Comparison of human and chimpanzee genomes reveals striking similarities and differences

The first comprehensive comparison of the genetic blueprints of humans and chimpanzees shows our closest living relatives share perfect identity with 96 percent of our DNA sequence, an international research consortium reported today. Led by scientists from the Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, and the Washington University School of Medicine in Saint Louis, MO, the Chimpanzee Sequencing and Analysis Consortium reported its findings in the Sept. 1 issue of the journal Nature.

Comparison of the chimpanzee and human genomes reveals extraordinary similarities, significant differences and new paths for biomedical research:

• It provides unambiguous confirmation of the common and recent evolutionary origin of human and chimpanzees, as first predicted by Charles Darwin in 1871.

• It provides key information for human medicine by revealing important properties of the human genome, including the types of genes that have been evolving most rapidly over millions of years and specific chromosomal regions that have undergone strong positive selection during recent human history. This sheds light on human biology and especially on human disease, because at least some of these reflect responses to recent infectious agents or evolutionary changes relevant to human health.

• It demonstrates that the human and chimpanzee species have tolerated more deleterious mutations than other mammals, such as rodents. This confirms an important evolutionary prediction, and may account for greater innovation in primates than rodents, as well as a high incidence of genetic diseases.

"We now have a nearly complete catalog of the genetic changes that occurred during the evolution of the modern human and chimpanzee species from our common ancestor," said the study's lead author, Tarjei S. Mikkelsen of the Broad Institute. "By cross-referencing this catalog against clinical observations and other biological data, we can begin to identify the specific changes that underlie the unique traits of the human species."

"The evolutionary comparison of the human and chimpanzee genomes has major implications for biomedicine," said Eric Lander, director of the Broad Institute. "It provides a crucial baseline for human population genetic analysis. By identifying recent genetic changes and regions with unusually high or low variation, it can point us to genes that vary as a response to infectious agents and environmental pressures."

Among the major findings of the Consortium are:

1. The chimpanzee and human genomes are strikingly similar and encode very similar proteins. The DNA sequence that can be directly compared between the two genomes is almost 99 percent identical. When DNA insertions and deletions are taken into account, humans and chimpanzees still share 96 percent sequence identity. At the protein level, 29 percent of genes code for the same amino sequences in chimpanzees and humans. In fact, the typical human protein has accumulated just one unique change since chimpanzees and humans diverged from a common ancestor about 6 million years ago.

2. A few classes of genes are changing unusually quickly in both humans and chimpanzees compared with other mammals. These classes include genes involved in perception of sound, transmission of nerve signals, production of sperm and cellular transport of ions. The rapid evolution of these genes may have contributed to the special characteristics of primates.

3. Humans and chimpanzees have accumulated more potentially deleterious mutations in their genomes over the course of evolution than have mice, rats and other rodents. While such mutations can cause diseases that may erode a species' overall fitness, they may have also made primates more adaptable to rapid environmental changes and enabled them to achieve unique evolutionary adaptations.

4. About 35 million DNA base pairs differ between the shared portions of the two genomes. In addition, there are another 5 million sites that differ because of an insertion or deletion in one of the lineages, along with a much smaller number of chromosomal rearrangements. Most of these differences lie in what is believed to be DNA of little or no function. However, as many as 3 million of the differences are found in crucial protein-coding genes or other functional areas of the genome. Somewhere in these relatively few differences lies the biological basis for the unique characteristics of the human species, including human-specific diseases such as Alzheimer's disease, certain cancers, and HIV/AIDS.

5. Although the statistical signals are relatively weak, a few classes of genes appear to be evolving more rapidly in humans than in chimpanzees. The single strongest outlier involves genes that code for transcription factors, molecules that regulate the activity of other genes and that play key roles in embryonic development.

6. A small number of other genes have undergone even more dramatic changes. More than 50 genes present in the human genome are missing or partially deleted from the chimpanzee genome. The corresponding number of gene deletions in the human genome is not yet precisely known. For example, three key genes involved in inflammation appear to be deleted in the chimpanzee genome, possibly explaining some of the known differences between chimpanzees and humans in respect to immune and inflammatory response. On the other hand, humans appear to have lost the function of the caspase-12 gene, which produces an enzyme that may affect the progression of Alzheimer's disease.

7. There are six regions in the human genome that have strong signatures of selective sweeps over the past 250,000 years (selective sweeps occur when a mutation arises in a population and is so advantageous that it spreads throughout the population within a few hundred generations and eventually becomes "normal.") One region contains more than 50 genes, while another contains no known genes and lies in an area that scientists refer to as a "gene desert." Intriguingly, this gene desert may contain elements regulating the expression of a nearby protocadherin gene, which has been implicated in patterning of the nervous system.

A seventh region with moderately strong signals contains the FOXP2 and CFTR genes. FOXP2 has been implicated in the acquisition of speech in humans. CFTR, which codes for a protein involved in ion transport and, if mutated, can cause the fatal disease cystic fibrosis, is thought to be the target of positive selection in European populations.

The initial complete sequence of the chimpanzee genome and comparison to the human genome is an important milestone in what will be several years of intensive work at understanding human evolutionary history and applying these data to biomedical research. The fact that these data, and all future data from the Consortium, are being placed in the public domain means that scientists worldwide can contribute to this work.

The 67 researchers who took part in the Chimpanzee Sequencing and Analysis Consortium share authorship of the Nature paper. The sequencing and assembly of the chimpanzee genome was done at the Broad Institute and at the Washington University School of Medicine in Saint Louis, MO. In addition to those centers, the consortium included researchers from institutions elsewhere in the United States, as well as Israel, Italy, Germany and Spain. The work of the Chimpanzee Sequencing and Analysis Consortium is funded in part by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health.

The team was co-led by Lander, Richard Wilson of the Washington University School of Medicine in Saint Louis, MO and Robert Waterston of the University of Washington, Seattle WA.

A complete list of authors and affiliations can be found at http://www.nature.com/.

About the Broad Institute of MIT and Harvard

The Broad Institute of MIT and Harvard was founded in 2003 to bring the power of genomics to biomedicine. It pursues this mission by empowering creative young scientists to construct new and robust tools for genomic medicine, to make them accessible to the global scientific community, and to apply them to the understanding and treatment of disease.

The Institute is a research collaboration that involves faculty, professional staff and students from throughout the MIT and Harvard academic and medical communities. It is governed jointly by the two universities.

Organized around Scientific Programs and Scientific Platforms, the unique structure of the Broad Institute enables scientists to collaborate on transformative projects across many scientific and medical disciplines.

For further information about the Broad Institute, go to http://www.broad.mit.edu/.