Mom's Genes or Dad's? Map Can Tell.
One Man's DNA Shows We're Less Alike Than We Thought

By Rick Weiss
Washington Post Staff Writer
Tuesday, September 4, 2007

Scientists have for the first time determined the order of virtually every letter of DNA code in an individual, offering an unprecedented readout of the separate genetic contributions made by that person's mother and father.

By providing a detailed look at maternal and paternal DNA strands, rather than the blended composite that was yielded by the 2001 Human Genome Project, the work offers the clearest snapshot yet of just how different those two contributions can be. Assuming the newly decoded sequence is typical, as scientists presume it is, there are five times as many differences between individuals' DNA as was previously thought.

Of more practical import, the ability to create such a detailed genetic profile with relative ease suggests that it may not be long before people of ordinary means will be able to have their complete DNA codes spelled out, scientists said. That could tell a lot about a person's health risks, because such a profile would include not only the few genes that significantly increase the likelihood of getting certain diseases but also the many "lesser" genes that pose modest risks individually but that together have the bulk of impact on health.

For better or worse, the advance also stands to bring science to the pastime of guessing which parent deserves blame or credit for passing along certain traits.

"This is the ultimate form of genealogy. You'll have incredible information about yourself," said Stephen Scherer of the Hospital for Sick Children in Toronto, who was part of the multimillion-dollar project described in today's issue of the journal PLoS Biology. "I wouldn't be surprised if Internet-based browsers pop up before long that allow you to compare your genome to others."

The genetic sequence that was unveiled in all its naked detail belongs to J. Craig Venter, the Maryland scientist who led the project at the J. Craig Venter Institute in Rockville. It carries significantly more information than the two previously sequenced human genomes, released with great fanfare six years ago.

Those sequences -- one assembled by Venter and co-workers at Celera Genomics and the other by federally funded scientists -- were composites of several people. And although they were referred to as complete, they were in fact half-genomes -- or "haploid" -- containing a mom-and-pop mosaic of the 3 billion DNA letters found on just one set of the 23 chromosomes paired in every cell.

Not emphasized in 2001 was the fact that people have in their cells two versions of each of those 23 chromosomes, one from each parent -- a "diploid" genome. And increasingly scientists are finding that the difference between being healthy and being sick has a lot to do with how those genomes interact.

From Dad, a person may inherit a version of a gene that predisposes her to a disease, but from Mom she may inherit a protective version -- or an entirely different gene elsewhere on the genome that counteracts Dad's contribution.

"I might want to know: Do I have an additive risk from the genomes from both my parents, or did I get some helpful ones from her that counteract the ones from him?" Venter said.

Sorting out those details has been daunting.

"It's very easy to start mixing up the readouts from each parent because they are so similar," said Samuel Levy, who led the research with Venter. But new sequencing technologies and computational methods allow scientists to chop a person's DNA into pieces and reassemble the maternal and paternal segments independently.

Challenges remain. Although Venter's method produces a 6 billion-letter diploid genome, it does not produce complete paternal and maternal genomes of 3 billion letters each. But it does produce chunks of DNA that are hundreds of thousands of letters long, all from one parent or the other, allowing the most meaningful maternal-paternal comparisons yet. Previous such snippets topped out at about 13,000 letters, too few to be medically informative.

And unlike the Human Genome Project, whose focus on individual letters made it blind to many larger mutations or variations involving hundreds or thousands of letters, the newer methods that Venter used capture all sizes.

The new work showed, for example, that Venter lacks one parental copy of the gstm1 gene, known to have a role in neutralizing toxins and carcinogens -- perhaps helping to explain why he has had asthma and skin cancer, Levy said.

All told, 44 percent of the genes Venter received from one parent were at least a little different from those he inherited from his other parent, and a third of those variations had never been seen in studies of those genes in other people. Although most of the differences may have no discernible health effect, the finding indicates that humans are more genetically diverse than was thought.

Specifically, older analyses suggested that humans' genetic codes are, on average, 99.9 percent identical (or 0.1 percent different), while the new estimate comes in at 99.5 percent (or 0.5 percent different). The true number may be as low as 99 percent, Venter said.

That means each person is the product of more genetic diversity -- and more biological negotiation and compromise during fetal development -- than was believed.

Venter is not alone in his effort to create personalized sequences, and at least one competitor offered a more tempered view of the work.

"I would call this a small, quantitative milestone," said George Church, a Harvard University professor of genetics who is also racing to produce cheap genomes.

He said Venter's sequence, like previous ones, still has many gaps, was cumbersome to make and, at a cost of tens of millions of dollars, was still way too expensive.

He also noted that recent research by Scherer had already suggested that human genetic variability is probably at least 0.3 percent, not the 0.1 percent floated in 2001, which Venter uses for comparison. So Venter's new finding of 0.5 percent amounts to something less than a sea change, Church said.

But Church sings with Venter's choir on the vast benefits that could come from inexpensive personalized genome sequencing.

Cost trends are encouraging. The first 3 billion-letter genome sequences took more than a decade to complete and cost billions of dollars. During Venter's latest project, costs dropped precipitously, and today, several scientists said, an entire diploid genome could probably be done for about $100,000. Some predict that a $1,000 genome will be available within five years.

Venter and others hope that at that point many people will get sequenced and, as Venter has already done with his own, will post their genomes on public databases along with their medical information and family history. That will allow computers to start drawing connections between gene patterns and diseases.

Given the risks involved in such personal revelations, including job discrimination and health insurance woes, no one knows how many people will take that route.

"It's going to be a very interesting social experiment to see the way people go," said Scherer, who has predicted that before long, parents of newborns will leave the hospital with a six-gigabyte computer file of their screaming bundle's genome loaded on their BlackBerrys. He said that people's fascination with technology -- and with themselves -- will prevail.

Among the ethics questions raised by the prospect of people posting their genomes is whether they have an obligation to kin who may not want their familial patterns put on display.

Asked if he had consulted his living parent, his three siblings or his 30-year-old son before posting his genome, Venter said: "I've not asked any of their permission, but we've discussed it all extensively. Their main response is not "Oh, my God.' It's 'Can I get my genome done, too?' "

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