Number of Human Genes 42 Percent More than Originally Estimated

By comparing the draft sequence of the human genome to approximately 450,000 bits of DNA sequenced from the rat genome, researchers have increased the estimated number of human genes to 42,500 – nearly 42 percent more than the 30,000 first predicted.

This finding by scientists at Baylor College of Medicine is one of the first to come out of the rat genome sequencing effort and exceeds estimates of the international human sequencing consortium.

The report, published in the November issue of the journal Genome Research, proves the value of comparative genome sequencing, said Dr. George Weinstock, co-director of the Baylor Genome Sequencing Center.

It was the comparison and contrast between the genetic codes of the two organisms that allowed the scientists to make their new estimate.

"These two organisms are sufficiently far enough apart in evolution so that most of the genome has diverged, and conserved regions stand out," said Dr. Weinstock. The conserved regions undergoing selection are mainly genes.

Using this fact, the Baylor researchers took 450,000 pieces of DNA for which they had determined the sequence during early studies and compared them to the working draft of the human genome. They found that approximately 10 percent of the rat sequences contained regions that are also found in the human genome and that one-third of these contain known genes that code for a particular cellular protein.

While the rat DNA represented less than 8 percent of the total rat genome, it was enough to allow the scientists, Drs. Rui Chen, John B. Bouck, Weinstock and Richard A. Gibbs, director of the center, to use statistical tools to extrapolate the numbers of genes in the human genome.

"Our goal was to create a sizeable amount of rat DNA sequence, compare it to the human and test the idea that conserved regions were highly enriched for genes. From that, we hoped to predict the number of genes in the human," said Dr. Weinstock.

This method is different from that used to analyze the working draft of the human genome sequence. The estimates from the human analysis were based on what researchers believed a gene looked like, using computers to compare the working draft of the human genome sequence to those known parameters. From those admittedly conservative tools, the genome sequencers estimated 30,000 genes.

In analyzing the rat, scientists eliminated the divergent sequences that were not evolutionarily conserved between rat and human. They then evaluated the conserved regions of DNA to determine those that contained known genes.

"In this analysis, we make a strong argument that most of these conserved regions include genes because of high enrichment found for known genes," said Dr. Weinstock.

Because the original estimate was known to be conservative, Dr. Weinstock is not surprised to find that this method has predicted more genes.

"The number is probably higher than this prediction," he said. "It’s probably more in the range of 70,000."

Those extra genes will be uncovered as new methods of gene finding are attempted, he said.

"This is just the beginning of what we can find when we compare the human genome to those of other organisms," said Dr. Gibbs. "Other analyses will tell us what genes are common to rat, mouse and human. By comparing multiple mammalian genomes and identifying similarities, we can then begin to understand evolution. What does it mean to be a mammal, a vertebrate? Comparative genomics gives us the opportunity to study how humans have evolved."

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©2006 Texas Medical Center

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