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May 20, 2010

Neandertal genome sequencing reveals new clues on human-specific gene changes

UW Health Sciences/UW Medicine

Intriguing differences were reported between the genomes of prehistoric Neandertals and modern people in a paper published May 7 in Science.

The distinctions between human and Neandertal genomes may reveal what set ancient humans apart from the now-extinct, human-like beings. Neandertals died out about 30,000 years ago.

Most news headlines — and several cartoons — around the globe played on the possibility that some Neandertals and early humans interbred in the Middle East, reportedly a place of struggle between the two species. About 1 percent to 4 percent of DNA in non-African people is traceable to Neandertals.

“Not to discount the importance of the data suggesting this, but other things are significant about the Neandertal draft genome,” said Dr. Evan E. Eichler, professor of genome sciences at the UW. “Comparing it to ape and modern human genomes identified a number of genes that may have been affected by positive selection since humans and Neandertals diverged from a common ancestor.” The researchers very roughly estimated that Neandertals and humans diverged from each other about 825,000 years ago.

“There’s evidence of selective sweeps occurring,” he noted. A selective sweep occurs when a beneficial mutation spreads throughout the entire population very quickly. Some of the more interesting regions included genes related to metabolism, cognitive ability, head shape and size, and skeletal development. Some occurred in regions of the human genome where abnormal mutations have been linked to autism and schizophrenia.

By comparing human, chimpanzee and Neandertal genomes, researchers also identified gene changes that occurred specifically in humans but not in the other two species. These include genes that encode proteins for a structure responsible for sperm tail beating; a cell adhesion molecule that may assist in wound healing; a factor that regulates gene transcription, a substance produced in the skin, sweat glands, hair roots, and taste buds; as well as a protein whose function is unknown.

Eichler and several researchers in his lab were among the scientists worldwide who worked on the draft sequence of the Neandertal genome. Eichler is also an investigator in the Howard Hughes Medical Institute. The international project was led by the Department of Evolutionary Genetics at the Max Planck Institute in Leipzig, Germany and included 57 scientists at about 20 institutions in Spain, Croatia, Russia, Germany, the United States, England and Ireland.

“The evolutionary history of a species is encoded in its DNA,” Eichler said. “The power and excitement of this project was that it allowed scientists to go further back in time by reliably recovering DNA sequences from hominins who were alive tens of thousands of years ago.” The genetic information, captured from a pinch of bone dust removed with a dental drill, allows evolutionary biologists to start to unveil what might have shaped early human lineage.

A major obstacle to tracking human origins is that so few fossils have been found, largely because humans emerged in parts of the world where conditions prevent preservation or destroy most artifacts. However, with new technological advances that permit genomic sequencing on minute specimens, Eichler said, geneticists are trying to sequence DNA from smaller fossil remains, similar to another recent study which sequenced mitochondrial DNA from a piece of finger bone corresponding to a human-like but unidentified species that lived more than 30,000 years ago.

The Neandertal genome project benefited from many recent advances in genome sequencing technology and in new methods to screen out contaminating DNA from microbes and people who handled the three fossil bones.

“By mapping DNA from just a fragment of bone,” Eichler explained, “geneticists are beginning to describe as yet unheard of species of hominins, even when skulls or larger parts of skeletons haven’t been discovered.” Some people question whether the time is yet right, however, Eichler said, in the belief that these precious samples should be conserved until DNA sequencing techniques become even more sophisticated.

The UW contributed its latest developments in analyzing duplicated segments of DNA, in determining the number of copies of particular sequences, and in locating deletions in sequences. Deletions, duplications, and differences in copy-number account for many genome variations between species, between populations of the same species, and between individuals. Eichler’s lab began working about nine months ago on DNA sequence data provided by the Max Planck Institute in Leipzig. His lab then compared the organization of the Neandertal genome to chimp and human genomes.

They specifically searched for genes that had increased in copy within the human lineage and identified a half-dozen such genes. Eichler cautioned that further work will need to be done to confirm these findings and to determine if any of these changes are functionally important.

Other UW researchers in the Neandertal genome project were Dr. Tomas Marques-Bonet and Dr. Can Alkan, both of whom were senior fellows in genome sciences at the time of the study. Earlier, Alkan and Dr. Jeffrey Kidd, who recently completed his Ph.D. at the UW, were leaders in designing a fast computational method for counting copies of duplicated genome sequences in DNA and initially assessing their contents. Marques-Bonet has led groundbreaking work on rapid bursts of segmental duplication of DNA during primate evolution.