these genes in tissues that are relevant to height," he says. "There are not so many: bone, cartilage and pituitary gland." He and others are also trying to coax existing height data into revealing stronger associations by grouping hits based on a single molecular pathway. Hong-Wen Deng, at the University of Missouri in Kansas City, is planning to analyse pathways involved in either bone health or stature. "Many genes which may have small effects for height may not be detected if you analyse them individually," he says. But jointly their effects may be may be detected. Others are looking at height at various points with the hope that differences in growth curves will reveal larger genetic associations. Researchers have already examined height and growth rates in about 3,500 people from Northern Finland. Of 48 height-associated variants that they tested, 12 were linked with the rate of growth during infancy or puberty8. some of the loci implicate molecular pathways already known to be involved in growth and development. A 1995 study had shown that a gene related to HMGA2 could influence height: mice lacking the gene were shorter, whereas mice with a truncated version developed gigantism9. The HMGA2 association has been further confirmed by most, but not all, GWAS. Predicting how hits outside genes will fare is more difficult, and depends to some extent on how close the hit is to the nearest gene. "If you look at the height loci, they are much more likely to be near a gene that causes abnormal skeletal growth, than a similarly sized random set of loci," says Joel Hirschhorn, a geneticist at the Broad Institute in Cambridge, Massachusetts. ADVERTISEMENT But the nearest gene is a poor marker for what is likely to be causal says Goldstein. "Depending on the genetic model for what is causing the association, it could be nearby or not nearby," he says. In some instances changes in DNA act on genes a million bases away. "It really is remarkable that there are hundreds of reported associations, and the number that you can actually track down to an actual cause of the association is probably countable on one hand." Researchers point to height as a 'model trait' because it is simple to measure and relatively constant compared with phenotypes such as blood pressure or glucose level. Then again, in GWAS of height, tens of thousands of people have been necessary to see the slightest associations. As a model trait, that could be problematic. "In some ways, it is showing us the future for other traits," says Karen Mohlke, a geneticist at the University of North Carolina at Chapel Hill who was involved in some of the initial height GWAS work. "What it means for many other complex traits is that there will be as many loci found, or more." Kelly Rae Chi is a freelance writer in Cary, North Carolina. * References * Menzel, S.et al. Nature Genet.39, 1197-1199 (2007). * Sedgewick, A. E.et al. Blood Cells Mol. Dis.41, 255-258 (2008). * Sankaran, V. G.et al. Science322, 1839-1842 (2008). * Sankaran, V. G.et al. Nature460, 1093-1097 (2009). * O'Donovan, M. C.et al. Nature Genet.40, 1053-1055 (2008). * Esslinger, C.et al. Science324, 605 (2009). * Weedon, M. N.et al. Nature Genet.39, 1245-1250 (2007). * Sovio, U.et al. PLoS Genet.5, e1000409 (2009). * Zhou, X. , Benson, K. F. , Ashar, H. R. & Chada, K.Nature376, 771-774 (1995). There are currently no comments.
• Environment: The disappearing nutrient
  - Nature 461(7265):716 (2009)
  Ten years ago, Don Mavinic was working on a way to get rid of a pesky precipitate that plugs up the works of waste-water treatment plants. Known as struvite, the solid crud forms in pipes and pumps when bacteria are used to clean up sewerage sludge. There are currently no comments.
• Plasmonics: Surfing the wave
  - Nature 461(7265):720 (2009)
  Toss a rock into a quiet pond, and watch the ripples spread out across its surface. This is pretty much what happens when a photon hits the surface of a metal — except that in this case, the 'ripples' consist of electrons oscillating en masse and have wavelengths measured in nanometres. There are currently no comments.
• Sanctions against scientists threaten progress
  - Nature 461(7265):723 (2009)
  Several European countries, including France, the Netherlands and Sweden, are now routinely refusing work visas and study positions in the physical sciences to Iranian scientists and students. This is in response to UN resolution 1737, imposing sanctions on Iran for failing to halt uranium enrichment, and reflects international concern about the potential proliferation of nuclear-weapons technology.
• Measures urgently required to prevent multiple submissions
  - Nature 461(7265):723 (2009)
  A recent experience leads me to believe that defiance of rules against simultaneous submission of papers to different journals may be growing more widespread.In a thorough review of a submitted paper (not for this journal), I pointed out that the study itself and the organization of the manuscript were below standard; I offered substantive constructive comments and recommended reconsideration after major revision.
