June 13, 2007 | Scientists from Baylor College of Medicine and 454 Life Sciences have presented double helix pioneer James D. Watson with a portable hard drive of “the first personal genome.” Watson received his DNA sequence in Houston from Jonathan Rothberg, founder of 454, and Richard Gibbs, co-director of Baylor’s Human Genome Sequencing Center. “There was too much data to fit on a DVD,” said Gibbs.
Looking fit and resplendent in a cream blazer, the 79-year-old Watson said he’s wanted the genome sequenced since 1986 when his son Rufus was hospitalized with suspected schizophrenia. “It’s a disease we [know] virtually nothing about at the molecular level,” 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.”
Rothberg and Gibbs hatched the idea of inviting Watson to have his genome sequenced back in 2005. “Jim invited me up [to Cold Spring Harbor],” Rothberg recalled. “I walked into his office shaking, and before I could say anything, he said, ‘yes.’” Watson says he’d forgotten about the project until he heard that 454 had embarked on the sequence, thanks to the enhanced throughput and accuracy of its second-generation FLX instrument.
Watson previously agreed to deposit his sequence into the public domain, only asking that his ApoE4 genotype, associated with Alzheimer’s disease, be withheld (Watson’s grandmother died from the disease). “Since we can’t do much about Alzheimer’s disease, I didn’t want to know if I was at risk,” he said. But he did reveal that he has “variants which are cancer inducing,” including basal cell carcinoma, which he has had since age 28.
The sequence analysis was conducted at Baylor by Gibbs, David Wheeler, and colleagues, who identified 23 known disease-causing mutations. For example, Watson carries a mutated version of the hereditary breast cancer gene, BRCA1. “My sister had breast cancer at age 50,” Watson explained. “I carry a variant of the BRCA1 gene.” 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 to see “the variability of the human genome” and hoped to see many more genomes completed over the next few years. “I hope ... I’ll get some advice to take some pill that will make my remaining years of my life more pleasant,” he said. He also hopes to see major programs launched in cancer diagnostics and mental illness.
But personal genome sequencing also brings enormous ethical challenges. Imagine, he said, “[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.” He ended on an upbeat note: “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.”
Rothberg says 454 sequenced 24 billion bases providing 8-fold coverage of Watson’s genome. A few instruments were dedicated to the project over two months, producing 106 million reads at an average length of about 230 bases. The total cost of the project was put at $1 to 2 million. 1.3 percent of Watson’s genome did not match the existing reference genome. (A recent CHI conference presentation by 454’s Michel Egholm revealed the existence of more than 600,000 novel SNPs, and more than 68,000 insertions and deletions compared to the reference sequence, ranging from 3 bp up to 7 kilobases.)
Gibbs said the 454/Baylor team has submitted a manuscript “to a high-profile journal,” where it is under review. Watson wants the data to be made publicly available, so Gibbs said, “they are streaming into the public databases as we speak.”
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