Post by Bozur on Nov 13, 2005 14:52:41 GMT -5
Genetic Catalog May Aid Search for Roots of Disease
By NICHOLAS WADE
Published: October 27, 2005
In a follow-up to the Human Genome Project, a consortium of scientists has compiled a partial catalog of human genetic variation that it hopes will speed the search for the genetic roots of many common diseases.
The catalog is based on analyzing the genomes of people from four ethnic groups - Europeans, Japanese, Chinese and the Yoruba of Nigeria - and it has so far identified about three million sites on the three-billion-unit human genome where some people have different DNA units. These variations help make everyone unique, but they may also be the reason why people have propensities toward certain diseases.
The $138 million project was undertaken by about 200 researchers in six countries. About a third of the DNA variations were analyzed in the United States, a quarter each in Japan and Britain, and 10 percent each in China and Canada. The analysis of the variations, reported in today's issue of Nature, was done principally by Dr. David Altshuler of Massachusetts General Hospital and Dr. Peter Donnelly of the University of Oxford in England.
The catalog is intended to provide a shortcut through a frustrating medical problem. Many common diseases run in families, indicating that they have a genetic basis, but the genes involved have so far proved elusive. Unlike rare diseases, which tend to be caused by a single gene with a clear family pedigree, common diseases like cancer and diabetes probably spring from several predisposing variant genes, each of which has only a small effect and so is hard to pinpoint.
In principle, researchers could decode the whole genome of hundreds of patients with a disease and see if they had any DNA changes - or mutations - in common. That would be far too expensive. But four years ago, Dr. Mark J. Daly, now of the Broad Institute in Cambridge, Mass., found that the human genome exists in a blocky structure, because long segments of DNA largely escape the shuffling of the genetic material that takes place between generations.
These blocks, known to geneticists as haplotypes, offer a shortcut to finding variant genes, because instead of looking at every DNA unit in the genome, researchers could ask just which blocks of DNA the patients with a particular disease have in common, greatly narrowing the search for the mutations that cause the illness.
Amid much skepticism from other geneticists, Dr. Daly and Dr. Altshuler, along with Eric Lander, now the director of the Broad Institute, set out to construct a catalog of the haplotypes in the human genome, known inevitably as the hapmap, although no map is involved. The haplotypes are simply chunks of DNA, often thousands of units in length, in which several common DNA mutations have been inherited as a block.
With the catalog now available, about 95 percent of the human genome has turned out to exist as haplotypes, a much larger proportion than at first expected. Researchers have already succeeded in identifying some variant genes with the approach, like one that contributes significantly to macular degeneration. "The pace of discovery will certainly accelerate," Dr. Altshuler said.
What is not yet clear is what degree of success the hapmap approach will meet with. It covers only one kind of genetic variation, although a major one, the common mutations in DNA. Other kinds of change in the human genome include the addition or deletion of DNA units, repetitions like those that underlie forensic DNA tests and the flipping of large segments of DNA within a chromosome.
In addition, the hapmap approach will work best if the mutations that cause disease are common, not rare, which is a matter of dispute. Dr. Kari Stefansson, chief executive of DeCode Genetics, an Icelandic company that has found several disease genes through an alternative, family-based approach, believes that many disease-causing mutations are rare and will therefore elude the hapmap strategy. Dr. Altshuler said, however, that all the disease genes found so far by Dr. Stefansson's company were in fact common.
In a commentary in this week's Nature, Dr. David Goldstein, a geneticist at Duke University who was not involved in the hapmap project, writes that "there are no guarantees" of the hapmap's success. If disease-causing mutations are common, Dr. Goldstein wrote, the hapmap "will greatly accelerate the identification of disease-related genetic variation."
"But if the responsible variants are rare," he said, "they will be more difficult to find."
Finding a causative gene shows researchers the biochemical pathway through which a disease is caused, and may lead to new treatments and diagnostic tests, though in some cases the information is hard to put to any use.
Besides the hapmap's potential importance for medicine, it has undoubted significance for understanding the biology of the human genome and its recent evolution. The hapmap team has already identified 14 regions of the genome that show signs of having changed in different ethnic groups under the pressure of natural selection. One of the most striking, though known already from earlier studies, is a DNA region in Europeans that confers lactose tolerance, the unusual ability to digest milk in adulthood. This genetic propensity is known to have arisen among cattle herders of northern Europe some 5,000 years ago.
Other genomic regions bear strong marks of natural selection but contain no known gene, a highly perplexing outcome that suggests, Dr. Altshuler said, that "our current ability to predict the function of DNA is very flawed."
The common variation picked up by the hapmap is much the same in different ethnic groups, because most of it is inherited from the ancestral human population before modern humans are believed to have dispersed from Africa about 50,000 years ago. The four ethnic groups studied so far have yielded four million sites of common variation, from which the total number in the world's population is expected to be 10 million.
The hapmap researchers have found that the Chinese and Japanese genomes are so similar that they can be grouped together for many purposes. The genetic differences between Europeans, East Asians and Africans lie mostly in the relative abundance in each of the common DNA mutations. But the hapmap team has found a handful of fixed differences in the first million mutations it studied - 11 between Europeans and the Yoruba, 21 between Europeans and Asians and 5 between the Yoruba and Asians. The role of these mutations is unknown.
A more marked difference emerged on the X chromosome, which is more highly differentiated between ethnic groups than are the other chromosomes. The reason, Dr. Altshuler said, could arise from the fact that men carry only one X chromosome and so, unlike women, have no backup copy if a gene on their single X is inactivated through mutation. That puts the X chromosome under heavy pressure of natural selection when it is carried by a man, and the different pressures experienced by various ethnic groups may have forced the X chromosome to differentiate more than the other chromosomes.
