Size doesn't matter

As scientists unveil the human genome findings, it turns out we have a lot fewer genes than we'd thought, and not many more than a fruit fly.

By Arthur Allen

Published February 13, 2001 5:27PM (EST)

If fate is truly written in our genes, it must be some cosmic scriptwriter's idea of a joke. Because our genetic code is awfully similar to that of the fruit fly.

In a Washington hotel room jammed with Nobel laureates and other brainiacs, two competing groups of researchers presented the 3 billion letters of the human genome to the public Monday with a whimper of surprise. Human genes, it turns out, are remarkably similar to those of lower life forms. Whatever it is that makes us unique is probably not solely in the code that DNA uses to instruct our cells to make proteins.

The biggest surprise of the rough analysis of the first sequencing of the human genome was the number of genes it contains. For years scientists had been predicting that human DNA would contain somewhere between 100,000 and 140,000 genes. It turns out we may have as few as 26,000 -- a genome about the size of a corn plant, with roughly a third more genes than the fruit fly.

When it comes to numbers of genes, size definitely does not matter. Not only that, but our genes look pretty similar, in structure, to most of the genes in fruit flies, roundworms and even brewer's yeast.

For example, we seem to have only about 300 genes that mice lack. We also have about 200 genes that have come down to us from bacteria. Some of those genes have important functions in the brain -- one, for example, is key to the processing of certain antidepressant drugs.

It turns out only 1 percent of our DNA is what we think of as genes -- i.e., chemical components that help build proteins, the building blocks of our bodies; scientists had thought at least 3 percent of our DNA was coded for proteins. Half of the rest of our DNA is made up of "jumping genes," semidecrepit strings of DNA that migrate like viruses in and out of our genomes with mysterious purpose.

People used to call jumping genes and other noncoding segments "junk DNA." Nobody was calling it junk on Monday. "Probably these other regions of DNA are important," said MIT's Eric Lander, a leader of the decoding effort. But neither he nor anyone else was all that sure how.

If nothing else, Monday's news will necessitate an overhaul of the bromides commonly used to describe our relationship with our DNA. We should no longer be identifying ourselves by "what's in our genes." It's not that we aren't biological beings. But our I.Q. and hair color and foot tapping and propensity for diabetes, and all the rest, are clearly caused by a mishmash of things -- not just genes and environment, but also interactions among genes and proteins and all the noncoding DNA, whose functions are still shrouded in a good deal of mystery.

There was something breathtaking about this event. Maybe it was the fact that all these intensely intelligent people, with the most modern machines at their disposal, had been taken by surprise by what they diligently found. In a way, it was science at its best.

As an enormous 15-foot banner filled with tiny script was trotted out before the podium -- a graphic representation of the DNA sequence and genes on a single chromosome -- the scientists expressed amazement at what they'd accomplished.

"We felt like Lewis and Clark, crossing new mountain ranges and entering new valleys, seeing new rivers," said Robert Waterston, who headed one of the large sequencing labs, at Washington University in St. Louis. "Even two years ago I didn't know if I'd live to see this day."

One of the groups presenting its findings Monday was a U.S.-led, international consortium of 20 major laboratories, some of which have been decoding DNA for 12 years or more. The other was Celera, the private biotech firm led by renegade scientist Craig Venter.

Surprisingly, it was Venter -- who engendered the envy and hatred of geneticists around the world three years ago when he announced he would beat the consortium to the complete sequencing of the genome -- who made the politically astute connection between the data and what they mean sociologically: a blow to genetic determinism.

"The smaller number of genes supports the notion that we're not hard-wired," said Venter. "We now know that the notion that one gene leads to one protein and perhaps one disease is false. One gene leads to many different protein products that can change dramatically after they've been produced. We now know that regions of the genome that are not genes may hold the keys to the complexity that we have in ourselves. We know now that the environment acting on biological steps may be as important in making us what we are as the genetic code."

