Science - HGP 10 Year Anniversary Specials

HGP 10 year anniversary writings from Science Feb, 2011
Table of Content
Waiting for the Revolution -------------------------------1 The Human Genome (Patent) Project ------------------------5 What would you do? ---------------------------------------7 Can This DNA Sleuth Help Catch Criminals? ---------------11 Beyond Human: New Faces, Fields, Exploit Genomics -------14 A Celebration of the Genome, Part 1 ---------------------19 A Celebration of the Genome, Part 2 ---------------------22 A Celebration of the Genome, Part 3 ---------------------25 A Celebration of the Genome, Part 4 ---------------------28
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Waiting for the Revolution

Having the complete human DNA sequence hasnt yet produced big advances in primary medicine, prompting some to ask whats delaying the genomic revolution in health care
IN 2009, THE SCHOOL OF MEDICINE AT Johns Hopkins University turned itself inside out for the human genome. Although ranking consistently among the top medical schools in the United States, it scrapped the existing curriculum and installed a shiny new Genes to Society agenda over the summer. A committee slotted genetics into every nook and cranny of the schools 4-year p r og r a m . E d wa r d Miller, dean and CEO of Johns Hopkins Medicine, who backed the change, said at the time, Its the biggest thing to happen in 100 years. Among the f aculty members, geneticist David Valle took the lead in championing the overhaul. Valle says the impetus came from his late colleague Barton Childs, a geneticist who argued in his writings that doctors have been trained in an overly rigid concept of disease. Students are taught everything in terms of the average patient and the classic case, Valle explains. But there are no such patients. Every case is unique because each persons genome is unique, Valle says. With its new education strategy, Johns Hopkins set out to show students that they should treat each patient as an individual. To do this, the school redid its course plan. Breaking with tradition, it added clinical encounters to the rst 2 yearsnormally a time for book-learningand inserted basic science into the third and fourth years, when doctors in training generally leave such lectures behind for clinical rounds. Johns Hopkins further added a series of short seminars over the 4 years to meld genetics and medicine in focused studies. With $20 million in gifts so far, Johns Hopkins has created a $2 million
simulation center and a $52 million new curriculum buildingcomplete with an anatomy lab where every dissecting table has an Internet connection. This departure is a gamble, but Johns Hopkins isnt taking it alone. Other medical schools and research centers are investing tens of millions of dollars each to join the genomic medicine bandwagon. Yet despite the excitement, some say this is a huge leap into uncharted clinical territory. Most doctors have not embraced the genomic revolution, according to leaders of medical professional groups, because they have trouble seeing how it will benet their patients. A survey of American Medi-
Can you prove it? No one is more aware of the gap between todays health care and the promised future of genomic medicine than Greg Feero, an M.D.-Ph.D. who lives in both worlds. Feero studied neuromuscular diseases but now practices as a family doctor in Fairfield, Maine. From 2007 to 2009, he worked at the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. The
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cal Association members last year found that only 10% of respondents thought they had enough knowledge to use gene tests in prescribing medicines, although nearly all thought such tests were useful. DNA testing is growing rapidly in oncology to guide the treatment of some cancers, and in screening couples before conception and newborns to nd dangerous mutations. Based on recent studies of cancer cell genetics, many labs are developing therapies to narrowly target tumor DNA. But aside from these situations, applications are scant; most public health reviews of DNA-based approaches have not found a health benet. As doctors and scientists look back over the decade since the human genome was published, some are asking tough questions. Is the translation of DNA research into medical practice taking longer than expected? Has the genomic medicine revolution faltered? Such questions can elicit a sharp response from leaders in clinical genomics. Eric Topol, a pioneering researcher on DNArelated treatments in cardiovascular disease and cancer at the Scripps Translational Science Institute in San Diego, California, says the medical establishment is slow to change because its sclerotic. In his view, studies that nd insufcient evidence of benet are often used as an excuse for not learning about new science. Still, Topol and many others in the eld agree that proof of clinical usefulness is in short supply. We need to demand evidence and not get caught up in a nave view that just because something sounds good, its going to be good, says James Evans, a medical geneticist at the University of North Carolina, Chapel Hill.
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agency employed him (and now retains him from afar) as an adviser. More than ever, he says, he is aware of the stresses piling up on primary care. In fact, you could say he is adding to them. Feeros job at NHGRI is to integrate genomics into medicine. Specifically, he aims to nudge primary care doctors, along with nurses and physicians assistants, to join the revolution, building up networks of like-minded medical leaders. They push credential-granting bodies to test for and certify competencies, or practical knowledge, of genetics. The approach has bite, because candidates learn whatever is required for board certication. Organizations that represent nurses and physicians assistants are quickly embracing genetic competency testing, Feero says. Specialist groups in cancer and cardiovascular disease have been ramping up training, too. But primary care physicians have been very difcult to engage. One reason, Feero says, is that doctors already have too many obligations. They are tying to adopt digital recordkeeping methods, follow more stringent rules in training, and adhere to new working-hour rules for residents. Their plate is more full than when I left [Maine] half a decade ago, he says. That often leaves physicians with little time for taking detailed family histories or learning about other genetic tools (see sidebar, p. 528). Competition for time is an important issue. But the bigger one, many doctors say, is the scarcity of data showing that gene-based methods actually protect or improve patients health. Practitioners are looking for evidence of impact before they make [genomic medicine] a priority, says Gary Rosenthal, president of the Society of General Internal Medicine and a professor at the University of Iowa Carver College of Medicine in Iowa City. Like many, he argues that doctors will move fast if they see clear benetsbut they dont see them now and dont want to jump the gun. Evans, who is also editor of Genetics in Medicine, agrees. We need to quit trying to push genetics into medicine, he says. We hear these grandiose statements that genomic technology is going to revolutionize medicine. That may be true, but the revolution is going to take decades, he thinks. Like Rosenthal, he believes doctors will embrace technologies as they prove valid. hoped its seal of approval would speed new ideas into clinical use. EGAPP has done six comprehensive reviews in 6 years. Four more are planned this year, says Khoury, adding that the group is trying to become faster and nimbler to take on a growing caseload. In the last 6 to 9 months, we have identied more than 200 new applications, mostly new genomic tests, and mostly in cancer, says Khoury. But rumors are circulating in the genomics community that CDC may cut funding for this ofce. Khoury has no comment. All but one of EGAPPs reviews have been unfavorable or neutral, generally because the panel didnt see evidence of a health benet. For example, in January an EGAPP group recommended against routine testing for factor V Leiden and prothrombin gene variants in people with a history of deep-vein blood clots. Both genes influence such clotting. People who have had such clots should be treated with anticoagulants anyway, regardless of genetic status, the panel concluded. And in a second grouprelatives of people who have had clots but who themselves have notthe panel judged that it would be too risky to treat preemptively with anticoagulants (which can cause hemorrhaging) based on genetic status alone. The exception to EGAPPs general pattern was a decision in 2009 in favor of a test for mutations linked to an inherited type of colorectal cancer, called Lynch syndrome. The evidence, EGAPP concluded, justies testing colon tumors of newly diagnosed patientsnot to help the patient but to alert relatives of those who test positive that they have a 50% risk of being affected. Although it won EGAPPs blessing, the Lynch syndrome test has complexities that may put off some clinicians. It looks simple and straightforward, says Douglas CamposOutcalt, a leader in family medicine and associate head of the University of Arizona Cancer Center in Phoenix. But it isnt. What if the patient doesnt want their test results spread around? Campos-Outcalt asks. And what do you tell the relatives about their own risk? Basically, he says, the message is, refer them to a genetic counselor. Theres another practical question: Who should pay? Theres no evidence so far that this test can be used to guide the treatment of the person with the tumor. So doctors must
This News article and another on gene patents (p. 530) launch a series of features this month commemorating the 10th anniversary of Sciences and Natures publications of the human genome (see Editorial, p. 511, and Essay, p. 546) and looking forward to the next decade of genomic research. All the stories and related material, including a podcast by the author of this story, will be gathered at http://scim.ag/genome10.
We need to quit trying to push genetics into medicine.

JAMES EVANS, UNIVERSITY OF NORTH CAROLINA, CHAPEL HILL
high risk for BRCA cancer gene mutations be evaluated for genetic testing. Genetics was not very much on [USPSTFs] radar screen, says Muin Khoury, director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC) in Atlanta. Thats why Khoury, a geneticist, pushed CDC to help evaluate DNA-based technologies for public health. In 2005, CDC created an independent working group called Evaluation of Genomic Applications in Practice and Prevention (EGAPP). Khoury says he
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But relatively few genomic approaches have been reviewed for clinical utility. For example, in 2 decades, the governmentfunded U.S. Preventive Services Task Force (USPSTF) has looked at just two topics in genetics. It approved one: In 2005, it recommended that women whose families have a
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be creative about billing. At Intermountain Healthcare in Salt Lake City, clinical geneticist Marc Williams has persuaded hospitals in the system that they should pay because the test returns money to the health plan in the long run. It appropriately enables the system to recruit other individuals who would subsequently pay for their own testing. And it identies a certain number of people who may be able to avoid cancer, and the accompanying health care costs, by having a polyp removed. Some genetic tests make sense primarily in a public health context, Khoury says. This is one of them. He speaks of using the Lynch syndrome assay for cascade testing of affected families. By screening 150,000 people, one can nd 4000 to 5000 high-risk individuals. Making medicine precise In contrast to those who focus on missing evidence, Topol sees genomic medicines glass as half-fulland lling fast. He rattles off a series of recent DNA-based technologies that appear to have important uses in medicine already. Tumor analysis heads his list: Topol points out that major clinical centersincluding the Massachusetts General Hospital in Boston, MD Anderson Cancer Center in Houston, and the U.K. National Health Serviceare now sequencing DNA from patients tumors with an aim to improving therapy. The data are used in research, but Topol expects DNA-guided clinical approaches to emerge soon. of other therapies. With a complete list of normal proteins (and mutations in tumors) from the human genome, they aim to narrowly target colon cancer, lung cancer, glioblastoma, and melanoma. Topols institute has recently been studying another hot topic: DNA mutations that affect how patients respond to medicines in cardiovascular therapy. Specifically, his group has been sequencing the exomes all the protein-coding DNAof hundreds of patients being treated with clopidogrel (Plavix), a drug given to prevent the formation of clots after a stent has been placed in a coronary artery. Some versions of the gene for the enzyme CYP2C19 have been identied as a major risk factor in patients who metabolize clopidogrel poorly, increasing the danger of blood clots and death. The stakes are high, says Topol, because the mutation is common and clopidogrel is widely prescribed. In March 2010, the U.S. Food and Drug Administration (FDA) added a blackbox warning, the highest level of alert, on the drugs label. It describes the genetic risk and notes that it can be tested for. This is one of hundreds of pharmacogenomic risks under study. Some have been well nailed down, such as those involving the patients response to warfarin (an anticlotting medicine), mercaptopurine (for immune suppression), abacavir (for HIV/AIDS), and interferon (for hepatitis C). There are many others in the on-deck circle, says Topol.
Skilled Practitioners
1990 1993 1996 1999 2002 2005 2007 2009 184 252 232 161 129 189 142 135
Medical geneticists
SOURCE: American Board of Medical Genetics (ABMG), lab and clinical specialties. ABMG in 1990, thereafter the American Board of Genetic Counseling (master's degree).
Limited resource. The number of U.S. medical geneticists certied each year has declined while the number of genetic counselors, who hold masters degrees, has risen.
For a decade, oncologists have been using the drug Gleevec to target tumor cells in patients with chronic myeloid leukemia. The same concept now drives the search for a host
Human Genetics in the Clinic, One Click Away

The number of genes identied as factors in human disease has exploded in the past decade. Although the exact inuence of many remains elusive, the potential impact on medicine is huge, as suggested by a global tally on a public Web site called GeneTests (www.genetests.org). It now lists 2267 available genetic tests.
The volume and the tentative nature of the information are a problem for medicine, however. The fact is, it is not possible for most primary care doctors to be highly knowledgeable about all aspects of medical conditions, wrote Gary Rosenthal, president of the Society of General Internal Medicine and a University of Iowa professor of medicine, in comments last year to a U.S. Health and Human Services panel on genetic education. He told the group that it seemed unjustied to ask doctors to keep up with everything in genetics. They dont have time. Finding a way to give medical practitioners the right genetic information, but not too much, at the point of care is one of the biggest challenges in the eld, says Bruce Korf, chair of human genetics at the University of Alabama, Birmingham. Indeed, Korf ranks this issue as second only to the main one: developing evidence that genomic medicine can make patients healthier (see main text, p. 526). Computer technology may come to the rescue. At Intermountain Healthcare network in Salt Lake City, geneticist Marc Williams (right) is using digital tools to slip up-to-date education into the daily run of medicine in ways that doctors may nd helpful. One trick is to insert info buttons into Intermountains data les. This health care network uses electronic records throughout the system to track patients progress. As doctors ll in the forms, they see an Do it yourself. Marc Williams helped create a Web site at Intermountain Healthcare that invites patients to create their own family medical histories.
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141 181 258 340 401 360 Genetic 347 331 counselors
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One indication that genetic funds to do more regulatory scitesting has value is that busience. And to help keep up with Growth of Genetic Testing ness clients are willing to pay the pace of discovery, FDA and for it, says epidemiologist Robthe National Institutes of Health Genetic testing labs ert Epstein, president of the last year agreed to work together Diseases for which Medco Research Institute of to identify, monitor, and evalutesting is available Franklin Lakes, New Jersey. ate new therapies as they emerge Several years ago, his comfrom research labs. pany began to look for customIf Johns Hopkinss gamble is ers who would pay for expert right, its not only FDA that will advice on the utility of gene need to adapt. Medical genetitests, particularly those used in cist Bruce Korf of the University prescribing drugs. Since 2008, of Alabama, Birmingham, has he says, the company has signed been involved in national efforts up 300 health plans, insurto reshape medical school curriers, and unions, representing cula, and he argues that although 65 million individuals. In that theres little published evidence time, Medco has reviewed of health benets from genomhundreds of genetic tests and ics, clinical institutions across 1993 2009 approved 12 as valid and worth the board will need to keep up or paying fora judgment that risk nding themselves behind SOURCE: GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 19932011. Available at http://www.genetests.org. Accessed [1/28/2011]. is both about clinical efcacy the eight ball. Changes are comand economics. ing, perhaps slowly at rst, but Epstein is bullish on pharmacogenomic D.C., FDA Commissioner Margaret Ham- the effect over time will be pervasive and tests. They give more precision to medicine, burg noted that despite $2.7 billion spent to transformational, he maintains. he says, and who could not want that? In his decode the human genome and a decade of The genomic revolution is sometimes view, EGAPP has been unduly conservative analysis, fewer than 50 therapies actually described as a tidal wave thats racing toward in its approach to vetting new technologies, have genetic tests as part of their labeling to the shore, says Feero. He thinks thats the and he thinks its high rejection rate in the past guide users. Still, FDA expects to see a surge wrong metaphor. New ideas are flooding may not be a good indicator of the quality of of new gene tests and gene-targeted therapies in, he says, but they are ltering through the products now in the pipeline. His company is this decade, and Hamburg is concerned that health care system in spurts, as they always now running half a dozen major pharmacoge- the agency may not have the data or the sci- have. Most people will perceive the change nomic trials. entists it will need to do the necessary evalua- not as tsunami but as a slowly rising tide. Speaking last October in Washington, tions. She made a pitch in her October talk for ELIOT MARSHALL
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i surrounded by a small blue circle pop up at certain points, explains Williams, director of the Intermountain Healthcare Clinical Genetics Institute in Salt Lake City. These clickable spots offer help when doctors are describing a patients complaint, ordering a lab test, or prescribing drugs. If one entered Marfan syndrome as a patient problem, for example, a blue info button would appear with a list of links offering a genetic reference service, gene reviews, or perhaps more readable articles from Internet resources. You get the content much, much more quickly than going to Google, he says. Info buttons of the future may gently direct the course of treatment. For example, cardiac patients can get into serious trouble if, because of the genes theyve inherited, they metabolize the anticlotting agent Plavix (clopidogrel) too slowly. An info button might therefore note a genetic test to evaluate how fast a person metabolizes the drug. But Williams says that Intermountains cardiology department has decided that the genetic test isnt as useful as a platelet reactivity test, which gives a more direct indication of clotting risk. So the info button could say, Maybe you shouldnt order the genetic test, or Maybe you should consider a different test. Intermountain aims to use digital methods to crack another knotty problem in primary care: the failure to gather useful family medical histories. Asking patients about their relatives is a quick way to get into genetic risks. But doctors typically dont do this thoroughly, many studies have concluded, mainly because they dont have time. Intermountain is trying a new tack. A few months ago, it added a program to its Web site, Williams says, in which patients are
invited to build their own family medical history. Its too early to say whether the strategy is working, but the idea is that the patient gathers the raw information, the computer analyzes it, and the doctor and patient together discuss the results. It should help identify highrisk cases of genetic diseases. Intermountain is one of several networks in the United States that are beginning to integrate genetic data into primary health care. A wave of innovation in point-of-service education is likely to spread over the wider health community in time, but this may be limited by the sluggish rate of change in electronic health recordkeeping. At the moment, Williams says, not one of the commercial programs hes seen is capable of converting results from genetic tests into data les. This means that automated tools like those at Intermountain designed to scour medical records and give summary reports to physicians cant incorporate genetic data. Williams is waiting for two revolutions: one in medicine and another in records management. E.M.

