Less Is More, Gene Study Shows

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Humans and chimps share most of their genes, yet they differ dramatically in many ways -their 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 from the University of Michigan shows how one process - gene loss - may 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 we ended up with our unique traits, Zhang said. The first possibility is that we acquired completely new genes that other apes don’t have. Another is that some of our genes have taken on different functions through mutation.

It’s also possible that we 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 us smaller jaw muscles, making room in our 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 said. “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.”

Zhang’s group started by scrutinizing a database of human pseudogenes - stretches 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 that remained, 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. They ended up with 67 human-specific pseudogenes, to which they added 13 that had been reported in the literature but not included in the original database, bringing the total to 80.

Next, Zhang and his team consulted another database called Gene Ontology, which lists the functions of all genes for which such information is known. That’s when things got interesting. 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. The findings made sense to Zhang.

“We know that humans have reduced olfactory sensitivity, so the finding is consistent with that observation. Also, in a previous paper we showed that bitter taste receptor genes tended to become unimportant in humans, and we put forth a hypothesis to explain why: The ability to taste bitterness is important for detecting toxins in food, and most of those toxins are in plants. About 1 to 2 million years ago, we started eating more meat rather than plants, and also there was use of fire, which can detoxify foods.”

Loss of function also is expected in genes related to the immune response. “Immune system genes respond to pathogens, which change rapidly, so the genes also change rapidly,” Zhang said. “If the pathogen is no longer there, then you don’t need the immune system gene in the host.”

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 - which is present and functional in rhesus monkeys and chimps as well as mice, but has lost its function in humans - might confer protection against severe bacterial infection in the blood (sepsis). But humans lost that gene so long ago, 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 has completely lost its function in non-Africans, but a small percentage of Africans and African Americans have a functional copy of the gene. Interestingly, 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.” However, using population genetics techniques, the researchers were able to demonstrate just that. They also determined when the loss occurred - somewhere between 51,000 and 74,000 years ago - which is consistent with the idea that it happened not long before humans began migrating out of Africa 40,000 to 60,000 years ago.

As for exactly how lacking the gene - which appears to be essential in all mammals except humans - became more advantageous than having the gene, Zhang believes he has an answer.

The immune system, he explained, must constantly be turned up or down to give the proper response. “It’s a delicate balance - you don’t want it too strong or too weak.” 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 said. “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. The University of Michigan and the National Institutes of Health provided funding.

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