The structure of DNA was first publicly described 55 years ago at Cold Spring Harbor Laboratory (CSHL) on Long Island in New York by James Watson. Thursday night, the now 80-year-old Watson opened up the 2008 Personal Genomes meeting at CSHL by telling the story of the origins of the Human Genome Project, which he headed from 1990 to 1992. In 2003 the Human Genome Project produced a (nearly) complete reference DNA sequence of a human genome that is now essential to basic and applied human genetic research.

These days, Watson pointed out, scientists are able to read the DNA letters of the double helix so quickly and inexpensively that it is becoming practical to sequence the genomes of large numbers of people. With this progress comes a flood of research questions, technological challenges, and hope that these insights from the lab will translate into advances in personalized medicine.

Watson was followed on Thursday night by Francis Collins, who also followed him as director of the Human Genome Project, and later by Mary-Claire King, the renowned breast cancer geneticist from the University of Washington. Collins pointed out that health care costs have risen steadily over the years to the current level of roughly 20% of the US GDP. How much of this is spent on treatments that might have been identified as unnecessary with the availability of genetic information? He suggested that widespread genomic sequencing and analysis could lead to the discovery of the genetic causes of common diseases, such as lung cancer and Type II diabetes, for which some genetic links are now known, but much more remains to be learned.

Mary-Claire King considered breast cancer as a case study for personalized medicine. In the case of breast cancer, she noted, there are more than a thousand known mutations in each the genes BRCA1 and BRCA2 that can predispose a woman to the disease. Many of these are unique to specific families, or specific localities — she gave the example of one BRCA mutation endemic to a Norwegian valley. King illustrated through recent breast cancer studies that linking newly-discovered mutations to disease is a formidable technical challenge, but emphasized that the rewards for succeeding in doing so would be immense: roughly 5% of new breast cancer cases in the US each year — around 10,000 — are linked to known BRCA1/2 mutations, and thus might have been prevented through such measures as prophylactic mastectomy.

Friday moved into reports from the trenches. The morning session consisted of talks by researchers from major genome sequencing centers and from the companies behind the so-called “next generation” sequencing methods that underlie this conference. The new technologies, namely Illumina’s Solexa, 454’s FLX, and ABI’s SOLiD, follow the same general plan as the venerable Sanger sequencing method: scan short fragments, or ‘reads’, of DNA letters, and then reconstruct the original sequence from the reads. They just do it much faster than before, mainly by doing the scanning of many reads in parallel. Much of the concern these days is on the reliability of these new techniques — considering that a single changed DNA letter can mean the difference, for example, between getting Alzheimer’s or not — and so the presentations tended to focus on technical topics like error rates and comparisons across platforms. Even so, there were suggestions that some exciting new scientific findings might be around the corner; Richard Gibbs of Baylor showed early data from their sequencing of a HapMap trio (a father, mother and child) suggesting that the human mutation rate might be much higher than previously thought. And Elaine Mardis from Washington University showed that her lab had been able to find mutations unique to tumor tissue in a lung cancer patient. Known as somatic mutations, they had arisen in the patient during their lifetime, and were not found in non-tumorous skin tissue from the same patient. Her study did not show that one of these mutations had actually caused the cancer, but the demonstration that such changes may even be found is intriguing.

The afternoon session moved into the imposing task of storing, processing and interpreting the flood of data these new technologies generate. Paul Flicek from the European Bioinformatics Institute produced that rarest of things, the funny bioinformatics talk, in describing the travails of dealing with the 100 terabytes (that’s 100,000 gigabytes, or 100 million megabytes) generated so far by the pilot phase of the 1000 Genomes Project , and the specter of dealing with a petabyte (1,000 terabytes) of sequence data. Carlos Bustamante of Cornell described some of the insights into human evolutionary history that have made possible by the DNA deluge, including using sequence data to infer possibly the most detailed models yet of historical human population size and migrations. He also described his lab’s and John Novembre’s recent findings on the relationships between geography and human genetics; a topic we’ve blogged on recently at the Spittoon here and here.