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Legal limit. Patents can limit a companys ability to test for multiple genes with gene chips.
The Human Genome (Patent) Project

A decade of research has scientists asking if patent priorities are misaligned
The start-up company Foundation Medicine in Cambridge, Massachusetts, has an impressive pedigree. Its founders and advisers include veterans of the Human Genome Project (HGP) as well as scientists from various elite institutions around Boston. But when Foundation Medicine hired its rst ofcial employee last April, it ignored the scientic community and tapped Gary Cohena lawyer. That turned out to be a good thing. Foundation Medicine plans to offer a type of diagnostic cancer test: Oncologists would send the company tissue, and it would search for aberrations in 100 or so genes to determine how to treat the cancer. Many important cancer genes are covered by patents, however, so not everyone can legally analyze them for commercial purposes. And when Cohen surveyed the patent landscape, it appeared grim: Investigating all the relevant patent claims (issued and pending) for possible infringement would cost at least $35 million, he estimated. On top of that, the company would have to negotiate licenses and possibly pay to use many genes. The company has $25 million, total, in venture capital. Once upon a time, before the HGP, patenting criteria aligned very nicely with genetics. The patents granted early in the game that period of intense gene discovery from the mid-1990s to early 2000sread like the science of the day: all Mendelian traits, focusing on one gene associated with one disease, says Robert Cook-Deegan, director of Duke Universitys Center for Genome Ethics, Law & Policy in Durham, North Carolina. He pauses. We now know thats wrong. Scientists now realize that any one gene accounts for only a small risk for most diseases. Whats more, many common diseases like diabetes are in fact idiosyncratic on a molecular level, the result of many distinct DNA variations. Many diagnostic companies have therefore shifted focus and offer so-called multiplex tests, which can scan dozens of genes and study the molecular products of each. Cheap sequencing technology already has some scientists talking about whole-genome scans for diseases. Many diseases are caused by multiple factors, so we want our products to be as unbiased as possible, says Sandra Wells, chief intellectual property counsel at Affymetrix, a diagnostics company in Santa Clara, California. Patents last up to 2 decades, however, so they cannot evolve as quickly as genetics has. Many companies have already set up businesses around one or a few genes, most notably Myriad Genetics, which tests for hereditary breast cancer genes. In fact, onefth of human genesespecially potential moneymakers associated with diseases
Workarounds? There are two basic kinds of gene patents. The rst covers gene sequences and related products. Some patents of this kind cover stretches as short as 15 nucleotides and also cover any attempt to synthesize that DNA. Other patents claim all genetic variation within a stretch of DNA and variation in the protein it produceseven products not identied by the patent ler. Most DNA sequencing machines still rely on synthesizing DNA, says James Evans, a geneticist at the University of North Carolina, Chapel Hill. As a result, he says, even with research sequencing, its extraordinarily hard to argue that when we sequence an individuals genome we arent violating patents right and left. Testing for the presence of certain DNA variations also strays into gray legal territory, says CookDeegan. For instance, the hip sequencing companies 23andMe and Navigenics test for, respectively, Myriads breast cancer genes and variants of APOE, a gene linked to Alzheimers disease. The second gene patents are method patents, which are often extremely broad many cover any attempt by any means to associate a stretch of DNA with a given disease, like heart disease or hereditary colon cancer. A 2009 study in Nature Biotechnology examined two dozen commonly testedfor genetic diseases and concluded that three-fourths of method claims are difcult or impossible to circumvent. The danger for companies hoping to use patented genes in their products isnt nec-
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are covered by patents. So a commercial outt developing a diagnostic test faces quite a patent thicket. One survey by Mildred Cho of Stanford University in 2003 found that one-quarter of diagnostic labs had already stopped providing a test because of patent worries, and half had scrapped plans to develop one. Diagnostics is the most obvious area in which critics say gene patents and gene science have become misaligned. But disputes over the proper way to patent genes especially how many patents to grant and how broad to make themhave affected most areas of biotechnology. Because the patent system has collided with something inherently huge and inherently balkanized like the genome, says Cohen, the ability to analyze each relevant gene and do one-at-atime licensing has become untenable.
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essarily getting sued by hundreds of oppor- sis might be overblown, too, says Evans. Its tunistic patent trolls. Universities and non- not clear what platform will be the technolprotsgroups less likely to enforce pat- ogy of choice. In fact, its almost assured ents aggressivelyown most patents on that a variety of platforms will be used for the genes used in diagnostic tests, and when foreseeable future. Cohen fully analyzed the patents on a handFor these reasons, many lawyers and sciful of genes that Foundation Medicine might entists argue that the sheer number of patuse, he was encouraged, finding plenty ents poses unnecessary barriers for biotech of room to operate. But that doesnt lower companies and can even squelch investment. the cost of investigating hundreds of pat- Says Wells: The absence of clear guidance ents, because biotech patent holders swap on the patentability of genetic information rights constantly and because most licensing almost certainly results in delays of new agreements are condential. product launches. As for basic research, To avoid potential lawEvans says it moves ahead nowadays suits, a Foundation Medicine or an Affymetrix has to negotiate individual royalGENE AND DNA PATENTS ties with each patent holder, which presents its own problems. One is royalty stacking: 1970s 12 If 50 companies each want 2% of net 143 1980s profits, thats not a good business 1606 1990s model. Even at fees can make diagnostics untenable, a situation Cohen describes as a $1000 genome with a $100,000 royalty burden. 2000 3827 Biotechnology isnt the only 4463 2001 eld to face dense patent thickets, of 3872 2002 course. Electronics companies do, yet 3536 2003 they still manage to inundate consum3055 2004 ers with goodsoften by invent2722 2005 ing around certain patents. Scien3474 2006 tists such as Steve Rosenberg, chief 3587 2007 scientic ofcer at CardioDx in Palo 3175 2008 Alto, California, which diagnoses 3237 2009 cardiovascular diseases via genes, 4288 2010 see a lesson here. Many genes are always expressed together, he explains, SOURCE: DNA Patents Database at Georgetown University, http://dnapatents. so tests can circumvent a patented georgetown.edu/. The database includes all U.S. patents related to DNA including sequence, method, and other patents. gene by searching for the products of an unpatented one. You can substitute genes, he says. That can give you a workaround. because scientists blatantly ignore patHowever, some scientists argue that ent claims. But as the nancial stakes get genetic workarounds can fall short of clinical higher, he says, its less likely that people standards. In April, the National Institutes of will continue to ignore them. Healths Secretarys Advisory Committee on Genetics, Health, and Society (SACGHS) Solutions? published a report on gene patents. (Both While some despair, a few people think Evans and Cook-Deegan sat on the commit- theyve found a machete to hack through tee.) The report noted that, if a test uses only the human genome thicket. But before they freely accessible genes, individuals with the start cutting, most are waiting for the outdisease who have a mutation in the patented come of an important and likely precedentgene would go undetected and undiagnosed. setting court case involving Myriad. A state Moreover, given the number of existing court in New York recently invalidated its patents, an unpatented substitute may not sequence and method patents, but Cookbe available. Deegan notes that the heavy betting among Hopes that new sequencing technolo- intellectual-property types is that the patgiessay, graphene-based DNA sequencers, ents will be upheld in federal court. If that which read bases electronicallycan cir- happens, he says, in a plain-English readcumvent patent restrictions on gene synthe- ing, most sequencing and diagnostic techBy Year By Decade (yearly average) www.sciencemag.org SCIENCE VOL 331
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nologies would violate many patents. This confusion is unlikely to evaporate no matter how the Myriad case turns out, so policymakers have considered other solutions. The SACGHS report recommended exemptions from infringement liability when using genes in diagnostic tests, for instance. But its hard to imagine this solution appealing to patent holders who did the hard work of discovering genes and want remuneration. And most biotech companies dont want the government involved anyway; they prefer their own, voluntary solutions. One solution could involve an independent clearinghouse to manage intellectual property, which could reduce the cost of compliance by providing a single place to nd patents and licenses. Along these lines, MPEG LA, a company headquartered in Washington, D.C., that specializes in creating patent pools (it brought 900 patents together to create the MPEG digital video standard), announced plans in April to set up a supermarket for diagnostic gene patents in the latter half of 2011. In the supermarket, people will have choices. They can literally shop for what they need, said Lawrence Horn, president of MPEG LA. He cant ensure a company will nd every patent it needs, but given that nonprofits own many patents, he feels condent that many will stock the supermarket with diagnostics licenses, even if they reserve other rights (like the right to develop DNA therapeutics). Meanwhile, in the absence of a central group, some companies have developed their own machetes. Navigenics posted a formula on its Web site that outlines how much it is willing to pay (not much) for any one gene among the thousands it sequences with every customer. Cook-Deegan, among others, praised the idea, saying its really smart. It says, We respect intellectual property but dont want to let it get in our way. It will take a similarly Solomon-like solution to appease both patent holders and companies clamoring to pursue promising genetic research in DNA diagnostics and sequencing and other elds. The HGP has yet to fulll the implicit promises it made to revolutionize medicine, and multiplex and whole-genome analysis could be the start. But when it comes to intellectual property, says Cohen, lawyers, businesspeople, and policymakers need to be as diligent and creative as the scientists working to bring this transformation to the clinic.
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What Would You Do?

