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One Gene, Many Proteins
Ultimately it will be necessary to measure mRNA in specific cell types to demonstrate
the presence of a gene
By Barbara J. Culliton

Featured Article.

We humans have approximately 30,000 genes that carry within them the instructions for making proteins. There is good evidence for 26,383 protein-coding genes, according to J. Craig Venter and colleagues at Celera Genomics. Based on a combination of computer data and human analysis, there is some evidence that the genome may contain another 12,731 or so genes, but it is too early to know for sure; some of the predicted genes may be overestimates.

Venter is the lead author on a landmark paper that appears in the February 16 issue of Science. Scientists participating in the Human Genome Project, partially funded by the U.S. National Institutes of Health, estimate the number of human genes to be between 30,000 and 40,000. They chose to publish their data in the British journal Nature, which is also out this week.

What does this mean? It means that the old paradigm that one gene makes one protein is clearly in need of revision. Through mechanisms that include "alternative splicing," one gene can direct the synthesis of many proteins. Victor A. McKusick, of the Johns Hopkins University School of Medicine, says, "It seems to be a matter of five or six proteins, on average, from one gene." McKusick, who is a co-author of the Science paper, suggests that people who now claim that the number of human genes is much higher, may be looking at and counting separate messenger RNAs—the molecules that take information from genes and direct the production of proteins. That being likely, mRNAs will now have to be reexamined against the human genome sequence.

Nobel laureate Richard J. Roberts, Research Director at New England Biolabs, Beverly, MA, who is also a co-author of the Science paper, says, "Since genes are [now] easy to discover by sequencing, and the transcriptional splicing variants are much more difficult to discover and characterize properly, it means that much work lies ahead." Or, as the Science paper says, "As was true at the beginning of genome sequencing, ultimately it will be necessary to measure mRNA in specific cell types to demonstrate the presence of a gene."

The finding that one gene makes many proteins also confirms (if confirmation were needed), that future research in drug discovery and medicine will rely heavily on an integration of genomics and proteomics, a newly coined word for the study of proteins and their biological interactions. Proteins are sensitive markers of early onset of disease, and of obvious importance to diagnosis. Proteins are equally vital to prognosis and treatment; it is proteins, for instance, that are the targets of most drugs and other therapeutic agents. Detailed understanding of proteins and the genes from which they come is the next frontier.

Small gene number was predicted ages ago.

For the past quarter century, estimates of the number of genes in the human genome have generally ranged between 80,000 and 150,000, so the much smaller number comes as an apparent surprise, though perhaps it should not. As early as 1937, the famed biologist J.B.S. Haldane speculated that if the number of genes in an organism becomes too large, deleterious mutations could drive it to extinction. In the 1960's, human geneticist James F. Crow and colleagues hypothesized (correctly) that human beings have about 30,000 genes.

The newly published human genome sequence, Venter and colleagues note, "provides the framework upon which all the genetics, biochemistry, physiology, and ultimately, phenotype depend.... Now we know what we have to explain."

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Venter, J.C. et al. The sequence of the human genome. Science 291, 1304-1351 (February 16, 2001).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860-921 (February 15, 2001).

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