Less is more, gene study shows
Humans and chimps share most of their genes, yet they differ dramatically in many waystheir walk, the sizes of their brains and their capacities for speech and language, for example.
Scientists would like to know how and when such differences arose, and new research conducted at U-M shows how one processgene lossmay have figured in. The work, by a group led by Associate Professor of Ecology and Evolutionary Biology Jianzhi Zhang, is reported in the Feb. 14 issue of the open-access journal PLoS Biology.
Researchers who speculate about human origins have come up with three main scenarios for how humans ended up with their unique traits, Zhang says. The first is that they acquired completely new genes that other apes don't have. Another is that some of genes have taken on different functions through mutation.
It's also possible that humans lost some genes along the way, and those losses provided opportunities for changes that otherwise could not have occurred. For example, scientists have shown that over the course of evolution, humans lost a gene that produces a particular jaw muscle protein. Perhaps the loss of that gene gave humans smaller jaw muscles, making room in their skulls for bigger brains.
That's just speculation, and until now there was no concrete evidence for the "less is more hypothesis" that losing certain genes offered tangible benefits, Zhang says. "So we wanted to know how many genes have been lost and what kinds of genes have been lost in human evolution, and second, whether any of those gene losses was a good thing," he says.
Zhang's group started by scrutinizing a database of human pseudogenesstretches of DNA that look like known genes but don't function as genes. Then the researchers weeded out pseudogenes that never had been functional in any organism.
From those remaining they further narrowed the field to only those human pseudogenes that had working counterparts in chimpanzees and also had mutations in places that would render the human versions inactive.
Next, Zhang and his team consulted another database called Gene Ontology. Instead of a random assortment of genes with various functions, they found that genes related to the sense of smell and the ability to taste bitterness were overrepresented in the collection of human pseudogenes. So were genes concerned with the immune response.
Having identified lost genes and their functions, the researchers next wanted to figure out whether losing the genes benefited humans in any way. Studies on mice suggested that loss of a gene called MBL1 might confer protection against severe bacterial infection in the blood (sepsis). But humans lost the gene so long ago that it was hard to pinpoint the evolutionary forces behind the loss.
So the researchers focused their attention on another human-specific pseudogene, CASPASE12. Work by other researchers had shown that the gene completely has lost its function in non-Africans, but a small percentage of Africans and African Americans have a functional copy of the gene. People who lack the gene are better able to resist sepsis than those who have a working copy.
"This is another indication that loss of the gene would be good for the individual, but it doesn't show that the gene became a pseudogene because of that advantage," Zhang says. "Using population genetics techniques, however, the researchers were able to demonstrate just that. They also determined the loss occurred between 51,000-74,000 years ago.
As for exactly how lacking the genewhich appears to be essential in all mammals except humansbecame more advantageous than having the gene, Zhang says the immune system must constantly be turned up or down to give the proper response.
"It's a delicate balanceyou don't want it too strong or too weak," he says. The normal function of CASPASE12 is to keep the response from being too strong, and that probably served humans well at one time. But then, "during human evolution, either because of an environmental change or because of some other genetic changes in the human genome, the balance was broken, so that having the gene makes the response too low, and you can't fight infection," Zhang says. "If the gene is lost, the response returns to normal, and so does the ability to fight infection."
Zhang did the research with graduate students Xiaoxia Wang and Wendy Grus.