• Caution with claims that a species has been rediscovered
  - Nature 461(7265):723 (2009)
  We welcome the recent announcement by the conservation partnership BirdLife International that they have launched a "global bid to try to confirm the continued existence of 47 species of bird that have not been seen for up to 184 years" (see http://go.nature.com/6Hc2Cn
• An agenda for personalized medicine
  - Nature 461(7265):724 (2009)
  Pauline C. Ng, Sarah S. Murray, Samuel Levy and J. Craig Venter find differences in results from two direct-toconsumer genetics-testing companies. They therefore give nine recommendations to improve predictions.
• Let's celebrate human genetic diversity
  - Nature 461(7265):726 (2009)
  Science is finding evidence of genetic diversity among groups of people as well as among individuals. This discovery should be embraced, not feared, say Bruce T. Lahn and Lanny Ebenstein.
• Winning the arguments on Capitol Hill
  - Nature 461(7265):730 (2009)
  Harold Varmus enjoys a guide to the inner workings of the US Congress by legislator Henry Waxman.
• China's unofficial democracy
  - Nature 461(7265):731 (2009)
  In July this year, a 20-year-old university student in the southern Chinese city of Hangzhou was sentenced to three years in prison for driving recklessly and killing a pedestrian. This would have been a sad but unremarkable case, except that it was only brought following a huge national outcry.
• Darwin's legacy down under
  - Nature 461(7265):732 (2009)
  Australia's unusual fauna and flora, encountered by Charles Darwin during his eagerly anticipated visit of 1836, surely influenced his evolutionary thoughts. Yet writing in his Journal of Researches (later known as Voyage of the Beagle), he focused more on Australia's human inhabitants — its convicts, settlers and Aboriginal people — than on its natural history.
• A creative celebration of evolution
  - Nature 461(7265):733 (2009)
  The Burning Man festival is a unique happening. For one week in September every year, the featureless Black Rock Desert in Nevada hosts a temporary community of artists, technologists and visionaries.
• Human genetics: Sharp focus on the variable genome
  - Nature 461(7265):735 (2009)
  Copy-number variation — deleted or duplicated regions of DNA — is widespread in the human genome. A systematic population survey of the common variants provides an invaluable resource for further studies.
• Quantum mechanics: Passage through chaos
  - Nature 461(7265):736 (2009)
  A quantum system can undergo tunnelling even without a barrier to tunnel through. The latest experiments visualize this process in exquisite detail, completely reconstructing the state of the evolving system.
• Vision: Gene therapy in colour
  - Nature 461(7265):737 (2009)
  Replacing a missing gene in adult colour-blind monkeys restores normal colour vision. How the new photoreceptor cells produced by this therapy lead to colour vision is a fascinating question.
• Cosmology: Dark is the new black
  - Nature 461(7265):740 (2009)
  Rival experimental methods to determine the Universe's expansion are contending to become the fashionable face of cosmology. Fresh theoretical calculations make one of them the hot tip for next season.
• Microbiology: Life on leaves
  - Nature 461(7265):741 (2009)
  The surface of plant leaves — the phyllosphere — is home to many microbes. A 'community proteogenomics' approach offers a fresh look at what it takes to survive and thrive in this unique habitat.
• Structural biology: Tracing Argonaute binding
  - Nature 461(7265):743 (2009)
  Argonaute proteins inhibit gene expression by binding to messenger RNA via a small nucleic-acid guide. Structures of the Argonaute complex bound to target RNA reveal snapshots of a silencing machine at work.
• Photonics: One-way road for light
  - Nature 461(7265):744 (2009)
  The transmission of information from one place to another by light waves sent through waveguides is hampered by light attenuation and scattering loss. Magnetic photonic crystals could provide a solution to such problems.
• Gal4 turnover and transcription activation
  - Nature 461(7265):E7 (2009)
  Arising from: K. Nalley, S. A. Johnston & T. Kodadek Nature 442, 1054–1057 (2006); Nalley et al.reply Growing evidence supports the notion that proteasome-mediated destruction of transcriptional activators can be intimately coupled to their function1, 2. Recently, Nalley et al.3 challenged this view by reporting that the prototypical yeast activator Gal4 does not dynamically associate with chromatin, but rather 'locks in' to stable promoter complexes that are resistant to competition. Here we present evidence that the assay used to reach this conclusion is unsuitable, and that promoter-bound, active Gal4 is indeed susceptible to competition in vivo. Our data challenge the key evidence that Nalley et al.3 used to reach their conclusion, and indicate that Gal4 functions in vivo within the context of dynamic promoter complexes.