THE PARENTS SAT TOGETHER IN THE EXAM room facing Leslie Biesecker, the geneticist in whose study they had enrolled their young daughter. She had unexplained mental retardation and a host of other problems. A close look at her chromosomes might illuminate why. And indeed it had. Biesecker shared the news that the little girl had a deletion in one chromosome, a chunk of DNA gone missing when she was conceived. Given that the parents had voluntarily enrolled her in a study whose goal was to nd DNA deletions like this one, he expected them to be pleased, or at least relieved. The reality was different. The father was enraged, enraged, slamming his closed st down on the table, Biesecker remembers now, more than a decade later. Here was someone involved in a study with the express focus of nding what was causing their daughters disability, and he was horried when we found it. The reason, the father suggested, was because the missing DNA couldnt be replaced. His daughter would never be normal. That moment stayed with Biesecker, a reminder that research participants may harbor intense hopes they expect scientists to conrm, or may not know what they want until the results are laid out in front of them. It left him treading carefully, though doggedly, into uncharted territory, as he began plotting how to return genetic ndings to people participating in research.
As technology makes it easier to sequence peoples DNA for research, scientists are facing tough decisions over what information to give back
Maryland, where Biesecker also works. This issue, which was a few years ago kind of theoretical, is becoming real. ELSI is now accepting applications for more than $7.5 million in studies on how to share genetic results with research participants. In December, 28 researchers convened by the U.S. National Heart, Lung and Blood Institute (NHLBI) in Bethesda published a set of ethical and practical guidelines for returning such results. Hospitals struggling with the issue are running focus groups and mailing surveys to patients and families, querying them on what they might want to learn, however unexpected, about their or their childs DNA. Do you really want to know that your child is going to get Alzheimers disease when theyre 60? asks Ingrid Holm, a pediatric geneticist and endocrinologist at Childrens Hospital Boston, which is launching a registry designed to return genetic research results. People say they want everything back, she continues. Im not sure they know what everything means. When to share The landscape in genetic testing has shifted irrevocably just in the past year or so. Until recently, technology and cost limited geneticists to querying very narrow stretches of DNA, or sequencing a relative handful of DNA variants across the genome. But high-powered, next-generation DNAsequencing machines are quickly mak-
This News Focus article, the related podcast by its author, and another News Focus on the genomic data explosion (p. 666) are part of a collection this month reecting on the 10th anniversary of the publication of the human genome. All the stories, and other related material (see also Essays p. 689), will be gathered at http://scim.ag/genome10
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With genetic studies multiplying and sequencing costs plunging, more than a million people worldwide are, sometimes unknowingly, sharing their DNA with hundreds or even thousands of researchers. And its slowly dawning on many scientists and ethicists that even if the DNA was offered to study diabetes or heart disease or some other specific condition, it may surrender many other secrets. Is a study participant at a high risk, or even just a higher risk, of breast cancer? Does she have a sex chromosome anomaly or carry a cystic brosis mutation that could threaten her offspring? Whether to divulge results like these, and how, is arguably the most pressing issue in genetics today. It comes up in every conversation, says Jean McEwen, a program director at the Ethical, Legal and Social Implications (ELSI) Research Program, which is housed in the U.S. National Human Genome Research Institute (NHGRI) in Bethesda,
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ically actionable, meaning something can be done to alleviate the risk once information is shared. Its dening these terms thats ing those approaches obsolete. With the the problem. Is a gene that confers a 30% new technology, its possible to affordably chance of developing a disease clinically sequence a persons exome, all the DNA relevant? How about 5% or 1%? And what that generates proteins, which, when defecqualies as actionable? A relatively clear-cut tive, can drive disease. Sequencing entire case is a woman found to carry certain mutagenomes of many research volunteers could tions in the BRCA1 gene; her risk of developsoon be the new norm. ing breast cancer is about 60% and is much Even simple quality-control measures increased for ovarian cancer. She could take common to genetic studies can wind up posadvantage of intensive surveillance or have ing a dilemma for researchers. Labs often her breasts and ovaries removed to reduce verify that samples are correctly her chance of cancer, something labeled: that a female sample The following scenarios could confront scientists con- hundreds of women with BRCA1 actually has two X chromomutations have done. somes, for example, and a males ducting genetic studies. Because preventive care can has an X and a Y. This doublemake a real difference for somewith a research participant one who carries a BRCA1 mutachecking can turn up sex chromosome disorders, like Kline- (or his or her parents) if it wasnt explicitly covered by tion, many researchers believe felter syndrome in which men that these results are worth shara consent form? If the shoe were on the other foot, ing. The NHLBI working group are XXY or Turner syndrome in which women have one X chroagreed and endorsed disclosing would you want to know these results? mosome instead of two. People many nds that are clinically relwith Klinefelters or Turners evant and medically actionable. vary in their symptoms, and a scientist may Drawing such boundaries speaks to the suddenly face the prospect of telling kind of narrowness of the medical professomeone who donated DNA that their sion and a certain patronizing view, sex chromosomes are abnormal and says Robert Green, a neurologist at that they are likely infertile. Boston University who has been Furthermore, the new breed of studying how people respond genetic studies are often shing expeto learning their genetic risk for ditions. Hunting all over the genome Alzheimers disease, which cant for DNA behind a particular disease, yet be prevented or treated. Most its easy enough to collide with the people dont make the distinction unexpected. Youre using a techbetween medically actionable and mednology that isnt just looking for ically not actionable that the medical the gene for X, says Bartha Maria and research communities keep tryKnoppers, who studies law and ing to make. genetics at McGill University in Of course, the data that are Montreal, Canada. Youre scanning shared must be accurate, says Ellen the whole genome; youre going to Wright Clayton, who studies law see Y and Z. and genetics at Vanderbilt UniverWhile many genetic studies strip sity in Nashville, and they should be DNA samples of personal identiuseful. But deciding your threshers and assign each a number, such old for that is an intensely valuecodes can often be linked to an individual by she calls some really big-ticket items laden question. The issue about whats a central computer or by the researcher who should be shared with research participants. returnable is anything but scientic. collected the samples in the rst place. In But despite widespread agreement that Many who have a voice in the discussion, some studies, the DNA is truly anonymous that category exists, there is real disagree- such as Clayton, say they would shy away and researchers couldnt contact the donors ment and ferment over what it encom- from sharing genetic results. One reason is even if they wanted to, but weve gotten passes. Some people but not all would that there could be legal implications if results away from that, says Benjamin Wilfond, a include mutations in genes such as BRCA1, are incorrect. Some researchers are doublephysician and bioethicist at Seattle Childrens MSH2, which predisposes one to colon can- checking ndings in clinically certied labs Hospital in Washington. cer, and factor V Leiden, which can cause called CLIA labs in the United States; others Genetics isnt the rst eld to come up blood-clotting problems and recurrent mis- are shifting their research work to CLIA labs. against so-called incidental findings. On carriages but is treatable. Then theres the issue of informed convirtual colonoscopies that use CT scans, at Many favor sharing results, whether from sent. Typically, informed consent forms least 20% reveal something atypical outside a functional MRI or a genetic test, that are for genetic studies are explicit in saying the colon. And a 2007 study found that mag- both clinically relevant, meaning they have that results will not be returned. Although netic resonance imaging (MRI) scans of the a real impact on someones health, and med- consent forms may change in the near
Question bank. The UK Biobank holds more than
500,000 samples available for DNA studies.
brains of adults in a Dutch population study turned up an unexpected abnormality 13% of the time. The unsettling nds included aneurysms, asymptomatic strokes, and tumors. Theres little public guidance for researchers on how to handle incidental ndings like these, according to Susan Wolf, a law professor specializing in bioethics at the University of Minnesota Law School in Minneapolis. Those enmeshed in genetics, facing potentially many more such cases, are now seeking common ground. I think there is growing consensus, says Wolf, that what
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futureand in a handful of cases already have for now, when something comes up, researchers must ask themselves whether it rises to a level where youre going to break that contract, says Holm. In one case at Boston Childrens, a blood sample from a child in an autism study suggested a fusion of two genes that would mean a still-undiagnosed cancer. A closer look dismissed this possibility, but had the result been accurate, the researchers assumed they would have shared it with the parents. The family of a boy in a research study at Childrens who was found to have Klinefelters was not told, however. Klinefelters and other sex chromosome anomalies make researchers especially uneasy, in part because theyre fairly common. If an older man in a genetic study is discovered to have Klinefelters, how should one decide whether to divulge that, asks Clayton, whos aware of such a case right now. If the individual agreed not to get information back, Claytons doubtful it should be shared. What good is going to come out of that? she asks. Others have erred on the side of openness. Alan Shuldiner studies the genetics of heart disease and diabetes at the University of Maryland School of Medicine in Baltimore and works with the Old Order Amish of Lancaster, Pennsylvania. Seven years ago he was parsing the DNA of 2000 Amish for sitosterolemia, a rare disease that causes the accumulation of plant sterols and leads to atherosclerosis and early death. Sitosterolemia is recessive, meaning that each parent must carry a copy of the defective gene to pass the disease along to their child. In his study, Shuldiner found one adult who carried two copies of the mutated gene and had the disease; because it can be treated by diet modications, there was no question that this person should be told. But another 80 or so Amish turned up as healthy carriers, far more than expected given that fewer than 100 cases of sitosterolemia have been described in the general population. Shuldiner hadnt considered this outcome when designing the study. He consulted with his Amish advisory board, who really felt we should share this information. He sent a letter to all the Amish in the studycarriers and noncarriers alike alone has more than 500,000 of them. If a scientist using a biobank sample chances upon a disease mutation and wants to get back to the donor, where does she turn? DNA and tissue deposited in such banks are usually stripped of identifying information, and the researcher who rst collected them may have retired, or moved, or died. Thats one reason Knoppers and Wolf hope biobanks themselves will help coordinate delivery of these ndings, something theyre only beginning to contemplate. Ethicists sit around a table and talk about the importance of returning DNA results, but if you talk to people like myself who have actually helped run biobanks, you cant imagine how unsuited we are to doing this, says Green. Biobanks would have to reach out to the hundreds of thousands of people who have already shared DNA samples and inquire whether they might want information back; currently, virtually all biobank consent forms say that genetic results will not be returned. Even if informed consent forms change, the banks might then need to interact with researchers uncertain about what to share with a DNA donor and make decisions, often on a case-by-case basis, before recontacting a participant with a potentially upsetting research nding. If were really going to commit to taking this on as a part of every major research study, what is that going to do to the research enterprise? asks ELSIs McEwen. Were becoming almost a clinical feedback center. One country may find out the answer to McEwens question especially quickly. In 2007, Spain passed a law requiring that the physician in charge of a genetic study share information that is necessary in order to avoid serious damage to the health of the participant or that of his biological family members. Knoppers, who has concerns about legislating this issue, notes that the law incorrectly assumed that a physician is invariably involved. Often, those running the research are Ph.D.s who have never cared for a patient. Hampering the debate is an absence of data, with only assumptions to fall back on: assumptions by researchers about
asking them to return a postcard stating whether they wanted their results. The overwhelming majority did, he says, and received them, along with counseling. What it takes Shuldiners story is unusual, because he has nurtured a personal relationship with his research subjects over many years something of a throwback in an era of massive biobanks and central DNA repositories accessed by hundreds of geneticists. The push to share data among scientists, across institutions and national borders, means that when a volunteer proffers DNA to one researcher, it often becomes accessible to many others who have no connection to the person who donated his DNA. This is especially true for biobanks, DNA collections that allow researchers everywhere to borrow samples. The UK Biobank
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whats useful to study participants and the feasibility and impact of sharing genetic ndings, and assumptions by participants about how they might benet from the data they receive. Theres a push now to move beyond guesswork. I wanted to see what it was really going to take to return genetic results, says NHGRIs Biesecker. In 2007, he enrolled the rst volunteer in a DNA sequencing study called ClinSeq that now has more than 850 participants. Initially, ClinSeq focused on analyzing 200 to 400 genes that were mostly linked to heart disease, but the plan was always to expand well beyond that when the technology allowed, which Biesecker is now doing. His group is sequencing the exome of every participant to identify DNA behind a host of diseases. With permission from the volunteers, the researchers are then offering to disclose portions of what they nd. Its a delicate process. I would call you up and say, Hey, you might remember you signed up for this study a year and a half ago. We have a medically signicant result; it is the kind of result that might tell you about your future disposition to develop a disorder, says Biesecker. If the participant is interested, the nding is validated and the individual comes in to learn about it, a meeting that normally takes at least an hour. One thing Biesecker has learned is that generating data is the easy part. He has sequenced the exomes of more than 400 people and communicated results to about 10. Interpreting and validating the ndings takes time, and so far Biesecker has focused on just a handful of genetic ndings beyond those related to heart disease. They include BRCA mutations and others that dramatically increase cancer risk, or mutations that predispose to late-onset neurological disorders. The middle-aged men and women in ClinSeq can also learn about recessive mutations they carry; because they are past reproductive age, the information isnt relevant to them personally but they could share it with their children, now young adults, whose own offspring could be affected by a genetic disease. Biesecker already sees a problem with expanding ClinSeqs strategy across an entire population: Its not sustainable, he says, to spend hours and hours parsing one persons genome, then bring them in for a 2-hour face-to-face meeting. The way we do it now doesnt scale, he says. It just doesnt. Farther up the East Coast, at Boston Childrens, Holm is grappling with the same issue. In October 2009, Childrens launched The Gene Partnership project, a DNA registry that has so far enrolled 1000 patients and families for a range of genetic studies. It plans to return many ndings related to disease risk, with guidance from an outside group of experts and Childrens families, including 7000 to whom Holm sent surveys last month. Although the project will begin with face-to-face meetings for delivering any news, it anticipates shifting at some point to a Web portal that will notify participants that genetic results are available and offer them a phone call with a genetic counselor to learn more. That risks fomenting confusion about what specic ndings mean, because sometimes the only way to ensure that people understand is to go face to face, says David Miller, a geneticist at Childrens who works with patients well and dont regret having learned it. But these examples are very different from what may become a more common scenario: an individual who donated DNA 5 years ago, has forgotten that the possibility of data return was listed in the consent form, and has no idea this information is barreling toward him or her. Theres no easy way to study this. Biesecker has found that most people in ClinSeq have taken the news of a disease gene mutation in stride. Still, one was distressed and has not shared the results with family members. And only a handful of ClinSeq participants have gotten results so far. Another concern is the impact on the health care system when individuals receive a data dump of genetic information. If you tell a million people that theyve got 500 risk factors, and you tell their doctors, how does this alter all the surveillance and treatment options that are available? asks Green. This is a huge concern of Claytons and a big reason why she generally opposes sharing genetic ndings. I think it will kill the health care system, she says. Holm takes the opposite view, arguing that imparting these ndings could actually reduce health care costs because care might become more personalized. And either way, she says, you cant say were not going to do this because of a potential cost crunch. Although some researchers have shared results from their genetic studies with participants, thats still uncommon; exome sequencing, which will expose many more incidental findings, is just on the cusp of rapid expansion. The Spanish law has generated much discussion but has apparently had little practical impactyet. Still, geneticists need to start thinking about what, if anything, they are willing to tell their research subjectsand how they might approach breaking the news. Biesecker, reecting back on that conversation years ago with the couple whose daughter had missing DNA, remembers that he asked the parents permission to invite along the Ph.D. who made the discovery. She joined them for that conversationand the fathers reaction so disturbed her that she needed counseling afterward to cope with it.
JENNIFER COUZIN-FRANKEL
who have developmental disabilities and isnt involved in the effort. But, he admits, I dont have the right answer either. What happens next In the early days of widespread clinical gene sequencingmeaning about 3 years ago the big question was how individuals would react when they learned what was buried in their DNA. Would knowledge of a looming fatal disease cause depression or even suicide attempts? Would those who learned about an uptick in heart attack or colon cancer risk embark on intense exercise regimes or overhaul their diets in hopes of staying healthy? Last month, a study published online in The New England Journal of Medicine reported that among 2000 people who bought genetic tests, 90% experienced no distress from the results. In Greens work telling people if they carry the APOE4 gene variant, which predisposes to Alzheimers disease, he has found that they generally handle the news
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ROTTERDAM, THE NETHERLANDSThe murder was heinous, there were no witnesses, and the police had few cluesexcept for some skin found under the ngernails of the victim that might belong to the killer. And that was all it took. From a few nanograms of DNA in the skin cells, a police lab determined that the murderer was a man of European origin with brown eyes and straight, dark-brown hair, approximately 45 years old and balding, and likely 1.90 meters in height. Within a few more hours, a police computer spewed out a sketch of the mans face seen from three different angles, which was all over the evening news. Soon, calls started pouring in from people who recognized the suspect. Sure, thats science ction. But according to German gene sleuth Manfred Kayser, the scenario might come true one day. Kayser, who leads the forensic molecular biology department at Erasmus University Medical Center here, is at the forefront of an emerging research area that seeks to predict peoples looks, age, and geographic ancestry from their DNA. If successful, the endeavor, sped along by the genomic revolution, could provide crime ghters with a powerful new toolbox. Kaysers group made headlines around the world last year with a paper showing how the DNA in a blood sample can give away someones agealbeit with a margin of error of at least 9 years. His group has developed a DNA test to predict someones eye color; work on hair color, skin color, and other traits is in progress. Kayser is an upcoming star in forensic DNA phenotyping, as the eld is called, says Bruce Budowle, a geneticist with 40 years of experience with the FBI who is now at the University of North Texas Health Science Center in Fort Worth. Hes a clear leader, adds Christopher Phillips, a forensic geneticist at the University of Santiago de Compostela in Spain. The genetic clues that Kayser and others are trying to glean from minuscule amounts of blood, semen, saliva, and hair are unlikely to be introduced as evidence in a courtroom. After all, when someone is suspected of a crime, or charged, a conventional DNA fingerprinting test can determine if his or her DNA matches traces found at the crime scene. Instead, forensic DNA phenotyping could be useful during an investigation, when predicting a criminals looks can help the police focus their search. Forensic DNA phenotyping raises new ethical and legal issues, and the Netherlands is the only country so far to regulate the practice in a new law (see sidebar, p. 840). But Kayser doesnt anticipate that the concerns will stop
Can This DNA Sleuth Help Catch Criminals?