There’s another big day of talks to come here at CSHL. I’m glad to be here keeping up to date on the latest research, so we can incorporate it into 23andMe, and to show off the site to a bunch of people on the cutting edge of genetics.

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A new paper by Venter and colleagues at his Rockville, Maryland-based institute provides a prime example. Writing in the September issue of Clinical Phamacology & Therapeutics, Venter et al. argue that knowing how genetic differences between ethnicities affect patients’ reactions to certain medications isn’t good enough. To make sure patients get the best healthcare, they say, doctors should be looking at how each person is likely to respond to a particular drug regimen based on his or her unique genetic makeup.

“Even the term ‘Caucasian’ can be deceptive,” the authors noted. “If a self-identified Caucasian originates from a founder population in which certain disease-specific alleles occur at higher frequencies (e.g. Quebec French Canadians or Ashkenazi Jews), his or her doctor may miss an important aspect of the patient’s medical history. One’s ethnicity/race is, at best, a probabilistic guess at one’s true genetic makeup.”

To further emphasize the differences between people within the same ethnic group, the authors compare the publicly available genome sequences of Venter himself and Nobel Prize winner James Watson, focusing on six genes involved in drug metabolism.

One of those genes revealed a substantial difference between the two men. CYP2D6 is involved in the metabolism of various drugs for high blood pressure, heart arrhythmia and depression. Venter’s genotype indicates that like most Europeans he is an “extensive metabolizer” of such drugs; but Watson’s genotype puts him in the “intermediate metabolizer” category, which is more common among Asians.

Using race as a guide, the authors noted, a physician would have no reason to expect Venter and Watson to react differently to drugs that are metabolized by CYP2D6.

Venter and his colleagues conclude by emphasizing the need for personalized health care based on genomic information, adding that the cost to do so is dropping rapidly.

“Given the complex nature of drug responses, it would ultimately better serve all to dissect the relevant factors of a drug response instead of categorically stereotyping a culture with a presumed genetic background.”

Images: Venter photo by Michael Janich; Watson photo courtesy of the National Library of Medicine

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You may have seen our recent posts about DNA-themed activities and events for DNA Day. But what is DNA Day all about anyway?

DNA Day was created in 2003 by concurrent (Senate and House) congressional resolution to celebrate two important milestones in the study of genetics: the 50th anniversary of the description of the double-helix structure of DNA by James D. Watson and Francis H.C. Crick and the completion of the Human Genome Project.

Watson and Crick

On April 25, 1953 James Watson and Francis Crick published their description of the structure of DNA in the journal Nature. This report is considered one of the greatest scientific contributions of the last century. In 1962 Watson and Crick, along with Maurice Wilkins (another scientist who was involved in solving the structure of DNA), won the Nobel prize in Physiology or Medicine for their work.

Biographies of each man, their Nobel lectures, and other resources are available at the Nobel Foundation’s website.

Rosalind Franklin, whose x-ray images of DNA were critical to solving its structure, was not included in the Nobel prize given to Watson, Crick and Wilkins (Franklin passed away in 1958 and the award is not given posthumously). You can learn about her career and how her work contributed to the solving of the structure of DNA at Nova’s online exhibit “Secret of Photo 51“.

Human Genome Project

The Human Genome Project, completed in 2003, was a 13-year endeavor coordinated by the U.S. Department of Energy and the National Institutes of Health. Scientists from around the U.S. and the world contributed to one of the greatest feats of science ever.

The goals of the Human Genome Project were to

• identify all of the approximately 20,000-25,000 genes in human DNA,
• determine the sequences of the 3 billion chemical base pairs that make up human DNA,
• store this information in databases,
• improve tools for data analysis,
• transfer related technologies to the private sector, and
• address the ethical, legal, and social issues (ELSI) that may arise from the project.

If you really want to get into the data, the NCBI Human Genome Resources page offers tons of information about the human genome – you can even download the sequence.

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