"It's clear that genes can't answer all, or even most, questions about human biology," he concluded.

Wunderkind Lander, who heads the consortium's largest sequencing laboratory, at MIT, concurred. "We have far fewer genes than we expected -- less than two times more than the fruit fly," he said. "What a comedown." But as Lander explained it, "We are far more complex than the fruit fly, and we manage it because our genes can make more proteins, and more proteins with multiple roles. Regulatory parts of DNA add to the complexity."

Even as the scientists presented their exciting findings, a parallel drama of human ambition was playing itself out -- with two teams of scientists and dueling science magazines squaring off. Science, the leading American scientific publication, this week is running Venter's version of the genome. Nature -- Science's British archrival, which published James Watson's seminal 1953 paper on the double helix -- is running data and analyses presented by the public international consortium.

In an arrangement reminiscent of the early Khrushchev-Kennedy meetings, the middle of the stage at Monday's news conference was shared by Venter and Francis Collins, director of the National Human Genome Research Institute at the National Institutes of Health.

Collins and Venter have often been at odds in the past. Venter has suggested, in so many words, that Collins, a loping, pedantic Virginian, is a flunky bureaucrat afraid of competition. Collins, meanwhile, has claimed that Venter, a millionaire many times over, is doing sloppy science while trying to privatize the patrimony of mankind.

But they kept their catty remarks to a minimum Monday. In fact, they seemed genuinely happy there were two copies of the genome out there -- especially since they seemed so similar. "This is a rare moment in science when you get virtually simultaneous confirmation of results," Collins said. "This means we can all build on this data."

For those who equate private biotech ventures with a fast-buck brushing off of the subtleties of science, it was instructive to hear that Venter's interpretation of the data put much more stress on its complexity.

On the other hand, Collins, a Christian in the C.S. Lewis vein, described the genome as the "first draft of the book of life ... written in the mysterious language of all the ages ... some would say the language of God."

Venter suggested that fewer genes would mean that diseases are likely to be harder to understand, because it was clear that so much other, nongenetic stuff was causing them. Collins voiced the more provincial view that fewer genes would make it easier for geneticists like him to find the ones responsible for diseases. "The haystack just got a lot smaller," he said.

Venter also stressed that he thought the sequenced human genome would "not aid those who want to perpetuate racial prejudice." Celera got the DNA for its sequencing effort from three women and two men, including African-American, Chinese and Hispanic donors. The donors' DNA was 99.99 percent similar, said Venter. Differences among members of the same "race" are far larger than those between races.

One couldn't help feeling that Monday was a vindication for Venter, who was a surfer dude until he went to Vietnam and witnessed the horrors of war and the frailty of the human body as a medical corpsman.

The international consortium and Venter's group used different techniques to sequence human DNA. The consortium took small pieces of DNA and painstakingly sequenced them. Venter's "shotgun" approach was to blast apart an entire complement of DNA, sequence the bits and then reconstruct them using computer programs.

But Venter ended up relying heavily on public databases, which his critics claimed undermined his claims of success. Also, in trying to map genes on the 46 chromosomes, both Venter and the consortium relied on DNA libraries established by publicly funded scientists.

Back in the early 1990s, when Venter quit the NIH and went private with the automated DNA sequencing programs he'd developed, Watson -- who headed the NIH's genome institute at the time -- famously dissed him. "Any monkey can do what he's doing," Watson said.

Watson, who co-discovered the double-helix structure of DNA back in 1953, was there today, his mad cornflower-blue eyes flashing over the flowered tie he had tucked into his belt. He displayed no animosity toward Venter at Monday's event. Instead, the men shook hands.

Chatting with a few reporters, Watson said competition had been good for the sequencing effort. "This is a historic day -- we have the instruction book," he said, adding: "I'd like to use this knowledge to cure senility before it gets me."

Arthur Allen

Arthur Allen writes on health, science and other issues for Salon. He lives in Washington.

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