Forensic geneticist Manfred Kayser is exploring whether DNA found at a crime scene can predict what a suspect looks like
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the eld. We are not doing anything else than what police are doing with eyewitnesses, he says. Except for one thing, he asserts: DNA will prove a more reliable witness. and stayed in his old college town until he was offered the leadership of a new forensics department at Erasmus University Medical Center in 2004. In an unusual arrangement, his department is co-funded by the NetherMusic and animals lands Forensic Institute (NFI), a governmenKayser, 43, isnt fascinated by crime. He tal lab in The Hague. NFI management recdoesnt read John Grisham novels or watch ognized that an academic setting would be CSI, the sleek TV hit show centered on foren- a more fertile place to invest in science and sic research. His lab looks as unexciting as development than a lab thats loaded with any other molecular biology casework, according to Kayser. lab in the world. In fact, Kayser When I saw the business entered the entire eld more or plan, I realized this departless by chance. ment was really going to He was born and raised in be a unique place, he says, East Berlin in the communist because it would run the full era. As a teenager, he developed monty from basic science passions for both music and the to developing and validating animal world, neither of which tests. Kayser works closely Find a podcast on this topic were particularly appreciated with NFI researchers and and other genome stories at in the German Democratic with Peter de Knijff, who runs http://scim.ag/genome10. Republic, he says. After high a well-established forensic school, he worked in the frog genetics lab at Leiden Univercollection of the Natural History Museum in sity Medical Center where Kayser did part Berlin; he was accepted as an accordion stu- of his Ph.D. work. The three groups have dent at the Weimar conservatory but eventu- formed a consortium that in 2008 bagged ally chose to study biology at the University of a 6.5 million grant from the Netherlands Leipzig in 1989. Two months later, the Berlin Organisation for Scientic Research. Wall came down. Kayser said it was relatively easy to setHis first experiences with forensic sci- tle in Hollandalthough he misses sourence left him frustrated. Between 1994 and dough bread and other things German. From 1998, at Humboldt University in Berlin, Kay- his 10th-oor ofce, he has a view of Rotser studied microsatellitesshort, repetitive terdams ultramodern skyline. And although DNA sequenceson the human Y chromo- he would have preferred a city with more hissome. The work, carried out mostly at the uni- toric character, he feels he cant complain: versitys Institute of Legal Medicines genetic After all, the Germans attened Rotterdams research lab, had obvious forensic applica- ancient center in 1940. tions; in rape cases, for instance, evidence often comes from vaginal swabs that contain Eyes, hair, and skin a mix of DNA from perpetrator and victim. The division of labor within Kaysers Zooming in on the Y chromosome ensures 15-person lab reects the stages within the that youre looking at the rapists DNA. full monty. Some researchers are primarKaysers work helped lay the groundwork ily focused on nding the genes and genetic for male identication using the Y chromo- markers that underlie phenotypic differences, some, a now widespread method. But Kayser utilizing so-called genome-wide association says it took a long time for the technique to studies, for instance. Others are working on become accepted in forensics. Forensic sci- turning whats found into actual forensics entists arent the most open-minded people tests and validating thema laborious prowhen it comes to innovative science, he says. cess governed by international standards. It was discouraging. He decided to join Eye color was low-hanging fruit. Over the anthropological geneticist Mark Stonekings past 2 years, his group has developed a test, lab at Pennsylvania State University, Univer- called Irisplex, based on the identity of just six sity Park. Stoneking was piecing together the so-called single-nucleotide polymorphisms. human history of Polynesia with mitochon- It can now predict with over 90% accuracy drial DNA, which is inherited via the maternal whether someone has blue or brown eyes line. Kaysers expertise with the Y chromo- not perfect, says Kayser, but a lot better than somewhich tells the male storycomplemented this work perfectly, Stoneking says. Predictable? Many visible traits are at least in part Less than a year later, Stoneking moved genetically determined and may be predictable to the Max Planck Institute for Evolutionary from a persons DNAbut the only validated test Anthropology in Leipzig. Kayser joined him so far is for eye color.
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eyewitness testimony, which research has shown to be off the mark at alarming rates. Last month, Kaysers team published a paper in Human Genetics that indicated hair color, too, can be predicted fairly accurately, at roughly 90% for red or black hair and 80% for blond or brown. Those ndings are now being translated in a test kit toomost likely combined with eye color, so as to save precious DNA. Skin color is the next candidate. Although his team and others have identied some of the genes involvedthey overlap with those for eye and hair colorthe picture isnt complete yet. Beyond that, forensic DNA phenotyping quickly gets complicated. Height, for
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instance, is known to have a high degree of heritability: Although diet plays a role in how fast and tall people grow, much of the variation between people is caused by genes. Indeed, a genome-wide association study among 180,000 people published last year revealed more than 180 genetic loci that appear to inuence adult heightbut together, they account for only 10% of the variation between individuals. De Knijff believes height to be so complex that a useful DNA test is a bridge too far. The age test offered a different challenge, as its not something one can easily read in a persons genome. People have tried to predict age by counting the number of mutations in a persons mitochondria, or measuring the length of their telomeres the protective caps on the ends of chromosomes, which fray as we agebut both pose practical problems. Kaysers method instead relies on circles of leftover DNA stored in T cells whose amount decreases as people get older. The eld could also target traits like hair structure, baldness, handedness, and earlobe attachment. Its greatest triumph, however, would be that computer-generated, DNA-based facial sketch. Kaysers group is working on it as part of a consortium of labs called VisiGen that Kayser founded with Tim Spector of Kings College London. Fan Liu, a genetic epidemiologist in Kaysers lab, is trying to link genome data to key facial morphology traits, such as facial width or nose size. Kayser is cautious about the prospects. On paper, its possible, he says. The extreme resemblance between monozygotic twins suggests that facial features are mostly genetic. But we have no idea yet what genes they are or how complex it is. Ingrained racism Kaysers department is also working on tests that can determine someones biogeographical ancestry. The technique appears to have been used in hundreds of crime investigations in the United States, but modesty is still in order, says Kayser. Although several companies offer detailed ancestry tests to the public, scientists dont have a strong basis to go much beyond the continental levelthat is, predicting whether someone is, say, European, sub-Saharan African, East Asian, or Native American. Distinguishing a Norwegian from a Swede, for example, is not usually possible, and Kayser rejects as totally baseless a controversial U.K. program to use DNA to determine asylum seekers nationality (Science, 2 October 2009, p. 30). This application of forensic DNA phenotyping is an area lled with explosive issues about race and crime about which the debate hasnt fully begun. Most forensic DNA phenotyping predictions will likely come with a signicant level of uncertainty, as opposed to conventional DNA fingerprinting matches, and police ofcers may have trouble interpreting them. Moreover, genetic ancestry does not equal race, a concept that most scientists shun because it has no well-dened meaning, and does not necessarily predict someones appearance. Ancestry and appearance overlap, but theyre not the same, Kayser says. Just how important caution is was driven home to Kayser by a series of psychology studies, published in 2004, that showed how deeply ingrained stereotypes about black men and crime are among U.S. law enforcement ofcers. It was an eye-opener to me, he says. It will be important for scientists like him to explain the uncertainties in DNA-based phenotyping carefully, he stresses. Fortunately, says Budowle, Kayser is unlikely to oversell his science to overzealous cops. Manfred knows the molecular biology but also the population genetics and the statistics, he says. He wont overstate the evidence, and hell make clear what the limitations are. MARTIN ENSERINK
Emerging Forensics Field May Hit Legal, Ethical Obstacles

A year after a 16-year-old girl was brutally raped and murdered in the Netherlands in 1999, forensic geneticist Peter de Knijff broke the law himself. At the polices request, he set out to determine the geographic ancestry of the murderer from DNA in his semen. That was, he later admitted, completely illegal under Dutch law, which at the time allowed using DNA for traditional DNA identication but not for determining race, looks, or disease risk. De Knijff has no remorse. The police were unable to solve the case, and tensions were escalating in the rural community where the girl lived. Many pointed ngers at a nearby hostel for Kurdish, Iraqi, and Afghan asylum seekers. De Knijffs analysis showed that the killer was most likely from northwest Europe, which helped cooler heads prevail. His dilemma could arise any day in many countries. In the wake of the murderstill unsolved todaythe Dutch parliament adopted a law in 2003 regulating forensic DNA phenotyping, the use of DNA samples to predict a suspects ancestry or physical characteristics (see main text). But the Netherlands is still the only country to have done so. Countries such as Belgium and Germanyand the U.S. states of Indiana, Rhode Island, and Wyomingexplicitly ban the practice, says BertJaap Koops, a professor at Tilburg University Law School who studies the issue. In the United Kingdom and most U.S. states, forensic DNA pheno-typing isnt explicitly regulated but is allowed under existing laws for forensic DNA. Geographical ancestry tests appear to have been used in several hundred U.S. investigations, says Pamela Sankar, a bioethicist at the University of Pennsylvania. Most were done by a company called DNAPrint Genomics, she says, which ceased operations in 2009. Sankar, who is tracking the eld with funding from the U.S. National Human Genome Research Institute, says forensic DNA phenotyping raises ethical and legal issues that need more debate. Her own research, for instance, suggests that police ofcers may not realize thatas opposed to the high degree of certainty in DNA ngerprintingphenotyping is probabilistic in nature. Cops could also use ancestry predictions, however imprecise, as an excuse to target minority populations, she says. Other dilemmas loom. In theory, knowing that a criminal is, say, a hemophiliac or a diabetic could help nab him. But the 2003 Dutch law categorically bans looking for disease-related genes because it would violate a suspects privacy and the right not to know, a basic tenet of medical ethics. (The law allows only the prediction of visible traits and race.) Koops argues that these restrictions are overly protective; if genetic sleuthing can reveal that a killer has a very mild or curable disease, or is likely to be a chain smoker, solving the crime might well trump individual rights, he says. The distinction between visible traits and disease is not always tenable anyway, says forensic geneticist Christopher Phillips of the University of Santiago de Compostela in Spain. A mutation in a gene called MC1R can cause pale skin, for instancewhich increases the risk of melanoma. Predictive tests should conne themselves to the visible, he says, but sometimes this encroaches on the private at the same time. The paradox is that conventional DNA fingerprinting has been introduced with the reassurance that it can never reveal any personal informationbut now, its personal information that forensic geneticists are after. Thats why caution is important, says Phillips. If we move too quickly, the whole edice of public condence in DNA proling could erode. M.E.
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Beyond Human: New Faces, Fields Exploit Genomics

Fast new genomics technology is not just for human geneticists and biomedical researchers anymore
Twenty years ago, the proposal to sequence the entire human genome was met with skepticism, even derision. Ten years later, the completion of the rst human genome sequence was a source of awe worthy of presidential recognition. Today, its a paragraph in a 3-year grant proposal. The Human Genome Project drove a technological revolution in DNA sequencing that has continued since the full draft sequences were published in Science and Nature in 2001. And as sequencing DNA has become faster and cheaper, opportunities have grown for elds outside human biology. Analyzing the genome of an organism once required extensive mapping of its chromosomes and the development of genetic tools specic for that speciesa time-consuming and, usually, too expensive
Find a podcast by the author of this feature, as well as other genome stories, at http://scim.ag/ genome10.
ELIZABETH PENNISI
Tracing the Tree of Life

In 1994, researchers came across a completely new animal in a spring on a large island off the west coast of Greenland. Looking a bit like a worm, this microscopic creature had complex jaws and was so unusual that the biologists could not assign it to a known phylum. Instead, they put it in a group of its own, called Micrognathozoa. The oddball, ofcially named Limnognathia maerski, has been little studied since. Indeed, researchers in Greenland have documented only a few hundred specimens. Yet with the help of next-generation sequencing, evolutionary biologist Casey Dunn and his colleagues plan to shine a scientic spotlight on micrognathozoans. During a recent eld trip to Greenland, they collected specimens of the tiny invertebrate and have stored them in a freezer in Dunns lab at Brown University. In a project that would have been unthinkably expensive for a single lab just a few years ago, they will now decipher much of the creatures genome and identify its genes. And thats just the beginning. Dunn and his colleague Gonzalo Giribet, a Harvard University invertebrate biologist, have freezers full of other unusual organisms whose genomes they plan to sequence so that they can rene the much-debated animal tree of life. Molecular systematists have long used individual genes to assess relationships
On a quest. Casey Dunn went to Greenland in
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search of rare animals for his phylogenetic studies. www.sciencemag.org SCIENCE VOL 331
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process. And decoding just one genome per species was the norm. Now researchers can skip those steps and even think about generating genomes or partial genomes for many members of a species. The new technology also lets researchers track gene activity on an unprecedented scale. Theres been a quantum change in what can be done and the number of organisms that can be studied, says evolutionary biologist William Cresko of the University of Oregon, Eugene. Thats why, in the last of our news features commemorating the 10th anniversary of the human genome, we look beyond human biology (although we peer inside the human gut in one case) to prole ve research teams that have embraced genomic-scale science to tackle questions they could not have easily addressed before.
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among organisms, identifying differences within equivalent pieces of DNA in various species. Controversy often ensued when those early results didnt agree with more traditional classication schemes, such as those based on fossils or morphology. To add clarity, researchers have, over time, increased the amount of genetic material they compare, creating a eld called phylogenomics in which many hundreds of genes are evaluated in each analysis (Science, 27 June 2008, p. 1716). A few years ago, it cost about $12,000 per animal to sequence 1000 or so genes, says Dunn. Now, a few thousand dollars delivers many more genes. We can do now what we couldnt do before, Dunn says. That includes sequencing little-studied organisms, such as micrognathozoans, so accurately that scientists may resolve the relationships of invertebrates whose lineages split off from a common ancestor 500 million years ago. There are often challenges to sequencing unusual organisms. Sometimes researchers dont have enough DNA to work with; other times the organism has odd ratios of DNAs four bases that make decoding samples difficult. But Giribet has already sequenced
Odd creatures. Siphonophores (top) and micro-
gnathozoans may clarify animal evolution.
and analyzed 20 of these animals, including a whip scorpion, a ribbon worm, and several mollusks. Dunn is excited about the prospect of resolving the animal tree as never before: Its clear we are going to be able to base our tree on lots of data from lots of species. Next-generation sequencing technologies are also allowing Dunn to explore the evolution of animals by documenting dif-
Using DNA to Reveal a Mosquitos History

Ten years ago, the mosquito Wyeomyia smithii lived a largely anonymous life inside the pitchers of the purple pitcher plant common in bogs along the eastern United States, the Great Lakes, and southeastern Canada. Unlike some of its nastier relatives, the insect isnt known to transmit diseases to people or livestock. Larvae feast on microbes and detritus inside the pitcher plant, and adults sip on nectar, not blood, for the most part. Then in 2001, husband-and-wife evolutionary geneticists Christina Holzapfel and William Bradshaw of the University of Oregon (UO), Eugene, made the mosquito a poster child for climate change when they demonstrated for the rst time that an animal had evolved in response to global warming. Now the same researchers are applying
Mosquito hunters. Christina Holzapfel and
William Bradshaw embraced next-generation sequencing last year.
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CREDITS (TOP TO BOTTOM): CASEY DUNN; REINHARDT MBJERG KRISTENSEN; CHRISTINA HOLZAPFEL AND WILLIAM BRADSHAW
next-generation DNA sequencing tools to probe further details of this species evolutionary historytools that have become so cheap and widely available that they can be applied to other poorly studied organisms as well. Its a transformative technology, says Mark Blaxter of the University of Edinburgh in the United Kingdom. Holzapfel and Bradshaw began studying W. smithii 30 years ago, curious about how the mosquito had made its way so far north, because its relatives tend to reside in the tropics. In the course of their studies, they found that from 1972 to 1996, the mosquitos larvae in Maine had gradually delayed the start of hibernation by a week. Mosquitoes from farther north had postponed hibernation even later, whereas those in Florida had stuck to the same schedule as 25 years earlier. The pair concluded that the change in this genetically controlled trait was triggered by the longer growing season that resulted from gradual warming in the northern United States (Science, 23 November 2001, p. 1649). Although the finding drew headlines, it still didnt explain how the mosquitoes had ended up in the north. To address that,
ferences in gene expression patterns across closely related species. The goal is to nd out how these changes inuence shifts in traits and behaviors across the tree of life. To do this, Dunn and his colleagues have turned to a new technique, known as RNA-Seq, that can gauge genetic activity in a sample by sequencing the complementary DNAs (cDNAs) that represent specic genes. The busier a gene is in a sample, the more times its cDNA will be sequenced. Dunn and Stefan Siebert, one of his postdocs, have already compared the gene activity of the swimming and feeding forms of a siphonophore, a marine colonial organism. That analysis yielded thousands of genes potentially responsible for the differences in the animals two structures. By repeating this experiment with multiple related siphonophore species, Dunn hopes to home in on those key to, say, the swimmers development. This will allow us to identify which genes have changes in expression that are associated with evolutionary changes, he says. E.P.
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Holzapfel and Bradshaw wanted to know where the mosquitoes were in the past, particularly following a glacial period 20,000 years ago, when a warming trend had allowed them to migrate to new habitats. And to trace the migratory history of the species, the couple needed to establish the relatedness of populations from across the mosquitos range. For years, they had tried to do this, but existing techniques were not able to resolve the differences between populations clearly enough. The mosquitoes from the various populations look too much alike to be distinguished morphologically, for example. In the 1990s, they tried in vain to reconstruct the biogeographical record by comparing proteins called allozymes among populations. Later, they fruitlessly looked at population differences in the insects mitochondrial DNA. Even microsatellites, short stretches of DNA used in constructing genetic fingerprints, werent up to the task. We needed a better tagging or sorting system, Holzapfel recalls. In 2009, they found one down the hall. UO colleague William Cresko had just teamed up with UO molecular biologist Eric Johnson to study the evolution of sticklebacks. They had genetically characterized populations of this sh by developing a catalog of single-nucleotide polymorphisms (SNPs), individual bases that vary frequently within a species. That work was made possible because a year earlier, Johnsons and Creskos labs had developed a shortcut SNPdiscovery method known as restriction-siteassociated DNA sequencing (RADSeq). This approach takes advantage of the speed and low cost of next-generation sequencing to quickly generate thousands of
CREDITS (TOP TO BOTTOM): CHRISTINA HOLZAPFEL AND WILLIAM BRADSHAW; ROLAND KNAPP
Test case. Researchers didnt need a sequenced
genome to make a dense genetic map of the pitcher plant mosquito.
SNPs that distinguish populations and individuals. Researchers start by taking animals from multiple populations of a species and using so-called restriction enzymes to, at specic DNA sequences, chop up the genomes of each one into short fragments. Each animals DNA fragments are then joined to a unique bar code, a synthetic five-base strand of DNA whose sequence reveals which animal the non-bar-code DNA came from. All the fragments are then pooled together for mass processing by a next-generation sequencing machine. Because the bar codes allow the resulting sequences to be associated with specic animals, researchers aided by bioinformatics software can quickly identify genetic differences among individuals or populations. For the mosquitoes, the researchers found 13,000 SNPs, 3700 of which helped to nally
Tackling the Mystery of The Disappearing Frogs

For more than a decade, Roland Knapp has watched and agonized as the mountain yellow-legged frog, which normally thrives in high-altitude lakes and ponds too cold for other amphibians, disappears from the Sierra Nevada. In 1997, Knapp counted 10,000 tadpoles in a single mountain lake the frogs seemed to occupy every possible bit of water, he recently recalled on his blog. This past summer there were almost none. Surveys of 15,000 sites by Knapp, a eld ecologist at the Sierra Nevada Aquatic Research Laboratory in Mammoth Lakes, California, and others have shown that this frogwhich is actually two species
Going, going. The mountain yellow-
legged frog has disappeared from 90% of its Sierra Nevada habitat.

