Key Brain Regulatory Gene Shows Evolution In Humans

They reported that, compared to lower primates, humans possess a distinctive variant in a regulatory segment of the prodynorphin gene, which is a precursor molecule for a range of regulatory proteins called "neuropeptides." This variant increases the amount of prodynorphin produced in the brain.

While the researchers do not understand the physiological implications of the activated PDYN gene in humans, they said their finding offers an important and intriguing piece of a puzzle of the mechanism by which humans evolved from lower primates.

They also said that the discovery of this first evolutionarily selected gene is likely only the beginning of a new pathway of exploring how the pressure of natural selection influenced evolution of other genes.

They also said their finding demonstrates how evolution can act more efficiently to alter the regulatory segments, or "promoters," that determine genes' activity, rather than on the gene segment that determines the structure of the protein it produces. Such regulatory alteration, they said, can more readily generate variability than the hit-or-miss mutations that alter protein structure and function.

Proteins constitute the molecular machinery of the cell, for example, catalyzing the multitude of chemical reactions in the cell. DNA genes constitute the blueprints for such proteins, with the regulatory segments of these genes determining how actively the genes churn out proteins.

The researchers published their findings in the December 2005 issue of the Public Library of Science. They were Gregory Wray and David Goldstein of Duke University; Matthew Rockman of Princeton University; Matthew Hahn of Indiana University; Nicole Soranzo of University College London; and Fritz Zimprich of the Medical University of Vienna in Austria. The research was sponsored by the National Science Foundation and NASA.

"We focused on the prodynorphin gene because it has been shown to play a central role in so many interesting processes in the brain," said Wray. "These include a person's sense of how well they feel about themselves, their memory and their perception of pain. And it's known that people who don't make enough of prodynorphin are vulnerable to drug addiction, schizophrenia, bipolar disorders and a form of epilepsy. So, we reasoned that humans might uniquely need to make more of this substance, perhaps because our brains are bigger, or because they function differently.

"Also importantly, the part of the gene that produces the prodynorphin protein shows no variation within humans, or even between humans and any of the great apes," said Wray, who is a professor of biology. "So, if we found any variation in this gene due to evolution, it was likely to be in its regulation. And our premise is that the easiest way to generate evolutionary change is to alter regulation."

In their studies, the researchers analyzed the sequence structure of the PDYN promoter segment in humans and in seven species of non-human primates -- chimpanzees, bonobos, gorillas, orangutans, baboons, pig-tailed macaques and rhesus monkeys. They found significant mutational changes in the regulatory sequence leading to humans that indicated preservation due to positive evolutionary selection. They also found an "evolution-by-association," in which sequences near the regulatory segment showed greater mutational change -- as if they were "dragged along" with the evolving regulatory sequence.

In contrast, the researchers found that the DNA segment that coded for the PDYN protein itself -- as well as other sites spread around the genome -- showed evidence of "negative selection" that would preserve their original structure.

A key experiment, said Wray, was a laboratory demonstration that such regulatory mutations did have functional significance. When the researchers cultured human neural cells with either the human or chimpanzee regulatory PDYN segments, they found that the human segments caused the cells to produce more PDYN neuropeptide.

"So, these experiments told us that those mutations that we flagged by a statistical method as being likely to be under selection actually do something important in terms of function," said Wray. "The human version increases expression of the gene and production of prodynorphin, which is the direction of change we predicted."

The researchers also found evidence of evolutionary selection when they compared the regulatory sequences in people from different populations -- including those from Cameroon, China, Ethiopia, India, Italy and Papua New Guinea. Those analyses showed higher differences among the individual populations, but reduced variation within them. Such a pattern is a signature of evolutionary selection acting on the genetic sequence, said Wray.

Still mysterious, he said, is how the prodynorphin gene changes affect human neural development.

"All we can conclude now is that this gene is a very strong candidate for having a functional role in human evolution, and that its role probably has something to do with cognition. But beyond that, it's very hard to make a clear argument about specifically what that role is.

"We do know that not making enough prodynorphin causes clinical problems, but we don't know what having more of it did for us humans. We're hoping the clinical psychiatrists and psychologists can give us more insight into that aspect."

Wray and his colleagues have already identified a collection of some 250 other candidate genes -- mainly those active in the brain -- that they are beginning to analyze for evidence of evolutionary selection. They plan to perform the same basic analyses, in which they compare sequence information between humans and non-human primates for signatures of evolutionary selection.