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GENOMICS

Venter’s Genome Sheds New Light on Human Variation
For the first time, researchers have pub- any good if he just gets my dad’s genome.” lished the DNA sequence from both sets of Venter and co-workers compared his chromosomes from a single person: none two haploid genomes to assess the differother than pioneering genome researcher ences between the DNA he inherited from J. Craig Venter. The new sequence suggests his mother and that from his father. Venter’s that there is substantially more variation DNA made up 60% of the reference between humans than previously recognized. It also pushes personalized medicine a step closer and stokes long-standing debates about genetic privacy. More than 7 years ago, Celera Genomics, a company then headed by Venter, and, separately, the international Human Genome Project consortium each described their f irst drafts of the genetic blueprint for a human. To save time and money, both teams combined samples from several individuals and created composite, or “reference,” genomes that contained only half of a human’s DNA. Humans have a diploid Vive la différence. J. Craig Venter’s genome offers the first thorough genome with 23 pairs of comparison of the DNA in the chromosomes inherited from each parent. chromosomes—with one of each pair contributed by the father and the genome produced by Celera; the new study other by the mother. The reference built on that work, repeatedly sampling his genomes effectively have the sequence DNA for completeness and accuracy. In information from only one member of all, the researchers sequenced some 20 bileach pair, the so-called haploid genome. lion DNA bases. They looked for everyThe researchers assumed that this thing from easy-to-find differences in sinapproach wouldn’t sacrifice much detail. gle bases to much more obscure variations Wrong, says a massive 31-page paper pub- in chunks of DNA sequence that had been lished in the October 2007 issue of PLoS inserted or deleted from chromosomes. Biology by Venter, his colleagues at the All told, the analysis found more than J. Craig Venter Institute in Rockville, 4 million variants between Ven ter’s Maryland, and collaborators from three maternal and paternal chromosomes. This different universities. suggests that humans differ by 0.5%, not According to the study, haploid 0.1%, as suggested by earlier estimates. genomes underestimate the amount of “To understand variation, you really need genetic variation between individuals by a to understand how much there is in the factor of 5. “We’ve just really underesti- genome, and we’ve never really been able mated this,” says Venter. “We all had very to do that head-on,” says co-author Stephen naive assumptions because we didn’t have Scherer, a medical geneticist at the Univerthat much data to go on.” sity of Toronto, Canada. Harvard University geneticist George Scherer hunted through Venter’s Church, an early proponent of the Human genome for copy number variations Genome Project and a leading developer of (CNVs), stretches of DNA that, when sequencing technology, praises Venter and compared to a reference genome, have co-workers. “This is a great study,” says extra or missing chunks. Scherer predicts Church. “We need to have diploid genomes that the rapidly growing number of investo sort out our full inheritance. If I walk in tigators who study CNVs will soon begin to a doctor, it isn’t going to do either of us routinely checking DNA samples against
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Venter’s diploid genome as an additional reference. “You’d be crazy not to,” says Scherer. “It’s like you’d be looking at the data with one eye shut.” Some researchers, including those enthusiastic about the availability of Venter’s diploid genome, question whether it actually sheds new light on the degree of variation that exists among individuals. As Harvard’s Church notes, recent studies of CNVs published by Scherer and others have emphasized the same point (see p. 1315). Venter won’t be the only celebrity to have a published diploid genome for long: James Watson, co-discoverer of the structure of DNA, had his completed in May, and it’s now available on the Cold Spring Harbor Laboratory’s Web site. And the advent of cheaper, faster technologies such as the one used to sequence Watson’s genome means that a steadily increasing number of individuals will soon join the diploid genome club. As more individual genomes are sequenced, privacy questions will inevitably come to the fore. Watson requested that the status of a key gene that predisposes people to Alzheimer’s disease not be disclosed (Science, 30 March, p. 1780). Venter, in contrast, went buck-naked, genetically. The paper includes a lengthy table that lists more than two dozen gene variants he has that have been associated with increased risks for alcoholism, antisocial behavior, tobacco addiction, substance abuse, heart disease, and Alzheimer’s. Venter says he has no concerns about making this information public, stressing that, in the vast majority of cases, traits and diseases are not determined by a single gene. “Will I really get Alzheimer’s and heart disease?” asks Venter. His father was a smoker who died at 59 from sudden cardiac arrest, and his 84-year-old mother still plays golf and sails with him. “Who wins out?” asks Venter. “There’s going to be a different answer in every one of us.” In the end, says Venter, the more people who make public their complete DNA and health histories and traits, the more readily scientists will be able to interpret the stillbaffling human genome. “I don’t think we have anything to fear,” says Venter. “And –JON COHEN we have a lot to gain.”

CREDITS (LEFT TO RIGHT): MATT HOUSTON/AP; J. CRAIG VENTER INSTITUTE

7 SEPTEMBER 2007

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