WASHINGTON, Wed., Aug. 31, 2005 -- The first comprehensive comparisonof the genetic blueprints of humans and chimpanzees shows our closestliving relatives share perfect identity with 96 percent of our DNAsequence, an international research consortium reported today.
In a paper published in the Sept. 1 issue of the journal Nature, theChimpanzee Sequencing and Analysis Consortium, which is supported inpart by the National Human Genome Research Institute (NHGRI), one ofthe National Institutes of Health (NIH), describes its landmarkanalysis comparing the genome of the chimp (Pan troglodytes) with thatof human (Homo sapiens).
"The sequencing of the chimp genome is a historic achievementthat is destined to lead to many more exciting discoveries withimplications for human health," said NHGRI Director Francis S. Collins,M.D., Ph.D. "As we build upon the foundation laid by the Human GenomeProject, it's become clear that comparing the human genome with thegenomes of other organisms is an enormously powerful tool forunderstanding our own biology."
The chimp sequence draft represents the first non-humanprimate genome and the fourth mammalian genome described in a majorscientific publication. A draft of the human genome sequence waspublished in February 2001, a draft of the mouse genome sequence waspublished in December 2002 and a draft of the rat sequence waspublished in March 2004. The essentially complete human sequence waspublished in October 2004.
"As our closest living evolutionary relatives, chimpanzees areespecially suited to teach us about ourselves," said the study's seniorauthor, Robert Waterston, M.D., Ph.D., chair of the Department ofGenome Sciences of the University of Washington School of Medicine inSeattle. "We still do not have in our hands the answer to a mostfundamental question: What makes us human? But this genomic comparisondramatically narrows the search for the key biological differencesbetween the species."
The 67 researchers who took part in the Chimp Sequencing andAnalysis Consortium share authorship of the Nature paper. Most of thework of sequencing and assembling the chimp genome was done at theBroad Institute of the Massachusetts Institute of Technology andHarvard University, Cambridge, Mass., and the Washington UniversitySchool of Medicine in Saint Louis. In addition to those centers, theconsortium included researchers from institutions elsewhere in theUnited States, as well as Israel, Italy, Germany and Spain.
The DNA used to sequence the chimp genome came from the bloodof a male chimpanzee named Clint at theYerkes National Primate ResearchCenter in Atlanta. Clint died last year from heart failure at therelatively young age of 24, but two cell lines from the primate havebeen preserved at the Coriell Institute for Medical Research in Camden,N.J.
The consortium found that the chimp and human genomes are verysimilar and encode very similar proteins. The DNA sequence that can bedirectly compared between the two genomes is almost 99 percentidentical. When DNA insertions and deletions are taken into account,humans and chimps still share 96 percent of their sequence. At theprotein level, 29 percent of genes code for the same amino sequences inchimps and humans. In fact, the typical human protein has accumulatedjust one unique change since chimps and humans diverged from a commonancestor about 6 million years ago.
To put this into perspective, the number of geneticdifferences between humans and chimps is approximately 60 times lessthan that seen between human and mouse and about 10 times less thanbetween the mouse and rat. On the other hand, the number of geneticdifferences between a human and a chimp is about 10 times more thanbetween any two humans.
The researchers discovered that a few classes of genes arechanging unusually quickly in both humans and chimpanzees compared withother mammals. These classes include genes involved in perception ofsound, transmission of nerve signals, production of sperm and cellulartransport of electrically charged molecules called ions. Researcherssuspect the rapid evolution of these genes may have contributed to thespecial characteristics of primates, but further studies are needed toexplore the possibilities.
The genomic analyses also showed that humans and chimps appearto have accumulated more potentially deleterious mutations in theirgenomes over the course of evolution than have mice, rats and otherrodents. While such mutations can cause diseases that may erode aspecies' overall fitness, they may have also made primates moreadaptable to rapid environmental changes and enabled them to achieveunique evolutionary adaptations, researchers said.
