Scientists from Baylor College of Medicine and 454 Life Sciences announced Thursday the complete sequencing of the genome of double helix pioneer James D. Watson. The Nobel laureate, chancellor at Cold Spring Harbor Laboratory in New York, is fittingly the first individual to have his or her genome completely sequenced. The sequence revealed among other things that Watson carries a mutated version of the BRCA1 breast cancer gene.

Jonathan Rothberg, founder of 454 Life Sciences (right), presents James Watson with his genome.

Looking fit and resplendent in a cream blazer, Watson said his motivation for wanting the genome sequenced dated back to 1986, when his son Rufus was hospitalized with suspected schizophrenia. “It’s a disease we knew virtually nothing about at the molecular level -- and still know almost nothing,” said Watson. “It seems to me it would be a hopeless task to ever understand schizophrenia or any other complex mental disorder unless we had a complete human genome sequence.”

At a conference in 2005, Rothberg, Gibbs, and 454 Vice President Michael Egholm came up with the idea of inviting Watson to be the first human to have his DNA sequenced. Rothberg had a carefully rehearsed spiel ready to secure Watson’s participation – but he didn’t need it. “I got a phone call,” recalled Rothberg. “Hold for Jim Watson. Jim invited me up [to Cold Spring Harbor’]... I prepared my pitch for hours, for days, how could I convince him to give us his genome? … I walked into his office shaking, and before I could say anything, he said, ‘Yes.’ ”

It was only the arrival of 454’s second-generation machine (FLX) at the end of last year, with significant enhancements in throughput and accuracy, which made “Project Jim” feasible. “As soon as you took my DNA away, I stopped thinking about it,” Watson told Rothberg. “So it was a great pleasure in January [2007] to hear you were having a go at it.”

Sons and Daughters
Watson spoke candidly about the experience of scanning his genome for potentially disease-related mutations. He had initially said he wanted his entire sequence to be put on the Web, but subsequently asked his ApoE4 genotype, which is associated with Alzheimer’s disease, be withheld. “Since we can’t do much about Alzheimer’s disease, I didn’t want to know if I was at risk. My grandmother…died of Alzheimer’s at the age of 84. So I had a one in four chance of sharing the wrong form of that gene.”

However, Watson did reveal that he has “variants which are cancer inducing,” including risk factors for basal cell carcinoma, which he has had since age 28. The precise significance of that DNA variant remains unclear.

Watson also divulged that he has mutations in the so-called breast cancer gene, BRCA1. “My sister had breast cancer at age 50,” Watson explained. “I carry a variant of the BRCA1 gene. I look forward to learning more about that gene.” With his characteristically dry humor, Watson quipped: “I take comfort in the fact it largely affects women. I don’t have a daughter -- I never thought that was a good thing until today.”

Watson said he was thrilled at seeing “the variability of the human genome” and hoped to see many more genomes completed over the next few years. “What I hope is that… I’ll get some advice to take some pill that will make my remaining years of my life more pleasant,” he said.

Asked whether he had considered asking his sons for permission to publish his sequence, Watson said he had but ultimately didn’t think there was much harm in releasing it. But looking ahead, he predicted profound ramifications for the era of personal genome sequencing.

Imagine “[a] family won’t let someone marry their daughter until they look at her prospective husband’s genome. Will your genome complement my daughter’s? It sounds bizarre, but I can imagine that happening in India or Israel... it’s too important to take chances with your children. It sounds like eugenics, but … the aim is to have the next generation healthy,” Watson said.

He added: “I think, discrimination does exist, short or tall, whatever reason, we probably won’t increase the amount of unfair discrimination, but we may explain some of it. If we explain some of it, we’ll have realized we’re unfairly treating other human beings. I think we’ll have a healthier and more compassionate world 50 years from now due to this technology advantage which we’re celebrating here today.”

By the Numbers
Details on Watson’s sequence data were not presented at the press conference. However, Rothberg said that 454 had sequenced a total of 24 billion bases of sequence for 8-fold coverage of Watson’s genome, with a few machines dedicated to the operation over two months. The average read length for the 454 instrument is 250 bases. The total cost of the operation was put at $2 million. The data analysis was performed by Gibbs and colleagues at Baylor.

In a presentation earlier this year, Egholm revealed that about 3 percent of Watson’s sequence did not match the existing reference genome. The “missing” sequence in the reference genome is likely an artefact caused by the use of bacterial cloning and Sanger sequencing. Preliminary analysis of Watson’s genome revealed 1.9 million single-nucleotide polymorphisms (SNPs), 600,000 variants of which are novel. There are also more than 68,000 insertions and deletions compared to the reference sequence, ranging from 3 bp up to 7 kilobases.

Watson will reportedly receive a DVD with his full genome sequence. In the meantime, Gibbs said the sequencing team had submitted a manuscript “to a high-profile journal,” where it was under peer review. The paper will describe the analysis of the sequence and quality control measures. Following Watson’s wishes for the data to be made publicly available, Gibbs said, “they are streaming into the public databases as we speak.”

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