Missing DNA makes us human

(Press-News.org) University Park, Pa. -- Chimpanzees and humans are minimally different genetically, but the small differences are what make us human, according to a team of researchers who identified segments of non-coding DNA missing in humans that exist in chimpanzees and other animals.

"The technology now lets us look at the genomes of humans and other mammals and find sites where humans are unique," said Philip Reno, assistant professor of anthropology, Penn State. "We can now correlate that information with specific human physical characteristics."

DNA is composed of gene segments that code for proteins and non-coding segments that initiate and regulate the work of the coding segments. While the coding segments are important, the non-coding segments are the control mechanism of the organism. Without changing the coding gene, increasing or decreasing the amount the gene is expressed can have significant influence on what the organism looks like and how it functions.

The researchers, while at Stanford University, first compared the human genome with that of chimpanzees and other mammals to locate areas of complete deletion in the human genome.

"We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signaling and neural function," the researchers report in today's (Mar. 7) issue of Nature.

One sequence missing in humans is next to the androgen receptor gene. The absence of this particular region of non-coding DNA may have two consequences -- the human loss of sensory whiskers and small keratinous spines on the penis.

"We often think of brain size and bipedalism as key characteristics of what makes us human," said Reno. "But another difference is our sexual behavior."

He notes that chimpanzees have quick intercourse because the male chimpanzees are in a competition to see which male can fertilize the one receptive female. This situation occurs when many males copulate with one or a few females. The chimpanzee's penile spines, because they are tactile, may enhance this rapid copulation.

Human ancestors, however, likely evolved to favor pair-bonding relationships and group living. The loss of penile spines may have prolonged intercourse to reinforce the pair bond where partners are beneficial for the successful raising of offspring.

"We now have the genetic sequence of three separate Neanderthal individuals," said Reno. "Looking at these same non-coding areas, the Neanderthal genome lacks them as well."

The absence of these non-coding locations in Neanderthal positions the DNA losses to between 7 million years ago, when human ancestors split from chimpanzees, and 800,000 years ago, when human ancestors split from Neanderthal.

Another area of non-coding DNA the researchers found missing in humans was near a tumor suppressor gene expressed in the brain.

"During development of mammals, a lot of neurons die in the formation of the brain," said Reno. "The absence of this sequence down regulates expression of the gene that leads to cell death and leads to larger brains."

The researchers suggest that they can test other locations associated with human-specific characteristics using functional studies like those used in this research.

### Cory Y. McLean, graduate student in computer science, Stanford, was responsible for the computational aspects of this project. Reno was responsible for the androgen receptor work, and Alex A. Pollen, graduate student in neurosciences, Stanford, focused on brain development.

Other researchers on the project were Abraham I. Bassan and Xinhong Lim, graduate students; Terence D. Capellini, Vahan B. Indjeian, and Douglas B. Menke, post doctoral fellows; Catherine Guenther and Bruce T. Schaar, research scientists; Gill Bejerano, assistant professor, and David M. Kingsley, professor, all in developmental biology at Stanford and Aaron M. Wenger, graduate student in computer science, Stanford.

The Howard Hughes Medical Institute, National Institutes of Health and the Edward Mallinckrodt, Jr. Foundation supported this work.