Evolution's DNA difference: noncoding gene tied to origin of human brain.

Scientists have identified a gene that appears to have evolved rapidly in people and contributed to the emergence of the uniquely human brain.

Rather than coding for a protein, as about half of known genes do, the newly discovered gene regulates the assembly of an RNA molecule that ultimately affects cell migration to critical brain areas before birth, reports a team led by molecular biologist David Haussler of the University of California, Santa Cruz.

"We don't know the exact molecular action of this gene yet," Haussler says. "Overall, our data are consistent with the hypothesis that regulatory genes were important for human-brain evolution."

That hypothesis was first proposed in 1975 by researchers who noted that differences were rare between the protein-coding DNA of people and chimps. However, evidence supporting the importance of regulatory genes has remained elusive.

Haussler's group first delineated within the genome 35,000 DNA segments, most 100 to 140 base pairs long, that are nearly identical in chimpanzees, mice, and rats. The researchers then identified 49 DNA segments that in people contained large numbers of different base pairs compared with the chimp counterparts.

The greatest number of chemical substitutions, 18, occurred in a segment dubbed human accelerated region 1, or HAR1. In contrast, HAR1 differs by only 2 of its 118 base pairs in chimps and chickens, which the group had also analyzed. It thus appears that HAR1 has evolved especially quickly in the 6 million years or so since human ancestors branched off from chimp ancestors, Haussler says.

The researchers next established that HAR1 includes two overlapping genes. Laboratory evidence suggested that neither gene produces a protein. But in people, RNA resulting from one of these genes, HAR1F, forms a stable chemical structure that differs markedly from corresponding chimp RNA. The new findings will appear in Nature.

In further experiments, Haussler and his coworkers found that HAR1F stimulated cells taken from embryonic brains of both people and macaque monkeys. The reactions occurred in cells known to be critical for neural migration in the frontal brain, hippocampus, thalamus, and other structures that contribute to reasoning and learning.

Haussler suggests that slight differences in the way in which HAR1F works in the brains of people and those of primates would translate into major differences in brain anatomy.

Geneticist Bruce Lahn of the University of Chicago calls HAR1F "a strong candidate gene" for examining how changes in DNA sequence have contributed to the emergence of the distinctly human brain.

From research that he directed on two genes that make proteins acting on brain cells, Lahn argues that those genes have contributed to human-brain evolution. Other researchers, however, challenge that conclusion (SN: 6/3/06, p. 34.9).

Haussler's study directs "well-deserved attention" to regulatory genes as major players in human-brain evolution, remarks evolutionary biologist Pascal Gagneux of the University of California, San Diego.

Haussler and his colleagues are currently investigating whether four other human, noncoding genes that have undergone rapid evolutionary change affect the brain.