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http://www.nytimes.com/2002/06/11/health/genetics/11GENO.html

Human Genome Sequence Has Errors, Scientists Say

By NICHOLAS WADE

ased on a new genetic map of the human genome, Icelandic scientists say more than 100 large-scale corrections are needed in a recent draft of the human genome sequence produced by a public consortium of academic centers in the United States and abroad.

Corrections are not surprising in a draft that is continually being improved, but the presence of so many large-scale errors raises the question of whether the genome will really be finished by its target date next April, said Dr. Huntington F. Willard, a geneticist at Case Western Reserve University. Leaders of the Human Genome Project are aiming to declare it complete then, in conjunction with the 50th anniversary of the publication of the article by James Watson and Francis Crick on the double helix structure of DNA.

Dr. Willard, who served last year as president of the American Society of Human Genetics, said the new map "points up all sorts of errors in the human genome sequence assembly."

He added, "This isn't surprising to us in the field, who have tried to use the databases and inevitably find that for the regions we know best, the assemblies are often wrong, but may be surprising to the public at large."

A spokesman for the National Institutes of Health's human genome office said that the project had made use of genetic maps to correct the genome sequence and that because 80 percent of the genome was now finished, "such misassemblies should be increasingly rare."

The errors were discovered by Decode Genetics, a company based in Reykjavik, Iceland, that is hunting for the genetic roots of common diseases by using special qualities of the Icelandic population.

Needing an accurate genome sequence for its gene-hunting program, Decode created a so-called recombination map of the human genome. The map, which tracks how sections of two parents' chromosomes are exchanged, or recombined, in the chromosome bequeathed to a child, yields the correct order of the sections on the chromosome. The company said it would make all the map's genomic data, though without the patients' names, available to researchers.

The Decode map indicates that numerous large sections of DNA were in the wrong order or flipped head-to-tail in the December 2000 version of the consortium's draft. The April 2001 version corrected some errors but introduced others. The August 2001 version, the latest analyzed, was a "real improvement," the Decode scientists say, but still contained 104 large-scale errors, according to their recombination map.

The authors of the Decode article, posted yesterday on the Web edition of Nature Genetics, include the company's chief statistical geneticist, Dr. Augustine Kong, and its founder, Dr. Kari Stefansson.

Dr. David Haussler, a computer scientist at the University of California at Santa Cruz, who is overseeing the assembly of data from the consortium's DNA sequencing centers, said he had used two genetic maps to help put the DNA sections in the right order. But these maps, known as the Genethon and Marshfield maps, suffered from small sample size and lacked good resolution. "So I am not surprised that with substantially more accurate genetic map data some further corrections to the assembly are suggested," he said.

Dr. James L. Weber, a geneticist at the Marshfield Medical Research Foundation in Marshfield, Wis., said Decode had found nothing to correct in the sequence of chromosomes 20, 21 and 22. These chromosomes, the three smallest, have been finished, showing that chromosome sequence can be tackled without a fine resolution genetic map. The new map from Decode "will certainly help the sequencers finish their chromosomes," he said.

Celera Genomics, a company that raced the public consortium to produce a first rough draft of the human genome, is not attempting to produce a complete version.

Having large sections of DNA in the wrong place or orientation probably makes little difference to biologists searching for genes with a particular sequence of DNA letters. But it throws off the statistics of gene-hunters like Decode Genetics who are trying to map a disease-causing gene to a particular section of the genome.

A spokesman for the National Institutes of Health office, which pays for the human project, said, "We are on track to complete the final and highly accurate version of the human genome sequence in April 2003."

But Dr. Willard said the draft human genome sequence, though "extraordinarily useful," was a long way from complete. Referring to leaders of the rival efforts to sequence the human genome, he said: "As much as Francis Collins and Craig Venter and others like to call the sequence complete, it is still sketchy in places and likely to remain so for some time. To call it complete, as will happen next April to match the 50th anniversary of the Watson-Crick paper, is a bit of a sham."

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