Genômica humana: os finalizadores do genoma

Published online 16 December 2009 | Nature 462, 843-845 (2009) | doi:10.1038/462843a

Human genomics: The genome finishers

Dedicated scientists are working hard to close the gaps, fix the errors and finally complete the human genome sequence. Elie Dolgin looks at how close they are.

Elie Dolgin

From her windowless fifth-floor office at the US National Institutes of Health in Bethesda, Maryland, Deanna Church has few distractions from the job that lies before her. On her computer sit 888 open 'tickets', or outstanding problems with the human genome sequence. Although that number fluctuates, it's a not-so-subtle reminder that she and her team at the National Center for Biotechnology Information (NCBI) have a long way to go to finish the job started nearly two decades ago by the Human Genome Project.

This is the same project that an international team of scientists spent close to US$3 billion on to complete. In 2000, the scientists announced, to much fanfare at a White House ceremony, that they had finished the draft sequence of the human genome. They waxed poetic about opening 'evolution's lab notebook' when they published the draft the next year1. And they uncorked champagne bottles again in 2003 when the sequence was officially deemed finished2. By then, media outlets were reporting the developments with a twinge of fatigue. "This time it is the real thing, scientists promise," New Scientist reported. Another year passed before the final analyses were published3, and two more went by before the paper detailing the last, fully polished chromosome came out in 2006 (ref. 4).

Still, three years later, Church is hunched over her computer, clicking away at her mouse, quietly clearing up the lingering troubles with the iconic sequence. Some of her tickets, submitted by her collaborators and users from around the world, are reports of missing bits. Others describe stretches in which someone thinks the sequence is mistaken. Still others are unique and unexpected challenges, such as complex DNA rearrangements, that could take years to sort out.

"It's a frustration," says Richard Gibbs, director of the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Texas. "It's an extremely high-quality genome. It's the best there is, period. The problem is that a very small percentage of uncertainties still translates into a significant number of problems."

Church and her colleagues are working to build a solid, accurate reference, but their efforts have revealed how slippery that concept can be. The sequence, for instance, does not represent any one person's genome. It is an amalgam of DNA from different people, both male and female. It was put together this way to maintain anonymity for those who contributed the DNA and to ensure that the sequence represented all humanity — "our shared inheritance", as then-head of the project, Francis Collins, said.

But that shared inheritance is hard to capture. The genomes of two individuals look less alike than many had originally assumed. Rather than following a linear path of 3 billion base pairs with a letter changed now and then along the way, human genomes detour into hundreds of vastly different stretches in which, depending on the individual, millions of base pairs can be deleted, inserted, repeated or inverted.

A finished reference genome — if attainable — will therefore look very different from the project's first renditions. That's where Church and her team of finishers come in. They are striving to smooth out the differences and to develop a more dynamic platform that can capture much of humanity's commonalities and uniqueness. Some say it's a wasted effort now that individual human genomes can be sequenced at a fraction of what it cost ten years ago, but most say the reference is invaluable as a bedrock to support the sequencing of future human genomes.

Resolving the problems in the sequence will not win Church many accolades. She won't meet the president or land any papers in high-impact journals as those who "finished" the genome before her did. And once she puts a ticket to rest, there's always another one waiting. "It's not sexy," she says. "But it's important."
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