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International Human Genome Sequencing Consortium
Describes Finished Human Genome Sequence
Researchers Trim Count of Human Genes to 20,000-25,000
BETHESDA, Md., Wed., Oct. 20, 2004 - The International Human Genome Sequencing Consortium, led in the United States by the National Human Genome Research Institute (NHGRI) and the Department of Energy (DOE), today published its scientific description of the finished human genome sequence, reducing the estimated number of human protein-coding genes from 35,000 to only 20,000-25,000, a surprisingly low number for our species.
The paper appears in the Oct. 21 issue of the journal Nature. In the paper, researchers describe the final product of the Human Genome Project, which was the 13-year effort to read the information encoded in the human chromosomes that reached its culmination in 2003. The Nature publication provides rigorous scientific evidence that the genome sequence produced by the Human Genome Project has both the high coverage and accuracy needed to perform sensitive analyses, such as focusing on the number of genes, the segmental duplications involved in disease and the "birth" and "death" of genes over the course of evolution.
"Only a decade ago, most scientists thought humans had about 100,000 genes. When we analyzed the working draft of the human genome sequence three years ago, we estimated there were about 30,000 to 35,000 genes, which surprised many. This new analysis reduces that number even further and provides us with the clearest picture yet of our genome," said NHGRI Director Francis S. Collins, M.D., Ph.D. "The availability of the highly accurate human genome sequence in free public databases enables researchers around the world to conduct even more precise studies of our genetic instruction book and how it influences health and disease."
One of the central goals of the effort to analyze the human genome is the identification of all genes, which are generally defined as stretches of DNA that code for particular proteins. According to the new findings, researchers have confirmed the existence of 19,599 protein-coding genes in the human genome and identified another 2,188 DNA segments that are predicted to be protein-coding genes.
"The analysis found that some of the earlier gene models were erroneous
due to defects in the unfinished, draft sequence of the human genome,"
said Jane Rogers, Ph.D., head of sequencing at the Wellcome Trust Sanger Institute
in Hinxton, England. "The task of identifying genes remains challenging,
but has been greatly assisted by the finished human genome sequence, as well
as by the availability of genome sequences from other organisms, better computational
models and other improved resources."
The Nature paper also provides the scientific community with a peer-reviewed
description of the finishing process, and an assessment of the quality of the
finished human genome sequence, which was deposited into public databases in
April 2003. The assessment confirms that the finished sequence now covers more
than 99 percent of the euchromatic (or gene-containing) portion of the human
genome and was sequenced to an accuracy of 99.999 percent, which translates
to an error rate of only 1 base per 100,000 base pairs - 10 times more accurate
than the original goal.
The contiguity of the sequence is also massively improved. The average DNA letter
now sits on a stretch of 38.5 million base pairs of uninterrupted, high-quality
sequence - about 475 times longer than the 81,500 base-pair stretch that was
available in the working draft. Access to uninterrupted stretches of sequenced
DNA can greatly assist researchers hunting for genes and the neighboring DNA
sequences that may regulate their activity, dramatically cutting the effort
and expense required to find regions of the human genome that may contain small
and often rare variants involved in disease.
"Finished" doesn't mean that the human genome sequence is perfect.
There still remain 341 gaps in the finished human genome sequence, in contrast
to the 150,000 gaps in the working draft announced in June 2000. The technology
now available cannot readily close these recalcitrant gaps in the human genome
sequence. Closing those gaps will require more research and new technologies,
rather than industrial-scale efforts like those employed by the Human Genome
Project.
"The human genome sequence far exceeds our expectations in terms of accuracy,
completeness and continuity. It reflects the dedication of hundreds of scientists
working together toward a common goal - creating a solid foundation for biomedicine
in the 21st century," said Eric Lander, Ph.D., director of the Broad Institute
of MIT and Harvard in Cambridge, Mass.
In addition to reducing the count of human genes, scientists reported that the
improved quality of the finished human genome sequence, compared with earlier
drafts, provides a much clearer picture of certain phenomena such as duplication
of DNA segments and the birth and death of genes.