• Nalley et al. reply
  - Nature 461(7265):E8 (2009)
  Replying to: G. A. Collins, J. R. Lipford, R. J. Deshaies & W. P. Tansey Nature 461, 10.1038/nature08406 (2009) Proteasome-mediated turnover of some1, 2, but clearly not all3, 4, transcriptional activators is important for their activity. To facilitate the analysis of activator–promoter complex lifetime in vivo, a parameter relevant to this issue, we developed a competition chromatin immunoprecipitation (ChIP) assay in which binding of a native transactivator to its cognate promoters is challenged by a ligand-activated competitor protein with the same DNA-binding specificity. We applied this technique to the yeast Gal4 system5 and concluded that under non-inducing conditions (raffinose media) Gal4–promoter complexes exchange rapidly, but under inducing conditions (galactose media) the activator–promoter complexes are long-lived. Collins et al.6 report that, surprisingly, the addition of oestradiol to yeast lacking Myc–G4–ER–VP16 increased the amount of DNA co-immunoprecipitated with native Gal4.
• Finding the missing heritability of complex diseases
  - Nature 461(7265):747 (2009)
  Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
• Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes
  - Nature 461(7265):754 (2009)
  The slicer activity of the RNA-induced silencing complex resides within its Argonaute (Ago) component, in which the PIWI domain provides the catalytic residues governing guide-strand mediated site-specific cleavage of target RNA. Here we report on structures of ternary complexes of Thermus thermophilus Ago catalytic mutants with 5'-phosphorylated 21-nucleotide guide DNA and complementary target RNAs of 12, 15 and 19 nucleotides in length, which define the molecular basis for Mg2+-facilitated site-specific cleavage of the target. We observe pivot-like domain movements within the Ago scaffold on proceeding from nucleation to propagation steps of guide–target duplex formation, with duplex zippering beyond one turn of the helix requiring the release of the 3'-end of the guide from the PAZ pocket. Cleavage assays on targets of various lengths supported this model, and sugar-phosphate-backbone-modified target strands showed the importance of structural and catalytic divale! nt metal ions observed in the crystal structures.
• Role of the polycomb protein EED in the propagation of repressive histone marks
  - Nature 461(7265):762 (2009)
  Polycomb group proteins have an essential role in the epigenetic maintenance of repressive chromatin states. The gene-silencing activity of the Polycomb repressive complex 2 (PRC2) depends on its ability to trimethylate lysine 27 of histone H3 (H3K27) by the catalytic SET domain of the EZH2 subunit, and at least two other subunits of the complex: SUZ12 and EED. Here we show that the carboxy-terminal domain of EED specifically binds to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, and that this leads to the allosteric activation of the methyltransferase activity of PRC2. Mutations in EED that prevent it from recognizing repressive trimethyl-lysine marks abolish the activation of PRC2 in vitro and, in Drosophila, reduce global methylation and disrupt development. These findings suggest a model for the propagation of the H3K27me3 mark that accounts for the maintenance of repressive chromatin domains and for the transmission o! f a histone modification from mother to daughter cells.
• Quantum signatures of chaos in a kicked top
  - Nature 461(7265):768 (2009)
  Chaotic behaviour is ubiquitous and plays an important part in most fields of science. In classical physics, chaos is characterized by hypersensitivity of the time evolution of a system to initial conditions. Quantum mechanics does not permit a similar definition owing in part to the uncertainty principle, and in part to the Schrödinger equation, which preserves the overlap between quantum states. This fundamental disconnect poses a challenge to quantum–classical correspondence1, and has motivated a long-standing search for quantum signatures of classical chaos2, 3. Here we present the experimental realization of a common paradigm for quantum chaos—the quantum kicked top2, 4— and the observation directly in quantum phase space of dynamics that have a chaotic classical counterpart. Our system is based on the combined electronic and nuclear spin of a single atom and is therefore deep in the quantum regime; nevertheless, we find good correspondence between the quan! tum dynamics and classical phase space structures. Because chaos is inherently a dynamical phenomenon, special significance attaches to dynamical signatures such as sensitivity to perturbation1, 5 or the generation of entropy6 and entanglement7, 8, for which only indirect evidence has been available9, 10, 11. We observe clear differences in the sensitivity to perturbation in chaotic versus regular, non-chaotic regimes, and present experimental evidence for dynamical entanglement as a signature of chaos.
