One down: A human chromosome sequenced.

It's not the biggest, or the smallest, or the one with the most genes. Still, chromosome 22 will go down in history as the first human chromosome to have almost its entire DNA sequence revealed to the world.

Scientists participating in the international effort to decipher the whole human genome announced this milestone in the Dec. 2 NATURE. The investigators report that they've determined more than 33 million bases--the chemical building blocks of DNA--of chromosome 22 and identified at least 545 genes.

"It's very exciting," says Bruce A. Roe of the University of Oklahoma in Norman, a leader of the sequencing project. "We've now got one book of the Encyclopedia Britannica of life.... We know all the words on its pages. We just have to go back to our dictionary and find out what all those words mean."

Twenty-two pairs of chromosomes, plus the X and Y chromosomes, carry almost all of a person's genes. Chromosome 22 ranks as the second smallest, holding just under 2 percent of all human DNA. It harbors many genes implicated in human disorders ranging from birth defects to cancers. Several studies have suggested that chromosome 22 may also contain a gene predisposing people to schizophrenia.

Four DNA-sequencing teams from Washington University School of Medicine in St. Louis, the University of Oklahoma, the Sanger Centre in Cambridge, England, and Keio University School of Medicine in Tokyo led the chromosome-22 effort. While a private firm is sequencing the human genome using a so-called shotgun strategy (SN: 5/23/98, p. 334), these investigators pursued a more traditional approach. They took small pieces of DNA whose locations on chromosome-22 were known and identified which of four possible bases---adenine, cytosine, guanine, or thymine---exists at each point along the DNA.

The international human genome project aims for 99.99 percent accuracy. Claiming less than 1 mistake for every 50,000 bases, the chromosome-22 sequencers say they've beaten that benchmark. "Since this is the first chromosome being completed, we wanted to set the standard," says Roe.

He notes that chromosome-22 crossed the finish line first because scientists working on specific regions overcame their competitiveness and freely volunteered copies of their regions' DNA to the four sequencing centers. The centers made the resulting sequence data freely available worldwide. "The community really worked together," says Roe. "There was a tremendous spirit of cooperation."

The ongoing public release of the sequencing data has already resulted in several published studies on newly identified chromosome-22 genes. Still, picking out all the genes remains a formidable task. A computer analysis of the sequence predicted the presence of more than 800 genes, but the software produces many false positives, warn the scientists. Using more stringent criteria, they count 545 genes.

"The real issue is how you find a gene if you know nothing about it. The problem is that genes don't come with little flags saying, 'I'm a gene,'" notes Peter Little of Imperial College in London, who wrote a commentary in the same issue of NATURE.

From their tally of genes on chromosome 22, the scientists who sequenced it predict that the human genome contains at least 45,000 genes. Finding all those genes isn't the ultimate goal, however.

"Even when you can identify the genes, there's a lot more to be done on what does a gene do, what does its protein do, and how is it expressed in different tissues," notes Ian Dunham of the Sanger Centre.

To address some of those questions, biologists must also study the noncoding DNA that surrounds genes and regulates their activity. "Because we have the entire [chromosome-22] sequence, we should have all the elements used to control the expression of its genes," says Dunham.

Beyond these genes and regulatory regions, about 40 percent of the chromosome-22 sequence turns out to consist of seemingly useless, repetitive stretches of DNA, often labeled junk DNA.

"We don't know what [those sequences] do, if they do anything at all. They may just be relics of the evolution of the genome," says Dunham.

The investigators haven't sequenced every base on chromosome 22. They've largely ignored one of its two arms, the much shorter one, because past research showed that it doesn't contain genes that encode proteins. Like the short arms of a few other chromosomes, it has many copies of genes that code for the RNA component of ribosomes, the protein-making factories in cells.

Even the DNA sequence for the long arm of chromosome 22 has 11 gaps, ranging from a few thousand bases to 150,000. Scientists expect to fill in some of those gaps, especially one thought to contain a gene involved in breast cancer, but a few may prove very difficult to sequence.