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First Study Hints At Insights To Come From Genes Unique To Humans
| Author: Tony Cappasso |
| Article Date: 3/27/2008 |
Among the approximately 23,000 genes found in human DNA, scientists currently estimate that there may be as few as 50 to 100 that have no counterparts in other species. Expand that comparison to include the primate family known as hominoids, and there may be several hundred unique genes.
Despite the distinctive contributions these genes likely make to our species, little is known about the roles they play. Now scientists at Washington University School of Medicine in St. Louis have produced the first detailed analysis of the cellular functions of a hominoid-only gene, TBC1D3. They affirmed earlier evidence linking the gene to cancer, showing that TBC1D3's protein can keep cellular growth factors active and helps turn on RAS, a protein that is active in a third of all human cancers. The paper appears online in The Journal of Biological Chemistry.
When scientists want to learn more about the function of a gene, they frequently disable or delete the gene in a laboratory animal, says senior author Philip D. Stahl, Ph.D., the Edward Mallinckrodt Jr. Professor and head of Cell Biology and Physiology. Then they look to see how the loss changes the animal. That won't be possible with genes unique to humans, Stahl notes. Researchers will have to resort to altering the genes' functions in human cell lines, or transplanting them into animals to see what effects they have.
When Stahl and colleagues determined in 2006 that the TBC1D3 gene is only found in hominoids, their curiosity was piqued. Evolution, Stahl notes, naturally tends to retain genes involved in the most important components of metabolism. If one of these genes mutated too dramatically, that would lead to an organism so sickly that it wouldn't survive long enough to perpetuate the mutation in its descendants. So evolution 'conserves' these genes, retaining them largely unchanged as one species evolves into another.
Therefore, if the genome is compared to an automobile, human-only genes are unlikely to be adding new wheels. But they could, for example, be contributing a new anti-lock braking system: a regulatory function that fine-tunes essential processes originally established millennia ago in other species.
Stahl found evidence that this is the case in TBC1D3. Human DNA has eight copies or paralogs of the TBC1D3 gene. His lab showed that the increased levels of the protein made by one of the paralogs makes human cells grow more rapidly. When they transplanted the gene for the protein into mouse cells, it had the same effect.
A closer look showed that the protein from the TBC1D3 paralog delays a process that labels growth factor receptors for breakdown, prolonging the time that their signal is active.
He also found evidence that the protein was helping to activate RAS, another gene whose protein is commonly found in human cancers.
Stahl and his colleagues plan additional research to learn whether the other paralogs of TBC1D3 have different roles. He also has several ideas for learning more about the functions of human-only genes.
'We might try an organ-by-organ approach, looking to see if any genes specific to a particular organs, such as fat, are specific to humans,' he says. 'We also should probably look at crystallizing the proteins from some of these genes, which can tell us more about what they interact with.'
There may be human diseases where these genes are mutated or missing, Stahl speculates. The effects of such conditions could provide important clues to what the humans-only genes do.
'It's also going to be very interesting for evolutionary biologists to try to develop a sense for where these humans-only genes come from,' Stahl says. 'The building blocks of these genes may be present but not active in earlier species.'
Despite the distinctive contributions these genes likely make to our species, little is known about the roles they play. Now scientists at Washington University School of Medicine in St. Louis have produced the first detailed analysis of the cellular functions of a hominoid-only gene, TBC1D3. They affirmed earlier evidence linking the gene to cancer, showing that TBC1D3's protein can keep cellular growth factors active and helps turn on RAS, a protein that is active in a third of all human cancers. The paper appears online in The Journal of Biological Chemistry.
When scientists want to learn more about the function of a gene, they frequently disable or delete the gene in a laboratory animal, says senior author Philip D. Stahl, Ph.D., the Edward Mallinckrodt Jr. Professor and head of Cell Biology and Physiology. Then they look to see how the loss changes the animal. That won't be possible with genes unique to humans, Stahl notes. Researchers will have to resort to altering the genes' functions in human cell lines, or transplanting them into animals to see what effects they have.
When Stahl and colleagues determined in 2006 that the TBC1D3 gene is only found in hominoids, their curiosity was piqued. Evolution, Stahl notes, naturally tends to retain genes involved in the most important components of metabolism. If one of these genes mutated too dramatically, that would lead to an organism so sickly that it wouldn't survive long enough to perpetuate the mutation in its descendants. So evolution 'conserves' these genes, retaining them largely unchanged as one species evolves into another.
Therefore, if the genome is compared to an automobile, human-only genes are unlikely to be adding new wheels. But they could, for example, be contributing a new anti-lock braking system: a regulatory function that fine-tunes essential processes originally established millennia ago in other species.
Stahl found evidence that this is the case in TBC1D3. Human DNA has eight copies or paralogs of the TBC1D3 gene. His lab showed that the increased levels of the protein made by one of the paralogs makes human cells grow more rapidly. When they transplanted the gene for the protein into mouse cells, it had the same effect.
A closer look showed that the protein from the TBC1D3 paralog delays a process that labels growth factor receptors for breakdown, prolonging the time that their signal is active.
He also found evidence that the protein was helping to activate RAS, another gene whose protein is commonly found in human cancers.
Stahl and his colleagues plan additional research to learn whether the other paralogs of TBC1D3 have different roles. He also has several ideas for learning more about the functions of human-only genes.
'We might try an organ-by-organ approach, looking to see if any genes specific to a particular organs, such as fat, are specific to humans,' he says. 'We also should probably look at crystallizing the proteins from some of these genes, which can tell us more about what they interact with.'
There may be human diseases where these genes are mutated or missing, Stahl speculates. The effects of such conditions could provide important clues to what the humans-only genes do.
'It's also going to be very interesting for evolutionary biologists to try to develop a sense for where these humans-only genes come from,' Stahl says. 'The building blocks of these genes may be present but not active in earlier species.'