• Observation of unidirectional backscattering-immune topological electromagnetic states
  - Nature 461(7265):772 (2009)
  One of the most striking phenomena in condensed-matter physics is the quantum Hall effect, which arises in two-dimensional electron systems1, 2, 3, 4 subject to a large magnetic field applied perpendicular to the plane in which the electrons reside. In such circumstances, current is carried by electrons along the edges of the system, in so-called chiral edge states (CESs). These are states that, as a consequence of nontrivial topological properties of the bulk electronic band structure, have a unique directionality and are robust against scattering from disorder. Recently, it was theoretically predicted5, 6, 7 that electromagnetic analogues of such electronic edge states could be observed in photonic crystals, which are materials having refractive-index variations with a periodicity comparable to the wavelength of the light passing through them. Here we report the experimental realization and observation of such electromagnetic CESs in a magneto-optical photonic crysta! l7 fabricated in the microwave regime. We demonstrate that, like their electronic counterparts8, 9, 10, 11, 12, 13, electromagnetic CESs can travel in only one direction and are very robust against scattering from disorder; we find that even large metallic scatterers placed in the path of the propagating edge modes do not induce reflections. These modes may enable the production of new classes of electromagnetic device and experiments that would be impossible using conventional reciprocal photonic states alone. Furthermore, our experimental demonstration and study of photonic CESs provides strong support for the generalization and application of topological band theories to classical and <1?show=[to]?>bosonic systems, and may lead to the realization and observation of topological phenomena in a generally much more controlled and customizable fashion than is typically possible with electronic systems.
• Early Palaeogene temperature evolution of the southwest Pacific Ocean
  - Nature 461(7265):776 (2009)
  Relative to the present day, meridional temperature gradients in the Early Eocene age (56–53 Myr ago) were unusually low, with slightly warmer equatorial regions1 but with much warmer subtropical Arctic2 and mid-latitude3 climates. By the end of the Eocene epoch (34 Myr ago), the first major Antarctic ice sheets had appeared4, 5, suggesting that major cooling had taken place. Yet the global transition into this icehouse climate remains poorly constrained, as only a few temperature records are available portraying the Cenozoic climatic evolution of the high southern latitudes. Here we present a uniquely continuous and chronostratigraphically well-calibrated TEX86 record of sea surface temperature (SST) from an ocean sediment core in the East Tasman Plateau (palaeolatitude 65° S). We show that southwest Pacific SSTs rose above present-day tropical values (to 34 °C) during the Early Eocene age (53 Myr ago) and had gradually decreased to about 21 °C by the early Late ! Eocene age (36 Myr ago). Our results imply that there was almost no latitudinal SST gradient between subequatorial and subpolar regions during the Early Eocene age (55–50 Myr ago). Thereafter, the latitudinal gradient markedly increased. In theory, if Eocene cooling was largely driven by a decrease in atmospheric greenhouse gas concentration6, additional processes are required to explain the relative stability of tropical SSTs given that there was more significant cooling at higher latitudes.
• Rapid ascent of rhyolitic magma at Chaitén volcano, Chile
  - Nature 461(7265):780 (2009)
  Rhyolite magma has fuelled some of the Earth's largest explosive volcanic eruptions1. Our understanding of these events is incomplete, however, owing to the previous lack of directly observed eruptions. Chaitén volcano, in Chile's northern Patagonia, erupted rhyolite magma unexpectedly and explosively on 1 May 2008 (ref. 2). Chaitén residents felt earthquakes about 24 hours before ash fell in their town and the eruption escalated into a Plinian column. Although such brief seismic forewarning of a major explosive basaltic eruption has been documented3, it is unprecedented for silicic magmas. As precursory volcanic unrest relates to magma migration from the storage region to the surface, the very short pre-eruptive warning at Chaitén probably reflects very rapid magma ascent through the sub-volcanic system. Here we present petrological and experimental data that indicate that the hydrous rhyolite magma at Chaitén ascended very rapidly, with velocities of the order of! one metre per second. Such rapid ascent implies a transit time from storage depths greater than five kilometres to the near surface in about four hours. This result has implications for hazard mitigation because the rapidity of ascending rhyolite means that future eruptions may provide little warning.
