or the professional news media, bad news is often best, but when it comes to scientific research good news is welcome, never more so than in the paper that has stormed to #1. The DNA sequence of human chromosome 22, published last December, foreshadowed this summer's announcement of the Working Draft of the entire human genome, and has gathered an astonishing number of citations in a very short time.

Why? Ian Dunham, of the Sanger Centre of the Wellcome Trust, outside Cambridge, U.K., coordinated the effort of the huge team working on chromosome 22. He acknowledges the "celebration that it had been done," but gives Science Watch an additional reason for the interest. "A lot of people in different fields—bioinformatics, molecular biology, and so on—have been waiting for a very long piece of human sequence in order to extrapolate to the rest of the genome." As soon as they had the sequence, Dunham says, those researchers "jumped on it and analyzed it in many different ways which we couldn't do at the time of publication because there were so many other things we had to do. So it acted as a model." Better estimates of the finishing time of the Human Genome Project, studies of repeated DNA sequences, and other somewhat arcane pieces of research were the rapid result.

But chromosome 22 is also of interest as home to a swath of developmental abnormalities acronymically referred to as CATCH 22—Cardiac defects, Abnormal facial features, Thymus underdevelopment, Cleft palate, and Hypocalcemia—caused by defects in chromosome 22. The sequence of chromosome 22 has given medical researchers new insights into the disorders. Peter Scambler, Professor of Molecular Medicine at the Institute of Child Health and Great Ormond Street Hospital for Sick Children, London, has been working closely with Dunham's group from the outset. One of Scambler's interests is DiGeorge syndrome, part of the Catch 22 parcel of abnormalities. "The sequence," Scambler tells Science Watch "has helped us understand this complex syndrome by allowing us to do experiments you couldn't do in people."

DiGeorge syndrome is a largely sporadic mutation that affects about 1 in 4,000 births. Although its severity varies, most patients are missing a large chunk of chromosome 22, typically about 3 million base-pairs. "That's over 100 genes," Scambler says, "and we don't know them all yet." With the human sequence known it was possible to look for the homologous sequence in mice. When found, it proved to be almost identical to the human sequence, although large blocks were shuffled between the two. Scambler expected that deleting genes one at a time in the mouse would throw light on the details of DiGeorge syndrome, "but to design the experiments we had to know which genes we were deleting." The region of interest in DiGeorge syndrome was sequenced in Oklahoma rather than at the Sanger Centre, but Scambler had access to new sequences coming in to the database in the Sanger Centre day by day, and used them to home in on the interesting genes. It is too early to talk about the genetic causes of DiGeorge syndrome, Scambler warns, but it seems that of the hundred or so genes deleted about 25 are truly critical to development.

This aspect of the project—being able to make use of the information it provides before that information is complete—is one of the key differences between the so-called clone-by-clone approach of the public-domain sequencing effort and the random shotgun wielded by the private company Celera Genomics. Both will probably be needed to close the book on the human genome sequence, and Dunham concedes that competition spurs people on. But the bigger accelerator, he said, has been technological: a new kind of sequencer that separates DNA fragments in a capillary tube rather than in a flat, thin gel. With it, for the past couple of years scientists have been able to sequence more fragments, more rapidly. "There has been an increase of five or ten times in throughput," Dunham tells Science Watch, "and that's been beneficial for Celera and the public-domain effort."

Chromosome 22 was hailed in the paper as "the first sequencing landmark of the human genome project." But there are others on the way. Chromosome 21 was published in March, and 14 (in France) and 20 (at the Sanger Centre) are close to completion. Will they be as well received? Chromosome 22 has the glory of primacy, but it could be eclipsed if latecomers offer even more insights into the human condition.

Science writer Dr. Jeremy Cherfas
works with the Biotechnology and Biological Sciences
Research Council of the U.K., Swindon.