By David N. Leff

Down syndrome isn't the only disorder - by a long shot - that's linked to human chromosome 21. Early onset Alzheimer's disease, the main cause of congenital heart disease, and increased risk for leukemias are tightly linked to 21. Other genetic stigmata of the syndrome, which strikes one in 700 live births worldwide, include amyotrophic lateral sclerosis (Lou Gehrig's disease), recessive nonsyndromic deafness, and probably bipolar affective disorder (manic depression), solid tumors and familial hyperlipidemia (which leads to atherosclerosis).

This partial rap sheet of chromosome 21's medical mayhem happens when the pre-fertilization ovum is formed, nine months before an affected newborn inherits three copies of chromosome 21, rather than the normal two. Now researchers who target these disorders have a new pathfinder's road map in the near-complete DNA sequencing of 21.

Although the full report, titled "The DNA sequence of human chromosome 21" will appear in Nature's issue to be dated May 18, 2000, the journal released the full data electronically on May 8th at Simultaneously, press conferences in Berlin and Tokyo announced the feat. Of 10 public sequencing centers in six countries that comprised the multinational consortium, the two in Japan and Germany accounted for the lion's share of the task.

Of the human karyotype's 24 chromosomes, 21 is the smallest - except for the sex-linked male Y. It's the second human chromosome to be sequenced. Late last year, Nature, dated Dec. 2, 1999, announced the first - chromosome 22 - achieved by sequencing centers in Britain, Japan and the U.S. (see BioWorld Today, Dec. 13, 1999, p. 1). Its reported total sequence of 33.4 million base pairs is slightly smaller that the 33,546,361 for chromosome 21. This number covers 99.7 percent of the latter chromosome's long arm. Only a few small gaps, aggregating about 100 kilobases, remain. The co-authors counted 225 known and predicted genes on chromosome 21, compared with 545 on 22.

These two runts of the chromosome litter make up between them 2 percent to 3 percent of the entire human genome. Molecular geneticist Roger Reeves, at Johns Hopkins University School of Medicine in Baltimore, commented to BioWorld Today apropos: "One really surprising thing that came out of this is the very small number of genes on chromosome 21. This was surprising not only for 21, but has implications for how many total genes there may be in the human genome. The authors of this paper combined their data with that from chromosome 22, and estimated that there may be 40,000 genes. That compares with more standard estimates of 70,000 to 140,000."

Gene Totals In Chromosomal Tea Leaves?

Reeves authored a "News & Views" commentary, titled "Recounting a genetic story," accompanying the forthcoming Nature paper. He said "DoubleTwist Inc., of Oakland, Calif., [which recently reported an estimated total of 105,000 genes], thought they'd found 1,400 genes on chromosome 22, rather than 545. In fact," Reeve observed, "for all of these guesstimates, the devil really is in the details. It's very easy to use computer algorithms and get numbers up in the thousands. It's not so easy to predict that all of those predictions are correct."

He added: "If the total number of human genes were around 100,000, chromosome 21 would be expected to contain 800 to 1,000 of them. The 225 genes now identified stand in stark contradiction to this prediction."

The consortium's mega-base-pair number for chromosome 21 spanned virtually all of its long arm, but only a fraction - 281,116 base pairs - of the short arm. "Actually," Reeves explained, "they covered considerably more of the short arm than the 22 sequence, which didn't do any. The reason is those arms are very difficult to map. They're composed mostly of elements that repeat over and over again, and vary in size quite considerably between individuals.

"So one argument is that once you've sequenced a little bit of it, you've seen it all anyway. The chromosome 21 group," he went on, "sequenced in the short arm a 281-kilobase region that had one gene, which had already been mapped there.

"But the big reason," Reeves related, "is that a large research community has been mapping on chromosome 21 for a long time, and it included some very adventurous and devoted scientists. They were able to put together a clone map, including some of that short arm, so there actually was a template there to sequence."

As for fundamental research, Reeves welcomes the total sequencing of 21 as "a major milestone that the international Down syndrome community has been working toward for many years."

"The immediate medical impact" of mapping chromosome 21, he foresees, "will be in the five genetic diseases that have been mapped to 21, for which the genes have not yet been identified. They are two forms of congenital deafness, Knobloch's syndrome (a neural-tube defect), Usher's syndrome (multiple sensory defects) and holoprosencephaly (failure of forebrain to divide)."

Medical Payoffs 'In Very Near Future'

"By having the sequence and a catalogue of all the genes," he pointed out, "you eliminate one of the most labor-intensive stages of making that correlation between the disease and the gene responsible. I think," Reeves added, "that all five of those pathologies are likely to be associated with genes in the very near future."

The forthcoming Nature paper concluded: "The complete sequence analysis of human chromosome 21 will have profound implications for understanding the pathogenesis of diseases, and the development of new therapeutic approaches [and] diagnostic tests. The challenge now is to unravel the function of all the genes on chromosome 21."

"Up until now," Reeves pointed out, "trying to correlate genes of chromosome 21 with the pathological phenotypes of Down syndrome was sort of like putting a jigsaw puzzle together when you didn't have all the pieces, and you didn't even know how many pieces there were. What this total chromosome 21 sequence does is give us all the pieces. Of course, now we still have the very big job of finding out what they all do and which ones are more or less important. But we have taken a very, very big step forward," he concluded, "in knowing at least what all the pieces are, so I think that everybody who works on Down syndrome research is very happy this week."