Scientists at the Washington University School of Medicine in St. Louis have shed light on the beneficial roles played by genes unique to humans, by producing the first detailed analysis of the cellular functions of a hominoid-only gene, TBC1D3.
Out of 23,000 genes 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, researchers at Washington University School of Medicine in St. Louis have come up with the first detailed analysis of the cellular functions of a hominoid-only gene, TBC1D3 and have verified previous evidence of its linkage with cancer gene.
The team of researchers led by Philip D. Stahl, Ph.D., the Edward Mallinckrodt Jr. Professor and head of Cell Biology and Physiology, affirmed this fact by demonstrating 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.
"I was astounded at how little attention has been given to human-specific genes, which make us what we are and could potentially offer a great deal of insight into human physiology. In addition, certain pathogens, such as the malaria parasite, have human specific-components in their infection cycle. Human-only genes could offer us unique insights into how the parasites take advantage of us and possibly provide potent new avenues for fighting back," said Stahl.
Usually, in order to learn more about the function of a gene, the scientists frequently disable or delete the gene in a laboratory animal and then examine how the loss changes the animal. However, Stahl said that this won't be possible with genes unique to humans. The only resort then would be to alter the genes' functions in human cell lines, or transplant them into animals to examine their effects.
Originally, TBC1D3 was identified by other scientists as a possible contributor to breast cancer. At the time of its discovery, researchers linked its protein to endocytosis, a process cells use to take in material from their surface.
This process is studied in Stahl's laboratory to know how growth factor receptors, proteins important for both normal and cancerous growth, are turned on and off. Growth factor receptors are found on the surfaces of cells and turn on when they bind to a growth factor protein. For turning them off, cells take in the combined receptor-protein through endocytosis and put it through a number of different processes before finally breaking down the growth factor receptor.
In 2006, the researchers found that the TBC1D3 gene is only found in hominoids, and their curiosity was piqued. Stahl said that evolution naturally tends to retain genes involved in the most important components of metabolism. In case, one of these genes mutated too drastically, that would lead to an organism so sickly that it wouldn't survive long enough to perpetuate the mutation in its descendants. Thus, evolution "conserves" these genes, retaining them largely unchanged as one species evolves into another.
Evidence was found that this is the case in TBC1D3. Human DNA has eight copies or paralogs of the TBC1D3 gene. It was shown that the increased levels of the protein made by one of the paralogs makes human cells grow more rapidly.
After transplanting the gene for the protein into mouse cells, it was found to have the same effect.It was also revealed that the protein from the TBC1D3 paralog delays a process that labels growth factor receptors for breakdown, delaying the time that their signal is active. The protein was also found to be helpful in activating 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. Stahl also speculated that there may be human diseases where these genes are mutated or missing. The effects of such conditions could provide important clues to what the humans-only genes do.
The details of this study are published in a paper appearing online in The Journal of Biological Chemistry.