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determine the relatedness of various populations of W. smithii. This gave us the resolution to discriminate between postglacial populations, says Bradshaw. Based on that information, the researchers deduced that after glaciation, a remnant population of the pitcher plant mosquitoes gradually expanded out of the mountains of North Carolinanot out of the Gulf Coast, as some had presumed. The expansion proceeded gradually northward, then westward, they reported online 26 August 2010 in the Proceedings of the National Academy of Sciences. When Cresko and Johnsons team tested RADSeq on the stickleback, they were able to match the shs already sequenced genome to the newly generated sequence to help look for differences. No one had the resources to sequence the genome of W. smithii, and yet RADseq still worked effectively on the mosquito, demonstrating that the technique could be useful for a variety of organisms, even those for which little is known about their genetics. This tagging system is denitely the wave of the future, says Holzapfel. Furthermore, the cost for the entire mosquito studyexamining all 23 populations of W. smithiiwas just $3000. The RADSeq method is cheaper, faster, and delivers thousands of markers, says Blaxter. He and his collaborators now have 18 RADSeq projects under way in snails, moths, nematodes, butteries, salmon, ryegrass, sturgeon, beavers, beetles, oaks, elms, and spruce. Already for the diamondback moth, a crop pest, they have used newfound DNA markers to help pinpoint a gene that makes this moth resistant to a certain insecticide. Says Bradshaw, This is an awesome technique. E.P.
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is now missing from more than 90% of its former habitat. There are multiple explanations for the frogs disappearing act, but a key one is the chytrid fungus, Batrachochytrium dendrobatidis, which has wiped out amphibians around the globe, including many populations of the mountain yellow-legged frogs. Yet every so often, some of these frogs survive the fungus, and Knapp has been unable to discern whether the amphibians immune response or some environmental factor made the difference. Its been pretty clear that our eld experiments and observations only take us so far, he explains. We needed to go to an entire new level of investigation. So he was thrilled when Erica Bree Rosenblum, an evolutionary biologist now at the University of Idaho, Moscow, approached his team about collaborating on the endangered amphibian. In the past, Rosenblum, who studies the genetic basis of animal traits such as color or limb length, had been limited to what she calls spearshing: sequencing specific genes already suspected of inuencing the trait. But about 5 years ago, she realized that new sequencing technologies would make it affordable to directly decipher all the active genes of a species without doing the extensive, and expensive, presequencing legwork required in the past. Thus, she could try net-shing, casting a net that could ensnare more than just suspected genes.
Gone. Roland Knapps genomic studies may help
explain the mountain yellow-legged frogs die-off.
Rosenblum, Knapp, Cherie Briggs of the University of California, Santa Barbara, and ecologist Vance Vredenburg of San Francisco
E.P.
Digging Deep Into The Microbiome

It isnt only animal studies that have beneted from the explosion in genomics tools. Nextgeneration DNA sequencing has transformed microbial ecology studies as well. The past decade has seen the growth of metagenomics, in which researchers sequence DNA from a soil sample, the gut, even a computer keyboard, to learn what bacteria live there. With the new technologies, you can sequence at a level deep enough that you can understand whats going on in the community, says Rob Knight, a microbiologist at the University of Colorado, Boulder. The microbial makeup of our gut is a case in point. In the past decade, scientists have come to realize that animal intestines naturally harbor diverse microbial communities that help provide nutrients and sustain good health. A landmark 2005 study by Stanford Universitys David Relman and colleagues
Bug hunt. Rob Knight studies the microbiomes of
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(Science, 10 June 2005, p. 1635) concluded that the bacterial communities in the human gut vary tremendously from one individual to the next. But that work looked at the guts of just three people, using traditional sequencing technology to probe for different variants of ribosomal RNA genes, each of which represented a different microbe. A new analysis of 146 people, made possible by the lower cost and higher efciency of DNA sequencing, is now telling a much more detailed story. Junjie Qin of BGI Shenzhen in China and colleagues recently collected fecal samples from 124 Europeans, some healthy, some obese, and a few with inammatory bowel disease. They not only identied and sequenced all available ribosomal RNA genes in the samples but also deciphered more than 3 million other genes from the bacteria in the peoples guts. (The 576.7 gigabases of DNA sequence data was
State University are now using this approach on wild populations of the frogs, comparing ones that persist despite exposure to the fungus to nonexposed ones that ultimately prove susceptible to it. The key step, which next-generation sequencing greatly facilitated, was elaborating the frogs transcriptome, its full repertoire of expressed genes, by sequencing the so-called complementary DNAs (cDNAs) that represent each gene. With these cDNAs in hand, the researchers could construct a device known as a microarray to assess which genes were active in various organs of exposed and unexposed frogs. Results so far suggest that in susceptible frogs, the immune system doesnt go on the defensive, says Rosenblum; the fungi somehow evades the bodys defenses. The researchers are also using the same microarray to evaluate gene activity in the amphibians skin to understand why it degrades during infection. And by sequencing microbial DNA swabbed from frog skin, they are examining whether resistant frogs have an unusual repertoire of surface bacteria, as some microbes have been found to make an effective antifungal compound. Such genomic insights are much welcomed, says Vredenburg; the sequencing projects have affected my work immensely.
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almost 200 times the amount generated in any previous study.) This more comprehensive analysis revealed limits to how much the common gut microbiome varies among people. There is a core set of gut bacteria, indicating that the prevalent human microbiome is of a nite and not overly large size, Qins team wrote in a 4 March 2010 Nature report. Certain bacterial gene sets and species in the gut also correlated with obesity, Knight adds. When you look at a lot more people, you see systematic patterns of variation in the gut microbiome, he says. A twist on next-generation sequencing is also providing a new way to evaluate which genes are must-haves for the microbes. To nd these genes, Knight and his postdoc Cathy Lozupone are working with Andrew Goodman and Jeffrey Gordon of Washington University in St. Louis, Missouri, who have developed a technique called insertion sequencing. This involves using mobile DNA elements called transposons to introduce mutations into tens of thousands of bacteria. Before adding the transposons to the bacteria, the researchers tag each transposon with an identiable DNA bar code that allows each mutant bacterium to be trackedand for the gene disrupted by the transposon to be characterized. With the new sequencing technology, researchers can follow mixed populations of these mutant strains on various growth mediums or in different environments. The relative number of copies of a bar-coded DNA sequence will reect the success of a particular mutant; bacteria carrying mutations in genes required for a specic environment or medium wind up poorly represented. The researchers rst tried the insertionsequencing technique on a human gut bacterium, Bacteroides thetaiotaomicron, introducing transposon-mutated strains into the guts of various kinds of mice. Some mice were normal and had their own gut microbes; others had various immune defects, were germ-free, carried human gut microbes, or had a combination of those characteristics. Two weeks later, the scientists took stock of how these bacteria fared in their different rodent hosts. In the germ-free mice, they saw a decrease in the abundance of 280 distinct bacterial strains, suggesting that the gene mutated in each had been essential to staying alive in the gut. Defects in about 90 genes seemed to provide a competitive advantage, as the corresponding mutant strains colonized the germ-free mice better than other strains did. Whether the mice carried other human gut microbes made a difference to the survival
Gut life. Researchers have pinpointed the must-
have genes in these capsule-shaped intestinal microbes.
Probing Pronghorn Mating Preferences

Pronghorns, the American antelope, are the fastest animals on the North American continent, yet coyotes still kill many of the fawns, catching them before they develop the quickness to run away. Animal behaviorist John Byers of the University of Idaho, Moscow, has shown, however, that if a female pronghorn picks the right male, her fawns will grow faster than normal and have a much better chance of surviving. Since 1981, he and colleagues have tracked six pronghorn generations at the National Bison Range in Montana. Byers suspects that female pronghorns, which he found favor males best able to ght off other males, are actually choosing mates with the lowest burden of so-called deleterious mutations. Byers hasnt had a good way to prove his theory, but thanks to the growing availability of next-generation DNA sequencing, he may nally have a chance. He and his colleague have over the years collected tissue samples from 835 pronghorns across the generations, and they now plan to genetically prole each animal to determine whether female pronghorns do indeed pick genetic studs. I think its going to be ultracool, Byers says. E.P.
CREDITS (TOP TO BOTTOM): J. L. SONNENBURG ET AL., SCIENCE 307, 5717 (25 MARCH 2005); JOHN A. BYERS

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of various strains of B. thetaiotaomicron, as a different subset of mutants disappeared in those mice, the researchers reported in the 17 September 2009 issue of Cell Host & Microbe. We were able to nd genes that determine the ability of a bacterium to thrive in the mammalian gut in specic microbial community contexts, says Goodman, now at Yale University. Goodman calls the insertion-sequencing approach exciting. Others agree. Several have begun to use it to characterize key genes for various microbes in different organisms and tissues. E.P.
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GENOME-SEQUENCING ANNIVERSARY
A Celebration of the Genome, Part I
en years ago, the first peer-reviewed reports of the sequencing of the human genome were published. At that time we announced that humanity has been given a great gift, which has proven to be the case in many ways but has also presented a great challenge. To commemorate the event, we have asked a cross section of insightful individualsrepresenting many viewpointsto look at what it has meant to them or their communities to have access to human genome sequences. We will be publishing their comments throughout the month of February.
Barbara R. Jasny and Laura M. Zahn
Faces of the Genome

Francis S. Collins Director, National Institutes of Health, Bethesda, MD, USA. When the draft sequence of the human genome was published in February 2001, Nature and Science featured human faces on their covers. As striking as these images were, they could be seen as more art than science, because systematic genome-wide sequencing had yet to be applied to individuals for medical purposes. What a difference a decade makes. Real faces are now appearing that demonstrate the medical value of comprehensive genome sequencing. Researchers with NIHs Undiagnosed Diseases Program recently identied a genetic cause for a rare and debilitating vascular disorder that had bafed the medical eld and evaded diagnosis. The discovery was spurred by the cases of Louise Benge and Paula Allen, two middleaged sisters from Kentucky who had calcication of the large blood vessels and joints in their hands and feet, in the absence of any effect on coronary arteries. Thanks to genomic analyses (just published in the New England Journal of Medicine), they now know that their severe leg and joint pain stems from a a mutation in NT5E, which encodes a protein that converts AMP to adenosine. Better understanding of the disease mechanism will help to guide development of treatments for such patients, as well as illuminate metabolic pathways involved in calcication. An even more impressive story of the revolution that genomic analysis is bringing to the clinic relates to Nic Volker (shown above), a 6-year-old Wisconsin boy who developed inammatory bowel disease shortly before his second birthday. Multiple intestinal stulas occurred, making it impossible for him to eat normally. Despite numerous tests and more than 100 surgeries, doctors remained at loss for a diagnosis and the little boy grew sicker. Then, researchers at the Medical College of Wisconsin carried out whole-exome sequencing, examining the protein-coding regions of every gene in Nics genome. They identied a mutation in his XIAP gene. XIAP mutations were not previously associated with bowel symptoms, but had been linked to a severe blood disorder that is curable through bone marrow transplantation. The medical team raised the possibility of a transplant, which would not have been considered without a rm diagnosis. It was per546
The Human Genome at 10: Successes and Challenges

J. Craig Venter President, J. Craig Venter Institute, Rockville, MD, and San Diego, CA; CEO, Synthetic Genomics Inc., La Jolla, CA, USA. Fifteen years ago, my team published the rst complete genome sequence of a living species, that of Haemophilus inuenzae, using our newly developed technique of whole-genome shotgun sequencing. This genome sequence was only 1.8 million base pairs in length and required 4 months of sequencing to produce. Five years later, as a result of dramatic changes in automation and massively parallel DNA sequencing, it was possible to sequence the human genome at 3 billion base pairs in only 9 months, a >1000-fold improvement. We published the rst individual, diploid human genome sequence in 2007, and now, with single DNA sequencing instruments producing 100 million base pairs per day, individual genome sequences are becoming commonplace. Most of the new generations of sequencing technologies, although faster and considerably cheaper, produce much shorter sequences (50 to
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CREDITS (LEFT): MILWAUKEE (WISCONSIN) JOURNAL SENTINEL; (SCIENCE COVER) ANN ELLIOTT CUTTING; (NATURE COVER) ERIC LANDER AND DARRYL LEJA; (BOTTOM) SCIENCE
formed in July 2010, using stem cells from the cord blood of a matched, healthy donor. Seven months later, Nic appears to be on the road to recovery. While he is still on immunosuppressants, doctors report the new stem cells are stably engrafted, blood counts are good, and theres been no return of bowel disease (http://journals.lww.com/geneticsinmedicine/ Documents/GIM200819_Revised.pdf). More important to Nic, he can nally eat solid foods! These cases, and others that are now appearing in the literature, document that we stand at a signicant juncturethe once-hypothetical medical benets of individual genome sequencing are beginning to be realized in the clinic. This transition will require hard work and ingenuity; in fact, its one of the many reasons that NIH plans to create a National Center for Advancing Translational Sciences. My hope is that when the day arrives to celebrate the 20th anniversary of the original human genome publications, we will be able to look at a world lled with the faces of people whose health has been improved by the sequencing of their genomes.
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200 bp) from smaller DNA fragments than did the strategies to produce the rst human genome sequences. Long DNA sequence reads (800 bp) from the ends of long DNA clones (>100 kb) provide scaffolding and extensive DNA assembly by linking together subassemblies. The short sequences can only produce small clusters; these make sequence assemblies of substantial length improbable. Because of these technical issues, some investigators only layer their short sequences against a reference and do not try to assemble a sequence, which makes it problematic to dene scientic standards for a genome sequence. As important as sequence quality standards are, a much larger issue rests with the current state of our ability or inability to interpret human genome sequence. Among the many improvements that are needed in human genome research, the most important is the collection of human phenotypes (according to agreedupon parameters and standards), in conjunction with tens of thousands of accurate human genome sequences. Such data sets will be the foundation for accurately predicting clinical outcomes from DNA sequence information. This is true not only for diagnosis but also in foreseeing and avoiding drug side effects, as well as monitoring stem cell genome mutations and/or variations before cell therapies. Although many genome companies and researchers are promoting personal genomics for medicine and/or life choices, regulation of data quality and standards is lacking, which has made deceptive marketing a reality in some instances. We have sequence and genetic data quality that is suitable for some scientic analyses but no standards adequate for clinical practice or even for informing individuals of results that exist. We have come a long way in genomics; however, for genome sequencing to reach its full potential we still have a long way to go.
Xavier Cortadas Sequentia Exhibit, 2010.
Genomics and Clinical Relevance

Tom Hudson President and Scientic Director, Ontario Institute for Cancer Research, Toronto, Ontario, Canada When I interact with physicians, I realize that the clinical questions they think are most relevant are more sophisticated than those posed by the rst wave of whole-genome studies. When I ask questions that are clinically relevant, they are not what I asked myself in 2001, when the landmark human genomesequencing papers were published. At that time, my thinking process was DNA-driven: What is functional? What is normal genome variation? What amazes me in retrospect is that I did not appreciate the fact that genomic information and technologies would grow more than a millionfold in the following decade and, in a way, leap-frog other critical initiatives in health research. Now, clinicians are more and more concerned by overdetection, overdiagnosis, and overtreatment of diseases, as a result of sensitive tests (e.g., prostate-specic antigen for prostate cancer). Whether the disease involves cancer, metabolism, inammation, or neurodegeneration, it becomes apparent that we have a limited knowledge of disease processes over time and, consequently, limited knowledge of when to intervene and to what degree. In some patients, this leads to unnecessary complications, whereas in others, the failure to act early is irreparable. If I could move the clock back to 2001 and change course, I would invest signicantly more in developing large clinical resources with detailed clinical histories, deep phenotyping, and longitudinal follow-up in order to better understand outcomes and treatment responses. If genomics was now being integrated with such resources, we would be closer to achieving a form of personalized medicine that clinicians would be eager to adopt. 547
The Golden Age of Human Population Genetics

Molly Przeworski Professor, University of Chicago, Chicago, IL, USA, Howard Hughes Medical Institute Early Career Scientist The rst draft of the genome provided the road map for the past decade of research in human genetics, allowing for the design of platforms that have been used to query variation in populations worldwide and helping to drive down the cost of sequencing by several orders of magnitude. Within years, tens of thousands of complete genome sequences will be available from humans and from extinct hominids, as well as from thousands of other species. Given the human mutation rate, we will soon know of variation among individuals at almost all sites in the genome. For population genetics, this ushers in a previously unimaginable opportunity to reconstruct the entire genealogical and
CREDIT (TOP): XAVIER CORTADA; (RIGHT) HEMERA/THINKSTOCK; (BOTTOM) N. KEVITIYAGALA/SCIENCE
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mutational history of humans and pushes us against the limits of what we will be able to infer about the evolutionary and genetic forces that affected every region of the genome. Why are disease mutations present in human populations? What is the genetic basis of our cognitive and physiological adaptations? What was the sequence of demographic events that led to the colonization of the globe by modern humans? Stay tuned, and before long, we should know as much as genetic data alone can tell us.
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What Denes Us?

