Humans May Have Fewer Genes Than Thought

October 20, 2004

By NICHOLAS WADE

A new and perhaps final report from the international consortium of laboratories that decoded the human genome has revised the number of expected human genes sharply downward.

Some 20,000 human genes have been identified for sure, and up to 5,000 more may await discovery, the consortium says in a report in Thursday's issue of the journal Nature. This fast shrinking tally is considerably less than the 30,000 or so human genes predicted by both the consortium and its commercial rival, Celera, when they first described their draft genome sequences in February 2001. The 30,000 figure was itself a surprising downgrade from the 100,000 human genes commonly said to exist five years ago, before the exact sequence of DNA units in the human genome was decoded.

Coincidentally, a French group reports in the same issue of Nature that they have decoded the genome of a biologically important fish. They say it has 20,000 to 25,000 genes, the identical range to that now estimated for the human genome.

How can it be that humans, seen by some as the apotheosis of creation, have the same number of genes as the spotted green pufferfish?

The question is the more pressing since genes are subject to a rigorous use-it-or-lose-it rule: those that are not vital to an organism are quickly rendered useless by mutations. Also, the human brain seems particularly dependent on genetic complexity, since about half of all human genes are active in brain tissue.

From the fishes' point of view, the problem may seem rather less acute. Their large number of genes "may relate to the fact that fish today are one of the most successful families of vertebrate on earth," said Dr. Hugues Roest Crollius of the French team. He and his colleagues have found that some time after 450 million years ago, when people and pufferfish took separate evolutionary paths, the puffer and most other fish doubled their genome in some freak cellular accident.

Though some of the duplicate genes were shed, many were put to alternative uses, giving fish a special evolutionary advantage. Humans have enjoyed no such doubling in the last half billion years, Dr. Crollius said.

People presumably overcome the relative poverty of their genetic patrimony by other means. "Clearly the complexity of the nervous system must derive from some other feature than the gene count," said Dr. Francis Collins, director of the federal agency that supports genome decoding in the United States.

One is alternative splicing, the mechanism through which a single gene can generate several proteins by selecting different combinations of the same set of building blocks. More alternative splicing goes on in human cells than in those of lower animals like flies and worms, Dr. Crollius said.

Another way in which humans may get more out of their genes is through more sophisticated control. Cells have a small set of regulatory genes that control the activity of all the other genes. Although the main human genes have recognizable counterparts in fish, the regulatory genes seem to be different, Dr. Collins said. It's possible they are more sophisticated and able to construct greatly more complex structures, like the human brain.

The consortium that decoded the human genome had failed, at the time of its first report, to close 147,821 gaps in the DNA sequence of the 24 human chromosomes. These gaps, stretches of DNA refractory to the usual sequencing methods, have now been reduced to just 341. The total size of the human genome is 3,080 million units of DNA, the consortium estimates. Besides the 341 gaps, a special kind of structural DNA at the center and tips of each chromosome continues to defy currently available sequencing techniques.

The international consortium - principally laboratories in the United States and Britain, but including contributions from France, Germany, China and Japan - together spent about $300 million to prepare the draft sequence of the human genome. Filling all the gaps and other finishing work has taken a further $320 million, Dr. Collins said. The journal article is probably the consortium's final report on the genome as a whole, he said, although work is still being done on specific aspects. Closing the remaining 341 gaps is a research project for the future.

Celera's version of the human genome was not taken beyond the draft stage, in part because the company had difficulty finding subscribers when the government, believing access to the human genome should be free, was making the consortium's work available for nothing. Celera's novel sequencing method, however, has now become the standard way of decoding other genomes.

"Celera proved that the whole genome shotgun technique is both technically feasible and provides a dramatic cost-saving over the clone-by-clone approach," the method used by the consortium, Dr. Lincoln Stein of the Cold Spring Harbor Laboratory writes in Nature.