Segmental duplications are large, almost identical copies of DNA, which are
present in at least two locations in the human genome. A number of human diseases
are known to be associated with mutations in segmentally duplicated regions,
including Williams syndrome, Charcot-Marie-Tooth and DiGeorge syndrome. "Segmental
duplications were almost impossible to study in the draft sequence. Now, through
the unstinting efforts of groups around the world, this important and rapidly
evolving part of our genome is open for scientific exploration," said Robert
H. Waterston, M.D., Ph.D., former director of the Genome Sequencing Center at
Washington University in St. Louis and now chair of the Department of Genome
Sciences at the University of Washington in Seattle.
Segmental duplications cover 5.3 percent of the human genome, significantly
more than in the rat genome, which has about 3 percent, or the mouse genome,
which has between 1 and 2 percent. Segmental duplications provide a window into
understanding how our genome evolved and is still changing. The high proportion
of segmental duplication in the human genome shows our genetic material has
undergone rapid functional innovation and structural change during the last
40 million years, presumably contributing to unique characteristics that separate
us from our non-human primate ancestors.
The consortium's analysis found the distribution of segmental duplications
varies widely across human chromosomes. The Y chromosome is the most extreme
case, with segmental duplications occurring along more than 25 percent of its
length. Some segmental duplications tend to be clustered near the middle (centromeres)
and ends (telomeres) of each chromosome, where, researchers postulate, they
may be used by the genome as an evolutionary laboratory for creating genes with
new functions.
The accuracy of the finished human genome sequence produced by the Human Genome
Project has also given scientists some initial insights into the birth and death
of genes in the human genome. Scientists have identified more than 1,000 new
genes that arose in the human genome after our divergence with rodents some
75 million years ago. Most of these arose through recent gene duplications and
are involved with immune, olfactory and reproductive functions. For example,
there are two families of genes recently duplicated in the human genome that
encode sets of proteins (pregnancy-specific beta-1 glycoprotein and choriogonadotropin
beta proteins) that may be involved in the extended period of pregnancy unique
to humans.
Additionally, researchers used the finished human genome to identify and characterize
33 nearly intact genes that have recently acquired one or more mutations, causing
them to stop functioning, or "die." Scientists pinpointed these non-functioning
genes, referred to as pseudogenes, in the human genome by aligning them with
the mouse and rat genomes, in which the corresponding genes have maintained
their functionality. Interestingly, researchers determined that 10 of these
pseudogenes in the human genome sequence appear to have coded for proteins involved
in olfactory reception, which helps to explain why humans have fewer functional
olfactory receptors and, consequently, a poorer sense of smell than rodents.
The molecular biology of the sense of smell was just recognized by the awarding
of a Nobel Prize in Physiology or Medicine to Richard Axel and Linda B. Buck.
Next, the researchers aligned the 33 pseudogenes with the draft sequence of
the chimpanzee genome to determine whether they were still functional before
Homo sapiens' divergence from great apes about 5 million years ago. The analysis
revealed that 27 of the pseudogenes were non-functional in both humans and chimps.
However, five of the genes that were inactive in humans were found to be still
functional in chimpanzees. "The identification of these pseudogenes and
their functional counterparts in chimpanzee provides fertile ground for future
research projects," said Richard Gibbs, Ph.D., director of Baylor College
of Medicine's Human Genome Sequencing Center in Houston, which currently is
sequencing the genome of another non-human primate, the rhesus macaque (Macaca
mulatta).
More than 2,800 researchers who took part in the International Human Genome
Sequencing Consortium share authorship on today's Nature paper, which expands
upon the group's initial analysis published in Feb. 2001. Even more detailed
annotations and analyses have already been published for chromosomes 5, 6, 7,
9, 10, 13, 14, 19, 20, 21, 22 and Y. Publications describing the remaining 12
chromosomes are forthcoming.
The finished human genome sequence and its annotations 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.
The International Human Genome Sequencing Consortium includes scientists at
20 institutions located in France, Germany, Japan, China, Great Britain and
the United States. The five largest sequencing centers are located at: Baylor
College of Medicine; the Broad Institute of MIT and Harvard; DOE's Joint Genome
Institute, Walnut Creek, Calif.; Washington University School of Medicine; and
the Wellcome Trust Sanger Institute.
NHGRI is one of 27 institutes and centers at the National Institutes of Health,
an agency of the Department of Health and Human Services. Additional information
about NHGRI can be found at its Web site, www.genome.gov.
Contact:
Geoff Spencer
NHGRI
(301) 402-0911
spencerg@mail.nih.gov
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