Ronald Cole-Turner Professor of Theology and Ethics Pittsburgh Theological Seminary, Pittsburgh, PA, USA As a theologian, I am sometimes asked: What, then, does it mean to be human? If I ever knew the answer, I am becoming less clear all the time, thanks in part to discoveries related to the human genome. The irony is discomforting. As we gain precision, we seem to be losing conceptual clarity. The human genome, it turns out, consists of sequences that are widely shared across the evolutionary tree. The microbes inside us, outnumbering our human cells ten to one, have their own genomes that interact with our DNA, contributing to our individual and species identity. Comparisons between the human genome and that of other primates, such as chimpanzees, suggest that the boundary of our much-vaunted human uniqueness is thin indeed. The sequence of a major portion of Nean-
At the Sequentia exhibits opening, I invited 400 museum visitors to help synthesize a DNA molecule. Through art, I wanted them to explore the sequence of events that make up life on the planet from the molecular to the monumental. Participants randomly selected postcards depicting one of the four nucleotide paintings and attached them along the exhibits wall. The participatory art installation generated a 400-nucleotide sequence. In Kalai Mathees laboratory at the College of Medicine, Florida International University, we synthesized the DNA strand, propagated it within bacteria in a petri dish, and analyzed it against other existing sequences. Our randomly generated sequence could have belonged to any (or none) of Earths species, but instead, it resembled the portion of human chromosome 3 that encodes proteins directing the navigation of axons in our neurons during development. More of us need to realize that we came about in the same way that all other life didwe share the same biology. May we use the knowledge we develop to act as best we can to sustain life for all species sharing this planet.
dertal DNA can now be compared with our own, and we are learning that Neandertals are hardly extinct, their DNA living on in many of us. Tantalizing discoveries now suggest that we once shared the planet with the newly discovered Denisova hominin, which appears to have interbred with some of our ancestors as recently as 40,000 years ago. The Human Genome Project undermines cherished ideas about human uniqueness. But it also hints at a new vision of humanity. We are less clearly dened than we once thought, less set apart from the rest of life, but uniquely able to probe the data and ponder the questions. And, being humans, we let our discomfort give way to wonder. Who are we, and where will we go next?
Bringing Genomics and Genetics Back Together

Richard A. Gibbs Professor, Department of Molecular and Human Genetics and Director, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA Ten years already? There have been cycles: When we produced the rst sequence, we were all amazed to see the lower-than-expected gene count and the size of each of the categories of the functional class of gene productseven though we had no clue about the functional roles of at least one-half of them. Many of us also expected wide enthusiasm for more sequencing, more biology, and more discovery. Instead, the community was slow to warm up to genomics. Sequencing the rst human genome really changed the way all biologists work, but it did not change many opinions about big science. Now, after several years of model organism genomes, deep surveys of genetic variation, and a burst of technical development, appetites are increasing for DNA sequencing and experiments on the scale of the human genome project. In studies of human biology, personal diploid genome sequences have shown the way forward, but the most exciting data now are from solving the genetics of individual Mendelian disorders, where the phenotype-genotype relationships really make sense. The new methods and the willingness to tackle human Mendelian genetics, with attention to modiers and heterogeneity, will enable the realization of the impact of genomics in genetics. Genomics became a discipline that was separated from genetics more than 20 years ago, but now the two are coming back together.
Painting the Genome for the Public

Xavier Cortada Artist, Miami, FL, USA Everything that lives, has ever lived, or will ever live on planet Earth has been created using adenine, cytosine, guanine, and thymine. Mapping how these four nucleotides arrange to create a human being helps us better understand how interconnected we are to one another and the natural world. I recently created portraits of lifes four building blocks shown below. It felt as if I were painting a relative, except that I was bringing molecular formulas, not ancestors, to life. Within each large colorful canvas, I painted imaginary subatomic landscapes with oating base-pairs.
Adenine 548
Cytosine
Guanine
Thymine

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CREDIT: PAINTINGS BY XAVIER CORTADA
The Human Genome Projecthints at a new vision of humanity
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A Celebration of the Genome, Part II
D
My Genome
uring the month of February, we are celebrating the 10th anniversary of the rst publications of the human genome sequence. This week, the commentaries explore the impacts of sequence information on our understanding of ourselves, as well as look at future directions for research and medicine.
CREDITS: (TOP) C. BICKEL/SCIENCE; (LEFT) ORYX MEDIA, CAPE TOWN, SOUTH AFRICA; (RIGHT) ROSANA AZAR/ WWW.ROSANAAZAR.COM
Desmond Tutu Archbishop Emeritus of Cape Town, South Africa This is a monumental month for human genomics as we celebrate 10 years since the publications of the human genome. It is time to reect on the advances that this endeavor has brought to mankind. The ability for scientists to generate a complete human genome sequence meant that, for the rst time, an individuals entire genetic code could be read from beginning to end. For the rst time, these amazing men and women could use the code to study disease, to make sense of inherited risks, and to assess how the body responds to medicines. These advances, however, were biased because the available information provided limited benet to the African continent and the people of Southern Africa. I have been known to refer fondly to my country as the Rainbow Nation, a land of wealth in its many diverse peoples and cultures. The majority of us have experienced many years of oppression, emerging as a free nation only in 1994. As a nation, however, we need to continue to ght against racial inequalities and socioeconomic disparities on a daily basis. My participation in the Southern African Genome Project was a step in this direction, generating the rst Southern African genome to be sequencedexactly 9 years after the publication of the human genomes. My reasoning was simple. Southern Africans are victims of many devastating diseases whose eradication requires immediate attention and international resources. My hope is that my genetic code may provide a voice for the region and serve as the starting point for a map of DNA variation signicant for Southern African peoples, to be used for medical research efforts and effective design of medicines. I implore the scientic community to continue what I hope was just a rst step to further medical research within the region. Many may ask if I learned anything signicant from having my genome sequenced. I was certainly not expecting anything dramatic. I have been blessed to be alive for 79 years; we have four beautiful, healthy children
Genome Literacy
Emmanouil T. Dermitzakis Professor, Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland The transition from knowing small patches of the genome to having whole human genomes available to explore has been a unique experience. The biggest surprise initially came from the number of proteincoding genesestimates anywhere from 15,000 to 160,000 had appeared in the literature before the publications came out in 2001 and settled at 20,000 to 30,000 genes. Although protein-coding genes were the most identiable functional elements in the human genome, 10 years ago, the exact location of regulatory regions was unknown, and only a small fraction of the variations existing within the human population had been characterized. Ten years later, the ability to use the complete human genome backbone to map sequence variation and the availability of technologies to interrogate genome function are driving our ability to read the compendium of functional elements and to understand how population variation effects them. The basic components in each genome are largely the same, but the way they are used differs from tissue to tissue and person to person. Understanding the rules of gene regulation, the grammar of the genome, is key to the understanding of the human body. And it is only with the full sequence that we will 689
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and seven gorgeous grandchildren. Wonderfully, I discovered that I was related to my fellow sequenced Southern African in this project, !Gubi, a Kalahari Bushman from Namibia. Meeting !Gubi and his wife Anna in Windhoek in February 2010 was for me a highlight of this project. Anna bore an uncanny resemblance to my mother. It was a truly uplifting experience to discover that I was genetically related to a long line of peaceful and gentle people that have trod the soils of Southern Africa for centuries. My dream is that by including all peoples in understanding and reading the genetic code we will realize that all of us belong in one global familythat we are all brothers and sisters. Wow!
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be able to learn the grammar of the genome. Each persons genome tells slightly different stories, and fascination comes with the discovery of the differences in those stories. To cite from the original papers: The sequence is only the rst level of understanding of the genome and Finally, it is has not escaped our notice that the more we learn about the human genome, the more there is to explore. only a handful of such cases had been identied. Technological and analytical advances in the past decade, however, have enabled us to progress from hypothesis-testing to hypothesis-generating science. Rather than examining single-candidate genes, we can scan the entire genome to identify variants under natural selection. In the initial phase of the postgenomic era, we have conrmed earlier hypotheses of evolution for malaria resistance, skin pigmentation, and lactose tolerance, and we have identied new adaptations for the formation of hair, resistance to trypanasomes, and response to high altitude. The challenge now is to uncover how hundreds of newly discovered candidate loci have shaped our evolution. In my laboratorys own recent scans, we identied more than 200 loci with strong evidence of selection. Of these, roughly half point to genes, and the other half point to large, intervening, noncoding RNAs (lincRNAs), other regulatory elements, and many yet-unknown regions. It is intriguing that whole new adaptive pathways are coming into view, such as those regulating sensory perception and thermoregulation in Asia, and metabolism and infectious disease in all populations. In the next decade, scientists can look forward to investigating these pathways and many other new hypotheses being generated through genome scans to uncover the vast landscape of human evolution.
Personal Genomes: For One and for All

Jun Wang Executive Director, Beijing Genome Institute Thanks to immense technological improvements in the 10 years since the draft of the rst human reference genome was published, we are now seeing the dawning of the personal genomics era. Breakthroughs in medical genomics and genomics-guided medicine allow ever deeper interpretation and application of the information contained in a personal genome. The accumulation of individual genomes with clearly documented phenotypes that are available for research signicantly facilitates such breakthroughs and discoveries. This virtuous circle is likely to spin faster in the coming years. Although the benefits of a personal genome for the owner are clear, proling everyones DNA is mutually benecial, acting with a strong network effect. Human populations are largely phylogenetically related as a result of recent population explosion. Considering that any two of us have common ancestry back to a certain point, people nearly always share a signicant fraction of genetic variation sites and allele types. Therefore, the health prole and personal genetic information of one individual will, to a certain extent, provide clues to better understand others genomes and their medical implications. In this sense, a personal genome is not only for one, but also for all humanity.
My Genome, My Identity, My Health

Charmaine D. M. Royal Associate Research Professor, Institute for Genome Sciences & Policy and Department of African and African American Studies, Duke University, Durham, NC, USA. As a genetic counselor and human geneticist, I am in awe of the human genomethe nucleus of our eld. Its potential to enlighten us about ourselves, our relationship to one another, and our place in the scheme of life makes it a distinctive reservoir for ground-breaking science and personal reection. Advances in genomics have taught us much about the biological underpinnings of disease. Nevertheless, the research itself is conrming that genome sequence does not tell the full story about human health and illness. Indeed, individual and group differences are the result of many variables. What is my socioeconomic status? Where do I live? Do I have supportive social networks? Access to health care? How do others perceive and treat me? Humans are so much more than a genome! If we truly want to decipher disease mechanisms and practice personalized medicine to achieve optimal health, we must adopt a more holistic approach. Genomic research has also prompted new, and resurrected old, conversations about race, ancestry, ethnicity, and identity. The ndings that human genetic variation is primarily continuous and that living humans have not subdivided into biological races (subspecies) mean that
The Landscape of Human Evolution

Pardis Sabeti Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA In the pregenomic era, evolutionary genetics was a painstaking process. From observations of the natural world, scientists hypothesized instances of selection and sought conrmation on a case-by-case basis. As of 2000,
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the (mis)use of the term race to refer to the groups and populations of national censuses and various geographical origins should cease. There are groups, populations, and lineagesdened in a variety of waysbut no human races. My enduring dream is that, over the next 10 years and beyond, there will be an upsurge in authentic and critical interdisciplinary and transdisciplinary biomedical research that breaks with previous paradigms of categorical thinking. In this dream, droves of biological, social, behavioral, and clinical scientists are stepping out of their silos, reaching across the corridors, transcending lip servicemaximizing our capacity to understand and prevent disease and to enhance the quality of human life. Our moral obligations and scientic integrity demand it.
An Anniversary Party
Kri Stefnsson President and CEO, deCode Genetics in Reykjavik, Iceland The decision to sequence the human genome constituted an unparalleled commitment on behalf of humanity. Ten years ago, it was announced that the sequencing of the reference human genome had been completed. Although it could be argued that the decision to do this was somewhat arbitrary, it is a reason for us to throw an anniversary party in 2011. The sequencing had been going on for years, yielding data that empowered the eld of human genetics to make discoveries as never before, and the sequencing has continued ever since. However, still today, we do not have the complete sequence of the reference human genome as parts (such as the centromeres or regions of copy number variation) are still incomplete. The suboptimal quality of the reference sequence is one of the limiting factors in the work of those who are using whole-genome sequencing to understand human biology. Hence, this is an anniversary of a moment in the history of our quest for an instrument (the reference sequence) to use in better understanding ourselves.
What Will Drive Genomics Over the Next 10 Years?