Despite the many similarities found between human and chimpgenomes, the researchers emphasized that important differences existbetween the two species. About 35 million DNA base pairs differ betweenthe shared portions of the two genomes, each of which, like mostmammalian genomes, contains about 3 billion base pairs. In addition,there are another 5 million sites that differ because of an insertionor deletion in one of the lineages, along with a much smaller number ofchromosomal rearrangements. Most of these differences lie in what isbelieved to be DNA of little or no function. However, as many as 3million of the differences may lie in crucial protein-coding genes orother functional areas of the genome.
"As the sequences of other mammals and primates emerge in thenext couple of years, we will be able to determine what DNA sequencechanges are specific to the human lineage. The genetic changes thatdistinguish humans from chimps will likely be a very small fraction ofthis set," said the study's lead author, Tarjei S. Mikkelsen of theBroad Institute of MIT and Harvard. Among the genetic changes thatresearchers will be looking for are those that may be related to thehuman-specific features of walking upright on two feet, a greatlyenlarged brain and complex language skills.
Although the statistical signals are relatively weak, a fewclasses of genes appear to be evolving more rapidly in humans than inchimps. The single strongest outlier involves genes that code fortranscription factors, which are molecules that regulate the activityof other genes and that play key roles in embryonic development.
A small number of other genes have undergone even moredramatic changes. More than 50 genes present in the human genome aremissing or partially deleted from the chimp genome. The correspondingnumber of gene deletions in the human genome is not yet preciselyknown. For genes with known functions, potential implications of thesechanges can already be discerned.
For example, the researchers found that three key genesinvolved in inflammation appear to be deleted in the chimp genome,possibly explaining some of the known differences between chimps andhumans in respect to immune and inflammatory response. On the otherhand, humans appear to have lost the function of the caspase-12 gene,which produces an enzyme that may help protect other animals againstAlzheimer's disease.
"This represents just the tip of the iceberg when it comes toexploring the genomic roots of our biological differences," said one ofthe study's co-authors LaDeana W. Hillier of the Genome SequencingCenter at Washington University School of Medicine. "As more is learnedabout other functional elements of the genome, we anticipate that otherimportant differences outside of the protein-coding genes will emerge."
Armed with the chimp sequence, researchers also scanned theentire human genome for deviations from normal mutation patterns. Suchdeviations may reveal regions of "selective sweeps," which occur when amutation arises in a population and is so advantageous that it spreadsthroughout the population within a few hundred generations andeventually becomes "normal."
The researchers found six regions in the human genome that havestrong signatures of selective sweeps over the past 250,000 years. Oneregion contains more than 50 genes, while another contains no knowngenes and lies in an area that scientists refer to as a "gene desert."Intriguingly, this gene desert may contain elements regulating theexpression of a nearby protocadherin gene, which has been implicated inpatterning of the nervous system. A seventh region with moderatelystrong signals contains the FOXP2 and CFTR genes. FOXP2 has beenimplicated in the acquisition of speech in humans. CFTR, which codesfor a protein involved in ion transport and, if mutated, can cause thefatal disease cystic fibrosis, is thought to be the target of positiveselection in European populations.
The chimp and human genome sequences, along with those of awide range of other organisms such as mouse, honey bee, roundworm andyeast, can be accessed through the following public genome browsers:GenBank (www.ncbi.nih.gov/Genbank) at NIH's National Center for Biotechnology Information (NCBI); the UCSC Genome Browser (www.genome.ucsc.edu) at the University of California at Santa Cruz; the Ensembl Genome Browser (www.ensembl.org) at the Wellcome Trust Sanger Institute and the EMBL-European Bioinformatics Institute; the DNA Data Bank of Japan (www.ddbj.nih.ac.jp); and EMBL-Bank (www.ebi.ac.uk/embl/index.html) at the European Molecular Biology Laboratory's Nucleotide Sequence Database.
NHGRI is one of 27 institutes and centers at the NIH, an agency ofthe Department of Health and Human Services. The NHGRI Division ofExtramural Research supports grants for research and for training andcareer development at sites nationwide. Additional information aboutNHGRI can be found at its Web site, www.genome.gov.
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