• Gene therapy for red–green colour blindness in adult primates
  Mancuso K Hauswirth WW Li Q Connor TB Kuchenbecker JA Mauck MC Neitz J Neitz M - Nature 461(7265):784 (2009)
  Red–green colour blindness, which results from the absence of either the long- (L) or the middle- (M) wavelength-sensitive visual photopigments, is the most common single locus genetic disorder. Here we explore the possibility of curing colour blindness using gene therapy in experiments on adult monkeys that had been colour blind since birth. A third type of cone pigment was added to dichromatic retinas, providing the receptoral basis for trichromatic colour vision. This opened a new avenue to explore the requirements for establishing the neural circuits for a new dimension of colour sensation. Classic visual deprivation experiments1 have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that the treatment of congenital vision disorders would be ineffective unless administered to the very young. However, here we show that the addition of a ! third opsin in adult red–green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour. Thus, trichromacy can arise from a single addition of a third cone class and it does not require an early developmental process. This provides a positive outlook for the potential of gene therapy to cure adult vision disorders.
• STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
  - Nature 461(7265):788 (2009)
  The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN)1, 2, 3. However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection4. Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes), were found to require STING to initiate effective IFN production. Accordingly, Sting-knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident bec! ause cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting-deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines.
• Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans
  - Nature 461(7265):793 (2009)
  Marked alterations in cellular energy metabolism are a universal hallmark of the ageing process1. The biogenesis and function of mitochondria, the energy-generating organelles in eukaryotic cells, are primary longevity determinants. Genetic or pharmacological manipulations of mitochondrial activity profoundly affect the lifespan of diverse organisms2. However, the molecular mechanisms regulating mitochondrial biogenesis and energy metabolism during ageing are poorly understood. Prohibitins are ubiquitous, evolutionarily conserved proteins, which form a ring-like, high-molecular-mass complex at the inner membrane of mitochondria3. Here, we show that the mitochondrial prohibitin complex promotes longevity by modulating mitochondrial function and fat metabolism in the nematode Caenorhabditis elegans. We found that prohibitin deficiency shortens the lifespan of otherwise wild-type animals. Notably, knockdown of prohibitin promotes longevity in diapause mutants or under con! ditions of dietary restriction. In addition, prohibitin deficiency extends the lifespan of animals with compromised mitochondrial function or fat metabolism. Depletion of prohibitin influences ATP levels, animal fat content and mitochondrial proliferation in a genetic-background- and age-specific manner. Together, these findings reveal a novel mechanism regulating mitochondrial biogenesis and function, with opposing effects on energy metabolism, fat utilization and ageing in C. elegans. Prohibitin may have a similar key role in modulating energy metabolism during ageing in mammals.
• Genetic variation in IL28B and spontaneous clearance of hepatitis C virus
  - Nature 461(7265):798 (2009)
  Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide1. Most (70–80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance3, 4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment5. To! determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
• A genome-wide linkage and association scan reveals novel loci for autism
  - Nature 461(7265):802 (2009)
  Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success1. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 10-7). We also demonstrated that e! xpression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
• Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution
  - Nature 461(7265):809 (2009)
  Recent advances in next generation sequencing1, 2, 3, 4 have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. Here we used these approaches to sequence the genomes (>43-fold coverage) and transcriptomes of an oestrogen-receptor--positive metastatic lobular breast cancer at depth. We found 32 somatic non-synonymous coding mutations present in the metastasis, and measured the frequency of these somatic mutations in DNA from the primary tumour of the same patient, which arose 9 years earlier. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier, six (in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A) were present at lower frequencies (1–13%), 19 were not detected in the primary tumour, and two were undetermined. The combined analysis of genome and transcriptome data revealed! two new RNA-editing events that recode the amino acid sequence of SRP9 and COG3. Taken together, our data show that single nucleotide mutational heterogeneity can be a property of low or intermediate grade primary breast cancers and that significant evolution can occur with disease progression.
