From the 25 November 2005 issue of Science:


Expression of Endorphin Gene Favored in Human Evolution

Michael Balter

Humans and chimpanzees share at least 98% of their DNA sequences. Yet chimps are an endangered species, whereas humans have used their superior cognition to transform the face of the earth. What makes the difference? Thirty years ago, geneticist Mary-Claire King and biochemist Allan Wilson proposed that changes in how genes are regulated, rather than in the proteins they code for, was the key (Science, 11 April 1975, p. 107). A new study of evolutionary changes in the regulation of a gene implicated in perception, behavior, and memory suggests that King and Wilson may have been at least partly right.

Other researchers say that the new study is one of the first human examples of selection acting on a regulatory element, and it adds to a short list of brain genes now known to have been favored during the evolution of humans. "The evidence is compelling," says evolutionary geneticist Bruce Lahn of the University of Chicago. But he and others note that it is not yet clear what mental or behavioral traits were favored by selection in this case.

An international team led by evolutionary biologist Gregory Wray of Duke University in Durham, North Carolina, focused on the gene that codes for the protein prodynorphin (PDYN), a precursor to a number of endorphins (opiatelike molecules involved in learning, the experience of pain, and social attachment and bonding). The PDYN gene is controlled by a promoter region just upstream from the gene's coding region. Earlier studies had highlighted a 68 DNA base pair (bp) segment of the promoter that varies among humans, who carry between one and four copies of it. It isn't clear how the number of copies and other variations in the segment affect the gene's function, although some variants have been linked to schizophrenia, cocaine addiction, and epilepsy.

Wray and his colleagues sequenced the promoter and some flanking DNA from 74 human chromosomes as well as 32 chromosomes from seven other primates, including chimps, gorillas, and orangutans. As the team reports in the December issue of PloS Biology, none of the nonhuman primates had more than one copy of the 68-bp segment. In addition, all human segments had five DNA mutations not seen in the other primates. The team concludes that the pattern is a solid example of natural selection acting on the human lineage after it split from the chimp line about 5 million to 7 million years ago.


To see whether the differences in promoters actually altered gene expression, the team introduced either the chimp or human 68-bp segment into human neural cells. The human segment induced a 20% greater expression of the PDYN gene than did the chimp segment.

The Wray team's work "speaks directly to King and Wilson's hypothesis," says molecular biologist Sean Carroll of the University of Wisconsin, Madison. Carroll adds that the authors have provided a "road map" for experimental tests of the evolution of gene regulation. Evolutionary geneticist Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, agrees that the paper provides "convincing evidence for positive selection." But Pääbo cautions that this one example does not prove that regulatory mutations were more important than structural mutations during human evolution.

Because of PDYN's importance in human biology, the authors suggest that the evolutionary changes in its regulation may have helped set chimps and humans apart. But Lahn says that such a conclusion is premature until researchers know more about why these changes were favored by natural selection. "It is a bit early to say that these changes were key to what makes us human," Lahn says. "But it seems like a reasonable hypothesis."