Arthur Caplan Director, Center for Bioethics, University of Pennsylvania, Philadelphia, PA, USA. When the announcement was made that teams led by Francis Collins and J. Craig Venter had jointly produced a rough map of the human genome, I was way in the back of a room crowded with a starry-eyed horde of media, NIH ofcials, representatives from the White House, and a variety of university and corporate scientists. I am fairly certain I was the only person at that press conference from the eld of ethics. In the decade since the human genome map was published, efforts Most thought that the to apply that knowledge to human health have greatly and appropriately ability to predict an increased the presence of ethics in the world of human genomics. individuals risk of Most thought that the ability to developing diseases predict an individuals risk of develwould drive the use of oping diseases would drive the use of genomic information. That did not genomic information. turn out to be so. That did not turn out Efforts to move personalized risktesting to the Internet and into pharto be so. macies did quickly follow the publication of the map and the creation of better array-based technology. A variety of companies jumped on the spitomics bandwagonencouraging individuals to spit in a cup in order to nd out whether they were at risk for cancer, diabetes, and drug dependency; to gain insight into the identity of their forebears; or to nd out if their kids were likely to have food allergies or become star athletes. These activities met with little enthusiasm. The lack of standards about the accuracy and sensitivity of claims about genetic tests, the absence of serious efforts to ensure competent counseling, and indifference to simply having information about risk slowed the growth of interest in personal risk assessment. Fear of repercussions has been an obstacle as well. Only in the past few years, with the enactment of the Genetic Information Nondiscrimination Act of 2008 and the Patient Protection and Affordable Care Act last year, has the requisite ethical and legal infrastructure for personal genetic risk analysis been created. It is not the analysis of risk factors that shows the most immediate promise for human genomics but the application of genetic information to permit the safer and more efcacious use of drugs. Pharmacogenomics is poised to capture the promise of the discovery and publication of our genome. Cure, not diagnosis, is the value driving human genetics and is likely to do so into the future.
First Steps on a Long Road

Eric Schadt Chief Scientic Ofcer, Pacic Biosciences of California, Menlo Park, CA, USA. DNA variations and their interaction with diverse environmental pressures are how natures fundamental forces shape nearly every facet of life. The rst human genome sequence, published in 2001, provided a canonical reference from which to understand genome structure, as well as a registry of functional units. Before 2001, only a handful of examples of genetic risk factors existed for common human diseases. At present, thousands of genes that inuence susceptibility to hundreds of disease-associated phenotypes have been identied. Today, with advanced, low-cost technologies, we have embarked on the characterization of genomic variation and associated gene networks. However, our understanding of complex phenotypes is far from complete. Knowledge of the human genome has led to a wave of discoveries (e.g., transgenerational epigenetic inheritance) that have shaken some of the foundations upon which biology is built. We have learned that the human genome is much more dynamic than previously thought. Elucidating its complexity will require a more systems-level approach, including comprehensive integration with other data dimensions, such as RNA, metabolite, protein, and clinical data. For me, although this past decade has exposed many amazing aspects of the genome, it has revealed the existence of a world about which we know very little. We will have to become masters of information if we ever hope to go from the big data sets coming to dominate biology to knowledge and to understanding. 691
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A Celebration of the Genome, Part III
his is the third in our series of vignettes celebrating the 10th anniversary of the sequencing of the human genome. You will nd vastly different perceptions of what the genome represents and its impact.
A Living Constitution
Sheila Jasanoff Pforzheimer Professor of Science and Technology Studies, John F. Kennedy School of Government, Harvard University, Cambridge, MA, USA A decade is not nearly enough time to measure the impact of a scientic revolution. We should not presume to judge how human lives will change as a result of the publication of the human genome sequence in Science in February 2001. It is clear, though, that simply weighing past predictions against present realities misses the mark. It is too soon to tell whether cures for genetic disease were oversold or fears of producing a genetic underclass were much overblown. What matters is that we found a powerful new way to represent human identity, and the moral implications of that re-representation are just beginning to unfold. Like the Constitution of the United States, the human genome turned out to be a sparse document, containing fewer genes than expected. This means that, as with the Constitution, the genomes meanings will evolve over time, as scientists, lawmakers, and publics make sense of the xed elements of the sequence in relation to the variables and unknowns in the surrounding environment. Some outlines of new thinking are already emerging, as importantly in law and ethics as in biomedicine. Unsettled questions about who can patent genes, how to regulate unconsented uses of genetic information, when to allow familial searching of data banks, who owns immortal cell lines, and what constitutes impermissible mixing of human and nonhuman genetic material all point to deeper uncertainty about the moral status of the human genome. These questions are contentious, but in disrupting our taken-for-
What Does a Normal Human Genome Look Like?

Maynard V. Olson Professor Emeritus of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA During the past 10 years, we have had our rst glimpse of why individuals differ so much from one another. This is not the right place to revisit the nature-nurture wars or to reect on the extent to which our impression of high phenotypic variability in humans is a narcissistic illusion. For the moment, let us just acknowledge the obvious: In any small group of people, we see a lot of variation in traits we care about and not just those that affect health. Geneticists shy away from studying these traitsand for good reason. They prefer not to revisit a subject whose premature investigation accounted for the worst moments of their young science. Nonetheless, questions about the genetic basis of variability among generally healthy humans will not go away. Public fascination alone will keep it alive, as will the realization that genetics is unlikely to revolutionize medicine until we develop a better understanding of normal phenotypic variation. So, what have our rst glimpses of variation in the genomes of generally healthy people taught us? First, balancing selection, the evolutionary process that favors genetic diversication rather than the xation of a single best variant, appears to play a minor role outside the immune system. Local adaptation, which accounts for variation in traits such as pigmentation, dietary specialization, and susceptibility to particular pathogens is also a second-tier player. What is on the top tier? Increasingly, the answer appears to be mutations that are deleterious by biochemical or standard evolutionary criteria. These mutations, as has long been appreciated, overwhelmingly make up the most abundant form of nonneutral variation in all genomes. A model for human genetic individuality is emerging in which there actually is a wild-type human genomeone in which most genes exist in an evolutionarily optimized form. There just are no wild-type humans: We each fall short of this Platonic ideal in our own distinctive ways.
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granted assumptions, they force us to rethink the nature and consequences of being human. In retrospect, this point leaps out as most signicant: 2001 marked the issuance of a founding document, a biological living constitution that remakes how we, as individuals and species, interpret our obligations to each other and to other entities on Earth.
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Of Mice and Humans

Shinya Yamanaka Director, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan Induced pluripotent stem (iPS) cells have great potential for human therapies. Although the rst such cells were generated by introducing four transcription factorsOct4, Sox2, Klf4, and c-Mycinto mouse somatic cells, we and our research benefited from the atmosphere generated in the community by the human genome project. We started in 2000 with the goal of generating embryonic-like stem cells from somatic cells. During the rst phase of the research, we decided to identify genes that are expressed specifically in embryonic stem cells. The most effective weapon for us to nd such genesveritable needles in the haystack of transcribed geneswas an expressed sequence tag database, a mouse cDNA library developed and made public by RIKEN. Construction of this database was inspired by the U.S.-led international project to decipher the human genome. Mice are usually used as a model organism for humans. As Japan lagged behind in genomic science in the mid-1990s, RIKEN launched the project of sequencing all RNAs that are expressed as genes and built the mouse cDNA library. The human genome sequence publications contributed to the development of numerous genetic databases and fundamental technologies, such as microarray analysis. The human genome project has brought tremendous changes to research methods today and has contributed to building the foundation of medical and life sciences.
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Gene Patents: The Shadow of Uncertainty

Robert Cook-Deegan Director, Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA. Twenty-two years ago, the Congressional Ofce of Technology Assessment released a report about policy options for federal support in scaling up genome research. It contained the misleading statement, genome projects raise no new questions of patent or copyright law. I wrote that sentence and have spent the past decade studying how wrong it was. The general parameters of intellectual property law do indeed cover all technologies, not just genomics. Patent law applies to new technologies in distinctive ways, however, and using and interpreting it differs markedly among elds. Genomics has served up more than its share of controversy. The year 2010 was tumultuous in the world of gene patents. In February, the Secretarys Advisory Committee on Genetics, Health, and Society approved a report that recommended exemptions from patent infringement liability for research and for diagnostic use. On 29 March, Judge Robert Sweet of the federal district court for southern New York turned gene patents on their heads by ruling that contested claims over BRCA1 and BRCA2 genes were invalid. Most of the ruling argued that DNA molecules cannot be patented because they are embodiments of information 873
Human Genome Sequencing: Celebrating 10 years

Lihadh Al-Gazali Professor, Clinical Genetics and Paediatrics, Department of Pediatrics, United Arab Emirates University, Al-Ain, United Arab Emirates The sequencing of the human genome has had a signicant impact on pediatric practice in the Arab region (the 23 states of the Arab league). It has facilitated research into the identication of genes of single-gene disorders, particularly the autosomal recessive type, which are a major cause of infant mortality, morbidity, and handicap in Arab countries. Of the 955 genetic diseases described in Arabs, 60% (586) are caused by recessive genes.

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The information obtained from the human genome, coupled with the high level of consanguinity (25 to 60%) and large family sizes in this region, has provided the perfect opportunity to identify the genes of recessive disorders via homozygozity mapping and DNA sequencing. The CTGA database, curated by the Center for Arab Genomic Studies, indicates that more than 60 recessive genes were identied, mostly during the past 10 years, in families from this region. Undoubtedly, these studies contributed to genome annotation and to unraveling the extent of genome variability. In addition, molecular characterization of well-described phenotypes in large families from this region will also, it is hoped, reveal genes that underlie complex and heterogeneous conditions. Despite recent progress, many recessive disorders in the Arab region are still not studied. At present, 36% of the genetic disorders reported in this region are only known as clinical observations. We expect that the molecular causes of the vast majority will be resolved within the next few years. This will result in a high-value knowledge base and will have direct implications on genetic counseling, prenatal diagnosis, and patient management. However, translating human genome research into clinical practice requires the development of comprehensive and effective programs by health authorities. Although progress has been made in this respect in some Arab countriessuch as the mandatory premarital screening for thalassemia and sickle cell anemia program, prenatal screening, and the diagnosis of congenital anomaliesthe limited options available for carrier couples remain a challenge in making these programs effective in the prevention of genetic diseases.
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and products of nature, and another section argued that the methods claims did not pass muster. That ruling is being appealed, and the nal resolution may not be for several more years. In December, the Court of Appeals for the Federal Circuit reafrmed the patentability of a diagnostic method. The stakes are high, because present uncertainty over the existence and extent of patent rights casts a shadow over those making decisions about clinical and other applications of gene patents. Promising new methods for full-genome analysis might or might not face patent infringement liability. Some assert that patent rights have hindered research, although evidence of such harm is not compelling, but the evidence that patent rights have fostered diagnostic innovation is even weaker. Many laboratories have gotten genetic tests to market without patent rights. Those with exclusive rights have rarely, if ever, been rst to market. Companies that became sole U.S. providers did so by clearing the market of competitors. This is not unique to gene patents, but it creates intense controversy. Patent rights could, however, prove crucial to product development if payers demand evidence of clinical utility or if the U.S. Food and Drug Administration begins to regulate genetic tests, because developing such tests would suddenly become more costly and time-consuming, and a patent incentive could help induce private investment. In 2011, we may nally begin to develop case law on how patent law will apply to DNA technologies beyond protein therapeutics. The debate over establishing a human genome project included disagreement over patent policy; that disagreement continues, but the effects of uncertainty are moving from equivocal and probably weak effects on research to actual impact on private investment decisions that will affect what genomic technologies get developed in the real world. Reducing the uncertainty surrounding diagnostic uses of gene patents is important. ers, such as chromatin modications, is far greater than that suggested by analyses of sequence conservation based on circular assumptions about the nonfunctionality of transposon-derived sequences. These observations suggest that we need to reassess the underlying genetic orthodoxy, which is deeply ingrained and has been given supercial reprieve by uncritically accepted assumptions about the nature and power of combinatorial control. As Nobel laureate Barbara McClintock wrote in 1950: Are we letting a philosophy of the [protein-coding] gene control [our] reasoning? What, then, is the philosophy of the gene? Is it a valid philosophy? There is an alternative: Human complexity has been built on a massive expansion of genomic regulatory sequences, most of which are transacted by RNAs that use generic protein infrastructure and control the epigenetic mechanisms underpinning embryogenesis and brain function. I see the human genome not simply as providing detail, but more importantly, as the beginning of a conceptual enlightenment in biology.
The Genomic Foundation Is Shifting

John S. Mattick Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia For me, the most important outcome of the human genome project has been to expose the fallacy that most genetic information is expressed as proteins. The biggest shock was that the number of conventional genes, despite some lineage-specic expansions and occasional innovations, does not scale with developmental and cognitive complexity: Humans and other vertebrates have only about 20,000 protein-coding genes, a similar number with functions largely similar to those in nematode worms that have just 1000 somatic cells. There have been several aftershocks: In contrast to protein-coding genes, the extent of noncoding intronic and intergenic sequences increases markedly with complexity; only 1.5% of the human genome encodes proteins. Subsequent tremors include the ndings that the vast majority of the mammalian genome is dynamically transcribed in a developmental stage- and cell type specic manner to produce huge numbers of noncoding RNAs and that the extent of the genome imputed to be functional by this measure and oth874
Eileen Hoal Associate Professor, Department of Biomedical Sciences, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa Current graduate students cannot conceive of the world before the human genome was available for their daily practical tasks. In Africa, the shortage of resources (in terms of scientists, equipment, and operating funds) for data acquisition has made the publicly available data particularly valuable. However, in a sense, the sheer volume of accessible data is a drawback. We have been made acutely aware of our need for computational tools and expertise, exacerbated by the brain drain through emigration of those who acquire these scarce skills. For complex analyses such as admixture mapping or copy-number variation, we often now have the data spread out in a tantalizing buffet, but are left feeling as though we are looking into the dining room window, our noses are pressed to the glass. The solution, to avoid simply exporting data or samples, is North-South collaboration and the formation of consortia to maximize the promise of the information still locked in the rich variety of African genomes. In a wholly South African effort, publicly available data allowed us to dissect the structure of a uniquely African population. Further application of this knowledge required us to foster collaborations with more experienced laboratories and researchers, which are already showing results. Human genome analysis has the potential to act as an accelerating enabler, helping us to understand how an individuals genome may affect susceptibility to infectious diseases such as tuberculosis. Approaches such as genome-wide association studies have been disappointing in this disease, and a search for rare variantsor simply understanding variation in the older, more diverse African populationsmay hold some answers. Ultimately, local initiatives need to grow local expertise and to retain the necessary talent.

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Famine in the Presence of the Genomic Data Feast
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A Celebration of the Genome, Part IV
I
The Accelerator
n this last of this series of genome anniversary vignettes, you will continue to nd provocative thoughtsranging from the impacts of this big science project on the rest of the research community to the commonalities between art and science. Exciting as all of the vignettes have been, our space was nite, and we know that there are many more opinions waiting to be expressed. We challenge you to reect on the implications of this landmark event and look forward to your letters and e-letters!
Barbara R. Jasny and Laura M. Zahn that never were and say Why not? Increasingly, young biomedical scientists are bringing this same attitude to their work. They are impatient with technological limits that stand in the way of knowledge. They transcend disciplinary boundaries, fusing experimental, computational, and clinical science into a new biology. They roll up their sleeves to create vast data sets, comprehensive reagent collections, and powerful new methodsand they share them freely. They are not afraid to work in teams, if by working together they can change the world. In the past week, I have attended three scientic meetings, where I heard young scientists brimming with vision about predicting all the ways in which tumors can become resistant to a therapy, unraveling the molecular basis of psychiatric diseases, characterizing the entire human immune response to stimuli, mapping the complete genomic landscape of all transcription factors through development, creating a comprehensive catalog of all cellular circuitry, and devising general methods to speed the development of new therapeutics. If I had been asked to pick out a present to celebrate the 10th anniversary of the HGP, I could not have chosen better.
Eric S. Lander President, Broad Institute of Harvard and MIT, Cambridge, MA, USA, and Cochair, Presidents Council of Advisors on Science and Technology When the Human Genome Project (HGP) was proposed some 25 years ago, the notion was so foreign to biology that commentators had to resort to metaphors from physics. The HGP was biologys Manhattan Project, biologys Moon Shot, biologys Superconducting Supercollider particle accelerator. To some, the project seemed like mindless drudgework aimed at a dubious goal. (Sydney Brenner waggishly suggested that the HGP be conducted in penal institutions, by inmates sentenced to 20 megabaseswith time off for accuracy.) In reality, of course, it was the human genetics research of that early era that was marked by tedium (10 years to clone the gene for Huntingtons disease!). What smart young student would want to be an ant in an army scaling a linkage peak? Ultimately, the HGP yielded discoveries as remarkable as any atomsmasher or deep-space telescope. It revealed that the spectrum of proteincoding genes is far smaller than imagined, that physiology depends on a vast universe of regulatory controls and noncoding RNAs, that diseases arise from many unsuspected genes and pathways, that so-called junk DNA may be the mother of much invention. In the end, though, the HGP might indeed best be viewed as a highenergy acceleratornot of particles, but of scientic work and scientic imagination. Individual investigators, the drivers of biomedical progress, can today carry out projects that once required legions: They can readily assay thousands of genes, millions of genetic markers, billions of nucleotides; they can interpret their ndings in the context of public data sets representing tens of thousands of experiments worldwide and billions of years of evolutionary information. These capabilities have liberated them to think creatively and boldly about important biomedical challenges. Once seen as big science, the HGP has proved to be the most powerful enabler of small science. Robert F. Kennedy famously said, Some men see things as they are and say Why? I dream things
Making Sense of the Data

