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Venter Institute Increasing Human Reference Genome by 3x; Will It Empower Genomic Research?

NEW YORK, Dec. 16 (GenomeWeb News) - The J. Craig Venter Institute's Joint Technology Center has been working to complete a roughly 3x additional coverage of Celera's human genome, which, if published, could be used as a reference genome for SNP studies and other comparisons against the sequence generated by the Human Genome Project, GenomeWeb News has learned.


Combined with the approximately 5x coverage originally generated by Celera, the JTC's 3x effort, which the center calls the Human Reference genome, will bring the sequence to approximately 8x coverage --- or to roughly the same coverage as the HGP's sequence.


JTC officials have always said the center would perform human genome re-sequencing. And, according to a Venter Institute spokesperson, the center continues to do this kind of research. But if JTC completes the 3x coverage and publishes its results --- the project was to have been completed this month, but had been overshadowed by other research --- it would mean that scientists could get a second "complete" human genome to compare against the public consortium's sequence. This resource, in turn, could play an important role in advancing genomic-based drug discovery.


"From a scientific viewpoint, the more human genomes we can sequence, the better," said Rick Wilson, director of the Washington University School of Medicine's GenomeSequencingCenter.


Celera's original sequence is available to researchers after completing a click-through agreement on the company's  website. Earlier this year, Celera, whose sequence is principally Venter's DNA, said it  planned to deposit its original 5x data in GenBank.


According to a presentation from a JTC oversight committee meeting distributed last November and recently obtained by GenomeWeb News, the center had budgeted to sequence 11 million lanes of a genome called "Human Ref," an abbreviation for Human Reference genome. Eleven million lanes of the genome roughly equates to 3x coverage.


The project, which is labeled "Internally Funded," was scheduled to run from November 2003 through December 2004. As of the date of the presentation --- Nov. 21, 2003---the JTC had received a "new work order" for 500,000 lanes, and had budgeted to sequence the balance of the roughly 11 million lanes during the remainder of the 13-month period.


Two months later, in a mid-January oversight committee meeting presentation also obtained by GenomeWeb News, the JTC said it had "completed [roughly] 4.9 million" human traces --- or roughly 1.5x coverage --- and expected to "resume [the Human Reference] sequencing" after other projects had been worked on. At the time, the presentation said JTC will "need another work order in 1-2 weeks."


Asked this week to comment on the status of the project, a Venter Institute spokesperson said that, while the research may have been overshadowed by other work at the JTC, "more money has been approved to continue human gene re-sequencing work."


"Right now and lately, the larger focus [at JTC] has been on" other projects, she said, referring to ongoing research into environmental genomics and synthetic biology, as well as certain projects at TIGR. "I would anticipate at this moment that, going forward, that might change.


"In a nonprofit research institute, you have to look at how to allocate your resources. As grants get funded on various projects, [work on] a particular project need to increase," the spokesperson said. She added that "more money has been approved to continue this and other projects. It's an ongoing project that has been receiving board approval to continue."


Asked whether she was talking specifically about the project to increase the Celera genome by 3x, the spokesperson said: "It's human gene re-sequencing, and there are a number of off-shoot projects under that umbrella. That was what the funding was for - under the broad heading of human gene re-sequencing."


Just Whose Genome?


Though Celera had maintained since the start of its race with the Human Genome Project that its data had been based on 20 donors from five ethnic groups, Venter in the spring of 2002 disclosed in a television news program that the DNA on which the sequence was based is principally his own.


As GenomeWeb News has since reported, the genome-sequencing community had largely known about this before Venter's appearance on the television program 60 Minutes II, and before the New York Times reported 10 days later that "the genome decoded [by Celera] was largely" Venter's. The paper went on to say that of the genome that Celera had been sequencing, "Venter's is recognizable as the largest contribution."


"Venter is at present the only person whose genome has been largely sequenced," the Times reported. However, the exact role that Venter's DNA played in the Celera genome is a secret; Venter maintained in the article that "only me and two other people" know the codes to the five Celera donors.


JTC's effort to increase to approximately 8x the coverage of this genome was met with different views in the genome-sequencing community. Some genome scientists believed that the project could help research into human comparative genomics, and shine a brighter light on the SNPs and other gene variations that could be used as a foundation for pharmacogenomics-based drug and diagnostic discovery.


But they wondered how researchers might be able to compare the Celera genome and the public consortium's genome given the fact that both comprise DNA from several individuals. And since this particular re-sequencing project has not yet been made public, and it is unclear whether or when it will be published, these questions and their answers are speculative in nature.


"Just how much of this is increasing [by] 3x? Is it just one sample, for example, Venter's DNA? Or are [JTC researchers] increasing all their internal individual DNAs to 8x coverage?" George Grills, director of DNA sequencing at Harvard-PartnersGenomeCenter, said in an interview. "If not, is it some 3x, some 5x, some 8x? Just how are [researchers] going to compare it?"


WashU's Wilson, who said that, generally, the more human genomes that are sequenced, the "better," said "we probably won't learn very much from just incrementally more sequence coverage on a second genome, so I'm not sure that this effort represents much of an advance."


Rather, he said, having low (1x-2x) coverage sequence "from many more genomes representing multiple ethnic groups" would be "more useful." He said these kinds of data "would be very valuable as a means for studying human genetic variation on a large scale."


Asked if there are any genomes other than the HGP sequence that can currently be referred to as a human reference genome ---if there is, in fact, another human genome sequenced as many times as the public consortium's genome --- Wilson said: "I don't know of any others at present." Wilson had not heard of the JTC project when GenomeWeb News interviewed him.


According to Eric Lander, director of the Broad Institute, "With the HGP sequence as a finished reference genome, the question is now: How do other genomes vary from it. This involves comparing many genomes to look for variation."


Lander, who also had not heard of the JTC project when GenomeWeb News interviewed him, said that "it's not clear how deep coverage of a single genome is very helpful in this regard: it's just one of many genomes." Lander added that he HGP sequence is "way past" 8x coverage.

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