• Direct RNA sequencing
  - Nature 461(7265):814 (2009)
  Our understanding of human biology and disease is ultimately dependent on a complete understanding of the genome and its functions. The recent application of microarray and sequencing technologies to transcriptomics has changed the simplistic view of transcriptomes to a more complicated view of genome-wide transcription where a large fraction of transcripts emanates from unannotated parts of genomes1, 2, 3, 4, 5, 6, 7, and underlined our limited knowledge of the dynamic state of transcription. Most of this broad body of knowledge was obtained indirectly because current transcriptome analysis methods typically require RNA to be converted to complementary DNA (cDNA) before measurements, even though the cDNA synthesis step introduces multiple biases and artefacts that interfere with both the proper characterization and quantification of transcripts8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. Furthermore, cDNA synthesis is not particularly suitable for the analysis of short, ! degraded and/or small quantity RNA samples. Here we report direct single molecule RNA sequencing without prior conversion of RNA to cDNA. We applied this technology to sequence femtomole quantities of poly(A)+Saccharomyces cerevisiae RNA using a surface coated with poly(dT) oligonucleotides to capture the RNAs at their natural poly(A) tails and initiate sequencing by synthesis. We observed transcript 3' end heterogeneity and polyadenylated small nucleolar RNAs. This study provides a path to high-throughput and low-cost direct RNA sequencing and achieving the ultimate goal of a comprehensive and bias-free understanding of transcriptomes.
• JAK2 phosphorylates histone H3Y41 and excludes HP1 from chromatin
  - Nature 461(7265):819 (2009)
  Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies1, 2, 3, 4, 5, 6. JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1 (HP1), but not HP1, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1 at the same site. &Tgr;hese results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two! genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia1, 2, 3, 4, 5, 6, 7, 8, 9.
• Structural insights into mechanisms of the small RNA methyltransferase HEN1
  - Nature 461(7265):823 (2009)
  RNA silencing is a conserved regulatory mechanism in fungi, plants and animals that regulates gene expression and defence against viruses and transgenes1. Small silencing RNAs of 20–30 nucleotides and their associated effector proteins, the Argonaute family proteins, are the central components in RNA silencing2. A subset of small RNAs, such as microRNAs and small interfering RNAs (siRNAs) in plants, Piwi-interacting RNAs in animals and siRNAs in Drosophila, requires an additional crucial step for their maturation; that is, 2'-O-methylation on the 3' terminal nucleotide3, 4, 5, 6. A conserved S-adenosyl-l-methionine-dependent RNA methyltransferase, HUA ENHANCER 1 (HEN1), and its homologues are responsible for this specific modification3, 4, 5, 7, 8. Here we report the 3.1 Å crystal structure of full-length HEN1 from Arabidopsis in complex with a 22-nucleotide small RNA duplex and cofactor product S-adenosyl-l-homocysteine. Highly cooperative recognition of the small ! RNA substrate by multiple RNA binding domains and the methyltransferase domain in HEN1 measures the length of the RNA duplex and determines the substrate specificity. Metal ion coordination by both 2' and 3' hydroxyls on the 3'-terminal nucleotide and four invariant residues in the active site of the methyltransferase domain suggests a novel Mg2+-dependent 2'-O-methylation mechanism.
• Dense packings of the Platonic and Archimedean solids
  - Nature 461(7265):828 (2009)
  Nature 460, 876–879 (2009) In Figure 1 of this letter, in the top row 'A1' was incorrectly listed as 'P6'. The correct figure is shown below.
• Stable single-unit-cell nanosheets of zeolite MFI as active and long-lived catalysts
  - Nature 461(7265):828 (2009)
  Nature 461, 246–249 (2009) In this Letter, the affiliations for Osamu Terasaki were incorrect. This author is associated with affiliations 4 and 5 from this Letter, the Graduate School of EEWS (WCU), KAIST, and Structural Chemistry, Arrhenius Laboratory, Stockholm University, and not with Nanoscience and Nanotechnology Research Center, Osaka Prefecture University.
• Genotypic sex determination enabled adaptive radiations of extinct marine reptiles
  - Nature 461(7265):828 (2009)
  Nature 461, 389–392 (2009) In this Letter, 'Dolichorhynchops osborni' was incorrectly listed as 'Dolichorhynchops osburni' at two occasions in the text.
• Life in a monastic lab
  - Nature 461(7265):836 (2009)
  A vocational career.