[Emapymosy]

http://www.nytimes.com/2007/05/31/sc...d-gene.html?hp
May 31, 2007
Genome of DNA Pioneer Is Deciphered
By NICHOLAS WADE

The full genome of James D. Watson, one of the discoverers of the structure of DNA in 1953, has been deciphered, marking what some scientists believe is the gateway to an impending era of personalized genomic medicine.

A copy of his genome, recorded on a pair of DVDs, is to be presented to Dr. Watson today in a ceremony in Houston by Richard Gibbs, director of the Human Genome Sequencing Center at the Baylor College of Medicine, and by Jonathan Rothberg, founder of the company 454 Life Sciences.

Dr. Rothberg’s company makes an innovative DNA sequencing machine, the latest version of which proved capable of decoding Dr. Watson’s genome in two months at a cost of less than $1 million, said Michael Egholm, 454’s vice president for research. The sequence was verified and analyzed by Dr. Gibbs’s center in Houston. It was Dr. Gibbs who proposed the idea of sequencing Dr. Watson’s genome.

Dr. Watson has said he will make his entire genome available for researchers to study, with the single exception of his apolipoprotein E gene, the status of which he does not wish to know because it predisposes a person toward Alzheimer’s disease.

Dr. Watson was “the right guy to do first” because of his discovery that DNA is the basis of heredity, Dr. Rothberg said in an e-mail. Dr. Watson was also the architect and first director of the government’s $3 billion human genome project, which completed the first human genome in 2003.

But that genome sequence, at present the standard reference for the human genome, belonged to a composite of anonymous donors from Buffalo, N.Y., and cannot be matched up with medical information from a whole person.

The first two genome sequences belonging to individuals are now being made available to researchers within a few days of each other. One is Dr. Watson’s and the other belongs to J. Craig Venter, who as president of the Celera Corporation started a human genome project in competition with the government.

Dr. Venter left Celera after producing only a draft version of a genome, his own, in 2001, on which the company did no further work. He has now brought his genome to completion at his own institute in Rockville, Md., and deposited it last week in GenBank, a public DNA database, he said.

Dr. Watson and Dr. Venter are both taking a considerable personal risk in making their genomes publicly available. As is probably true for everyone, their genomes are likely to contain mutations that could lead to disease, revealing possibly unfavorable information about themselves and their relatives. Even though the interpretation of the human genome sequence has only just begun, they are, in principle, exposing all their imperfections to public view for the sake of advancing research.

“The complexity of the analysis is such that I’m not worried about people making major discoveries that explain my idiosyncrasies,” Dr. Venter said.

Amy McGuire, a medical ethicist at the Baylor College of Medicine who was involved in the Watson sequencing project, said Dr. Watson and Dr. Venter were following the medical tradition of making oneself the first subject of a new experiment and would incur unknown risks. “I think that both have been motivated by their commitment to the science and genomic medicine and advancing the field,” she said.

Neither Dr. Venter nor 454 Life Sciences will talk in detail about the new individual genome sequences for fear of sanctions from the journals considering publications about them. But both genomes seem to be significantly better in many ways than the present reference standard.

Both are diploid genomes, meaning that they include the DNA sequence in the chromosomes inherited from both parents, whereas the reference genome completed by the Human Genome Project did not capture these differences.

Some 3.5 percent of Dr. Watson’s genome could not be matched to the reference genome. One reason may be that the project scientists had to amplify human DNA by growing it in bacteria and may have lost many regions of human DNA that are toxic to bacteria, said Michael Egholm, 454’s vice president for research. The 454 sequencer skips the bacteria stage entirely and is free of this source of bias.

Dr. Venter said 454 would have assembled Dr. Watson’s genome by comparing short lengths of analyzed DNA to the reference sequence, so the company might not have detected any structural errors present in the reference assembly.

Dr. Venter said his new genome has been assembled from scratch. There were many more differences than he had expected, including in single units of DNA that were extra or absent. “It’s clear we have grossly underestimated the extent of human variation,” Dr. Venter said.

Both he and Dr. Egholm said it would be valuable to compare the two new genomes, especially as they were generated by different methods. “We are looking forward to getting the data and layering it on my genome,” Dr. Venter said of his former rival’s genome sequence.

Dr. Venter’s new genome is “a real tour de force” and could become the new reference genome, said a researcher who heard him give a recent presentation on its technical details.

Some scientists believe that it will be medically useful to sequence patients’ genomes when the cost of sequencing falls to around $10,000 or less. Dr. Egholm said that with improvements already under way, the 454 sequencing machine will soon be able to sequence a human genome for $100,000. The cost of sequencing has been dropping so fast in the hands of groups like 454 Life Sciences and Solexa Inc. that some technologists predict the $10,000 genome will be attained in a few years.

At a news conference in Houston today, Dr. Watson urged that more human genomes should be sequenced, including those of successful people as well as those of medical interest. “I just want the information assessed as soon as possible,” he said.

Copyright 2007 The New York Times Company