Peter Donnelly Director of the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK There is an old aphorism that you wait forever for a London bus, and then two come along together. After the huge international efforts to sequence the human genome, the past 10 years have seen an explosion of data documenting human genetic variation, and we are at the tipping point for what will be an avalanche of high-quality human genomes. Within a few years, tens of thousands of human genomes will have been sequenced. A major strand in research since the human genome sequence has been the systematic attempt to identify, annotate, and understand the functional elements in the genome. For much of this time, the collection and analysis of human variation data might have seemed to be running in parallel to the functional work, with no direct connection. But that is illusory: Data on human genetic diversity have proved to be a valuable tool in the quest to understand human biology. One example is recombination. We have learned a great deal recently about this fundamental biological process through the study of humans and, in particular, of human variation. Another is population geneticsas others have noted, human variation data offer an unparalleled opportunity to understand the forces shaping patterns of genetic diversity and to identify genomic elements under selection. But perhaps most signicantly, the identication of DNA sequence variation associated with phenotypes of interest, particularly with human disease, provides the starting point
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on another route to understanding biological function. The growing number of examples where the path from sequence variant to function has been elucidated offers an encouraging pointer to coming progress. Although the collection of whole-genome data from large numbers of individuals in disease studies is set to become routine, making sense of that data is not yet straightforward. There are formidable analytical challenges ahead, even in the research context. Moving this kind of information into the clinic takes the challenge to another level. Like others, I am an enthusiast for personalized medicine, but one of the biggest obstacles to the use of individual genomic information in health care will be the need for robust analytical tools for its interpretation. We no longer need to theorize or speculate about evolution. In the genome sequences, we have data that fully and quantitatively document the evolution, from common ancestry, of all life on Earth. Insights about the functions of human genes and proteins continue to come fast, most often from studies of their homologs in model organisms. We now can study all the genes of an organism simultaneously via methods that were mostly invented to get the sequencing done in the rst place. The cost of sequencing has fallen dramatically. It is now literally easier and cheaper to sequence the genome of a bacterial or yeast mutant than it is to isolate the gene and sequence only the relevant bits. As sequencing costs have fallen, it has become practical to follow sequence heterogeneity in populations, which may allow us to understand the inheritance of complex phenotypes and the basis of complex human diseases. Such studies have transformed our understanding of the origins and history of the human species. The fears of big science around sequence technology have largely dissipated. T Today, individual investigators outsource routine sequencing to a thriving service industry at an astonishingly modest cost. Data-release practices introduced during the human genome sequence project facilitate reuse of existing data in place of pointless and expensive repetition. This has spread to the functional genomics community and beyond. As h with all technology development, some issues remain, such as the co cost of computational and sequencing infrastructure, which is still b beyond the means of individual small laboratories. These can be dealt with well short of big science by modest increases in funding for shared facilities. When I began my career, I never imagined that someday I co could simply look up a genes coding sequence; nd its orthologs in other organisms; and order, from a service organization, a mutation t my specication for an experiment to reveal gene function. Yet to this is now our world, the direct result of a collective agreement to make genomic sequencing a priority in the last decades of the 20th century. It s was a very good decision.
Fruits of Genome Sequences for Biology

David Botstein Director, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA When I first became interested in genetics in the early 1960s, DNA had just taken center stage. We studied its chemical and physical properties, and we understood that inferences about genes and genomes (yes, this word was used then) were actually about information encoded in DNA sequences, which we could not read or interpret. By the 1970s, we had learned how to use recombinant DNA technology to manipulate DNA in baccteria and viruses, which allowed ed us to recover (clone) sequences nces encoding proteins from any organism (including humans). The next step became obvious (and controversial) even oversial) before it had been reduced to reality: expressing these coding sequences in easily cultivated cells and producing pure recombinant proteins in quantity at reasonable cost. This enabled production of previously rare protein therapeutics and allowed biologists, biochemists, and structural biologists to study pure proteins. One would have thought, after these developments, that when the possibility of sequencing entire genomes was rst raised, it would be regarded as an obvious next step with great promise for science and medicine. Instead, it was met with much skepticism; in the beginning, I was among the skeptics. Unlike the controversy over recombinant DNA, which revolved around issues of safety, opposition to sequencing the human genome was driven by concerns about the extreme cost (estimated then at $3 billion) and effort required. The opposition (including me) felt that diversion of these kinds of resources to big science might so distort the nature of our scientic community that the cost would outweigh the benet. There was no consensus then around the benets of the genomic sequences, for science or for society. In 1988, a National Research Council study (on which I served), proposed a compromise whereby much smaller, and therefore cheaper, genomes of genetic model organisms would be sequenced rst. The critical argument for me, and indeed for much of the scientic community, was that the sequences of the model organisms could be interpreted through experimental work, yet the homology among similar proteins in diverse organisms would allow us to transfer much of the biological interpretation to the human genome. Genomic sequences of many organisms, not just the human, would allow us to read and ultimately interpret the information in DNA in all of them. So it turned out. The benets for science have been nothing short of revolutionary.
Presenting the Human Genome: Now in 3D!

Yijun Ruan Senior Group Leader and Associate Director, Genome Institute of Singapore, Singapore, Republic of Singapore The completion of the human genome sequence in 2001 was, to me, the most important accomplishment in biology. Since then, we have journeyed to the next frontier through signicant improvements in our ability to analyze and map gene expression and transcription factorbinding sites in the human genome. We now understand that the g genome is far more complex than linear informaation could explain. Therefore, to fully y appreciate the rules by which the e genome operates on an organismal level, we have to comprehend higher-order chromosomal organization. To reach that pinnacle, we need rst to understand how the genome is spatially organized and how that organization affects basic nuclear and cellular processes. We also need to learn how transcriptional dynamics and epi-
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genomic states affect the topological organization of chromosomes. Exciting progress has been made recently in mapping the three-dimensional (3D) chromatin architecture. Growing evidence suggests that long-range chromatin interactions are crucial for transcriptional regulation and genome rearrangement, for example, in cancer cells. Ten years ago, the linear composition of the genome was spelled out; I anticipate that in the next 5 to 10 years, we will be able to reveal the 3D topographic map of the human genome within cells, which will help us uncover new insights into development, as well as into the basis for disease. ever cheaper and more accurate DNA sequencing) are proving decisive. These advances have given investigators, clinicians, and patients hope that genetics will nally yield tools that neurobiologists have dreamt of to study the brain in health and in illness.
A Healthy Son
Mary-Claire King Professor of Genome Sciences and of Medicine (Medical Genetics) University of Washington, Seattle, WA, USA Gutenberg must have felt like this: the sense of endless possibilities, of innite applications exploiting the new technology, of the world having changed forever. It seems audacious, but is, I think, correct, to compare his time to ours. I offer a single case study to explain. K is the youngest of eight siblings. Three of her ve brothers were severely developmentally delayed, with cognitive impairment and intractable behavioral disorders. No one else in their large extended family was affected. The most likely explanation for her brothers condition was X-linked inheritance following a new mutation in their mother. Fragile X was excluded, and the critical gene had eluded detection. The region of the X-chromosome shared by the three affected brothers was 40 megabases, too long to enable prenatal diagnosis. K despaired of having a healthy son. Then early last spring, targeted X-exome sequencing of constitutional DNA from the affected brothers revealed a nonsense mutation in a gene known to be implicated in mental retardation. The mutation had not been detectable by conventional technologies but was transparent to massively parallel sequencing. K carried the mutant allele. Armed with knowledge of the mutation, K and her husband undertook pregestational diagnosis (PGD), which involves in vitro fertilization of their egg and sperm, then genotyping of embryos via the polar bodies, and implanting a normal embryo in the mothers uterus. In experienced hands, PGD works very well. K and her husband have a healthy newborn son. Genetics is a way of thinking. Genomics is a set of tools. If we think rigorously about genetics and use these tools well, the resolution of inherited disorders on behalf of our patients will be bounded only by our imaginations. One healthy infant at a time is not a bad way to begin.
The Meaning of the Human Genome Project for Neuropsychiatric Disorders

Steven E. Hyman Provost, Harvard University and Professor of Neurobiology, Harvard Medical School Boston, MA, USA The past 3 years have witnessed a series of replicable, credible, and increasingly useful genetic discoveries in autism, schizophrenia, and bipolar disorder. I cannot emphasize enough the signicance of this progress. Neuropsychiatric disorders are outsized contributors to global disease burden, yet treatment development has reached a near standstill. The problem is that the brain, with its myriad cell types and complex circuitry, represents such a difcult scientic frontier. Because genes play powerful roles in neuropsychiatric disorders, identication of causal variation could provide invaluable clues to their pathogenesis. Sadly, the genetic architecture of neuropsychiatric disorders is endishly complex, but unlike other areas of medicine wrestling with genetic complexity, psychiatry lacks objective phenotypic markers. When I became director of the National Institute of Mental Health (NIMH), NIH, in 1996, I did not foresee quite how complex the genetics would prove, but did recognize that the contemporary technologies were overmatched. (I ruefully joked that I had the only institute with no lowhanging Mendelian fruit to pluck.) With expert advice, I decided that the only rational approach was to amass large collections of patient DNAs with extensive phenotype information. Some investigators resisted sharing of samples, but for most, that day has long passed. I am pleased that these NIMH collections have proven useful, albeit as only a small fraction of the needed sample sizes. It was not, of course, the rst human sequence per se that turned the tide for neuropsychiatric disorders. As for much of medicine, the associated technologies and analytic approaches (above all, the availability of
Socializing Genetic Diseases

Vololona Rabeharisoa Professor of Sociology, Centre de sociologie de linnovation, MINES ParisTech, Paris, France The sequencing of the human genome has been a major scientic adventure of the late 20th and early 21st centuries. It has played a decisive role in the development of biomedicine and has led to numerous partnerships between researchers, clinicians, and the pharmaceutical and biotech industries. Patient organizations have also been involved in these partnerships from the very beginning. In France, for instance, the French muscular dystrophy organization, the AFM (Association Franaise Contre les Myopathies), is a classic example. To step up the struggle against neuromus-
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The Genome Dances

Liz Lerman Liz Lerman Dance Exchange, Takoma Park, MD, USA As the work to map the human genome was nishing, I began to contemplate a performance piece exploring some of the meanings inherent in genetic discovery. As often happens, my research endeavors yielded too much data, and I soon recognized that a dance about the human genome could be a dance about religion, capitalism, policy, race, population control, or a dozen other topics. But after exploring the subject for a year through encounters with scientists, I settled on a format that framed the surprising commonalities of art and science and ventured to use the medium of dance as a science delivery system, setting up three topics: aging, ancestry, and perfection. The dance eventually premiered in 2006 as Ferocious Beauty: Genome, a work combining live dance with video projections that capture the faces, voices, and moving bodies of some of our wonderful science collaborators. So for me, having the genome in hand meant that scientists were ready to talk to an artistan essential element in my ability to create this work. Amid sensationalistic speculations and Frankenstein scenarios, the geneticists, biologists, and ethicists I engaged seemed eager for a platform that would bring a personal voice, a sense of beauty and history, and a range of feeling to bear on this most human of topics. Audiences throughout North America have responded in kind: I didnt expect it to be so emotional. I didnt realize how human scientists were. I expected to be conrmed in my hatred for science, but now I have to reconsider. Along this path, I encountered amazing scientists pursuing knowledge with passion, creativity, and leaps of imagination that were akin to those of my own art-making colleagues. I found a commitment to embracing wide paradoxes, such as how we humans are both common and unique. I discovered both a profound interest in personal inquiry in the lab and a commitment to preparing the larger public to handle the outcome of all of this research. After 5 years of taking this dance to communities throughout North America, I have made many new friends in a eld that is not so far from my own, although we have been trained to think we are separate.
cular diseases, it created its own laboratory, Gnthon, which published the rst physical maps of the human genome and handed them over to the United Nations Educational, Scientic, and Cultural Organization (UNESCO) in 1993, as a heritage to humanity. Numerous patient organizations concerned with rare diseases (80% of which are of genetic origin), national alliances, and a European umbrella organization (EurordisEuropean Organization on Rare Diseases) have been created and have adopted and adapted this model of partnership with research and health institutions. The Marche des Maladies Rares (shown in the photo above) is an annual charity walk organized by the French Alliance on Rare Diseases. This collective mobilization is what led the European Union in 2009 to ask its member states to consider rare diseases a public health issue. The fact that the complete genome sequences are now available has had effects on patient advocacy. First, from my observations in France, patient organizations have multiplied, notably because many genetic abnormalities (and not only genes) have been discovered. Second, thanks to knowledge derived from the sequencing of the complete genome, patient organizations are confronting the complexity of their diseases in their multiple, heterogeneous, and sometimes singular manifestations. As a consequence, the very denition and contours of the conditions they are concerned with sometimes become strategic elements in their self-descriptions. Third, because the same biological pathways might be involved in different conditions, patient organizations are considering cross-condition research subjects and issues. What lessons can be learned from patient organizations active participation in genetic and now genomic research? First and foremost, it has shown lay peoples ability to engage in activities that were considered for a long time as the preserve of specialists. Second, patient organizations have made a crucial contribution to the socialization of genetic diseases. Through their involvement in research, they have fostered a strong sense of solidarity with patients whose diseases were, until recently, considered to be shameful defects that excluded them from a common humanity.
CREDIT: (LEFT) DURAND FLORENCE/SIPA/NEWSCOM; (RIGHT) MICHAEL MAZZOLLA

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HGP 10 year anniversary writings from Science Feb, 2011

Waiting for the Revolution

VOL 331 SCIENCE www.sciencemag.org

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We need to quit trying to push genetics into medicine.

CREDIT: KAREN TAM

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Human Genetics in the Clinic, One Click Away

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1990 1993 1996 1999 2002 2005 2007 2009

CREDIT (BOTTOM): COURTESY OF INTERMOUNTAIN HEALTHCARE.

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CREDIT (BOTTOM): COURTESY OF INTERMOUNTAIN HEALTHCARE.

The Human Genome (Patent) Project

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What Would You Do?

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HUMAN GENOME 10TH ANNIVERSARY | NEWSFOCUS

500,000 samples available for DNA studies.

CREDIT (ILLUSTRATION):N. KEVITIYAGALA/SCIENCE; (PHOTO DETAIL) STACY HOWARD/CDC

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Would you share such ndings

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HUMAN GENOME 10TH ANNIVERSARY | NEWSFOCUS

CREDITS (ILLUSTRATION):N. KEVITIYAGALA/SCIENCE; (PHOTO DETAIL) WIKIPEDIA

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Can This DNA Sleuth Help Catch Criminals?

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CREDITS: (PHOTO) RUDD KOPPENOL; (GRAPHIC TREATMENT) N. KEVITIYAGALA/SCIENCE

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HUMAN GENOME 10TH ANNIVERSARY | NEWSFOCUS

CREDITS: (PHOTOS) RUDD KOPPENOL; (GRAPHIC TREATMENT & DETAILS) N. KEVITIYAGALA/SCIENCE

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Emerging Forensics Field May Hit Legal, Ethical Obstacles

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Beyond Human: New Faces, Fields Exploit Genomics

Tracing the Tree of Life

CREDIT: GONZALO GIRIBET

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gnathozoans may clarify animal evolution.

Using DNA to Reveal a Mosquitos History

Mosquito hunters. Christina Holzapfel and

William Bradshaw embraced next-generation sequencing last year.

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Test case. Researchers didnt need a sequenced

genome to make a dense genetic map of the pitcher plant mosquito.

Tackling the Mystery of The Disappearing Frogs

Going, going. The mountain yellow-

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