Brain gene shows dramatic difference from chimp to human

One of the fastest-evolving pieces of DNA in the human genome is a gene linked to brain development, according to findings by an international team of researchers published in the Aug. 17 issue of the journal Nature.

In a computer-based search for pieces of DNA that have undergone the most change since the ancestors of humans and chimps diverged, "Human Accelerated Region 1" or HAR1, was a clear standout, said lead author Katie Pollard, assistant professor at the UC Davis Genome Center and the Department of Statistics.

"It's evolving incredibly rapidly," Pollard said. "It's really an extreme case."

As a postdoctoral researcher in the lab of David Haussler at UC Santa Cruz, Pollard first scanned the chimpanzee genome for stretches of DNA that were highly similar between chimpanzees, mice and rats. Then she compared those regions between chimpanzees and humans, looking for the DNA that, presumably, makes a big difference between other animals and ourselves.

HAR1 has only two changes in its 118 letters of DNA code between chimpanzees and chickens. But in the roughly five million years since we shared an ancestor with the chimpanzees, 18 of the 118 letters that make up HAR1 in the human genome have changed.

Experiments led by Sofie Salama at UC Santa Cruz showed that HAR1 is part of two overlapping genes, named HAR1F and HAR1R. Evidence suggests that neither gene produces a protein, but the RNA produced by the HAR1 sequence probably has its own function. Most of the other genes identified by the study also fall outside protein-coding regions, Pollard said.

Structurally, the HAR1 RNA appears to form a stable structure made up of a series of helices. The shapes of human and chimpanzee HAR1 RNA molecules are significantly different, the researchers found.

RNA is usually thought of as an intermediate step in translating DNA into protein. But scientists have begun to realize that some pieces of RNA can have their own direct effects, especially in controlling other genes.

The proteins of humans and chimps are very similar to each other, but are put together in different ways, Pollard said. Differences in how, when and where genes are turned on likely give rise to many of the physical differences between humans and other primates.

Researchers at UC Santa Cruz, the University of Brussels, Belgium and University Claude Bernard in Lyon, France, showed that HAR1F is active during a critical stage in development of the cerebral cortex, a much more complicated structure in humans than in apes and monkeys. The researchers found HAR1F RNA associated with a protein called reelin in the cortex of embryos early in development. The same pattern of expression is found in both humans and rhesus monkeys, but since the human HAR1F has a unique structure, it may act in a slightly different way. Those differences may explain some of the differences between a human and chimp brain.

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The chimpanzee genome was published in Nature in 2005, showing that the DNA sequences of humans and chimps are more than 98 percent identical. The current work was funded by the Howard Hughes Medical Institute, the U.S. National Institutes of Health and other agencies.


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