The hapmap team believe they have created a powerful new tool for exploring the human genome but they advise researchers to be careful about publicizing their work, especially when exploring genetic links to human characteristics that are not medical. "We urge conservatism and restraint in the public dissemination and interpretation of such studies, especially if nonmedical phenotypes are explored," they wrote.
By NICHOLAS WADE
Published: October 27, 2005
In a follow-up to the Human Genome Project, a consortium of scientists has compiled a partial catalog of human genetic variation that it hopes will speed the search for the genetic roots of many common diseases.
The catalog is based on analyzing the genomes of people from four ethnic groups - Europeans, Japanese, Chinese and the Yoruba of Nigeria - and it has so far identified about three million sites on the three-billion-unit human genome where some people have different DNA units. These variations help make everyone unique, but they may also be the reason why people have propensities toward certain diseases.
The $138 million project was undertaken by about 200 researchers in six countries. About a third of the DNA variations were analyzed in the United States, a quarter each in Japan and Britain, and 10 percent each in China and Canada. The analysis of the variations, reported in today's issue of Nature, was done principally by Dr. David Altshuler of Massachusetts General Hospital and Dr. Peter Donnelly of the University of Oxford in England.
The catalog is intended to provide a shortcut through a frustrating medical problem. Many common diseases run in families, indicating that they have a genetic basis, but the genes involved have so far proved elusive. Unlike rare diseases, which tend to be caused by a single gene with a clear family pedigree, common diseases like cancer and diabetes probably spring from several predisposing variant genes, each of which has only a small effect and so is hard to pinpoint.
In principle, researchers could decode the whole genome of hundreds of patients with a disease and see if they had any DNA changes - or mutations - in common. That would be far too expensive. But four years ago, Dr. Mark J. Daly, now of the Broad Institute in Cambridge, Mass., found that the human genome exists in a blocky structure, because long segments of DNA largely escape the shuffling of the genetic material that takes place between generations.
These blocks, known to geneticists as haplotypes, offer a shortcut to finding variant genes, because instead of looking at every DNA unit in the genome, researchers could ask just which blocks of DNA the patients with a particular disease have in common, greatly narrowing the search for the mutations that cause the illness.
Amid much skepticism from other geneticists, Dr. Daly and Dr. Altshuler, along with Eric Lander, now the director of the Broad Institute, set out to construct a catalog of the haplotypes in the human genome, known inevitably as the hapmap, although no map is involved. The haplotypes are simply chunks of DNA, often thousands of units in length, in which several common DNA mutations have been inherited as a block.
With the catalog now available, about 95 percent of the human genome has turned out to exist as haplotypes, a much larger proportion than at first expected. Researchers have already succeeded in identifying some variant genes with the approach, like one that contributes significantly to macular degeneration. "The pace of discovery will certainly accelerate," Dr. Altshuler said.
What is not yet clear is what degree of success the hapmap approach will meet with. It covers only one kind of genetic variation, although a major one, the common mutations in DNA. Other kinds of change in the human genome include the addition or deletion of DNA units, repetitions like those that underlie forensic DNA tests and the flipping of large segments of DNA within a chromosome.
In addition, the hapmap approach will work best if the mutations that cause disease are common, not rare, which is a matter of dispute. Dr. Kari Stefansson, chief executive of DeCode Genetics, an Icelandic company that has found several disease genes through an alternative, family-based approach, believes that many disease-causing mutations are rare and will therefore elude the hapmap strategy. Dr. Altshuler said, however, that all the disease genes found so far by Dr. Stefansson's company were in fact common.
In a commentary in this week's Nature, Dr. David Goldstein, a geneticist at Duke University who was not involved in the hapmap project, writes that "there are no guarantees" of the hapmap's success. If disease-causing mutations are common, Dr. Goldstein wrote, the hapmap "will greatly accelerate the identification of disease-related genetic variation."
"But if the responsible variants are rare," he said, "they will be more difficult to find."
Finding a causative gene shows researchers the biochemical pathway through which a disease is caused, and may lead to new treatments and diagnostic tests, though in some cases the information is hard to put to any use.
Besides the hapmap's potential importance for medicine, it has undoubted significance for understanding the biology of the human genome and its recent evolution. The hapmap team has already identified 14 regions of the genome that show signs of having changed in different ethnic groups under the pressure of natural selection. One of the most striking, though known already from earlier studies, is a DNA region in Europeans that confers lactose tolerance, the unusual ability to digest milk in adulthood. This genetic propensity is known to have arisen among cattle herders of northern Europe some 5,000 years ago.
Other genomic regions bear strong marks of natural selection but contain no known gene, a highly perplexing outcome that suggests, Dr. Altshuler said, that "our current ability to predict the function of DNA is very flawed."
The common variation picked up by the hapmap is much the same in different ethnic groups, because most of it is inherited from the ancestral human population before modern humans are believed to have dispersed from Africa about 50,000 years ago. The four ethnic groups studied so far have yielded four million sites of common variation, from which the total number in the world's population is expected to be 10 million.
The hapmap researchers have found that the Chinese and Japanese genomes are so similar that they can be grouped together for many purposes. The genetic differences between Europeans, East Asians and Africans lie mostly in the relative abundance in each of the common DNA mutations. But the hapmap team has found a handful of fixed differences in the first million mutations it studied - 11 between Europeans and the Yoruba, 21 between Europeans and Asians and 5 between the Yoruba and Asians. The role of these mutations is unknown.
A more marked difference emerged on the X chromosome, which is more highly differentiated between ethnic groups than are the other chromosomes. The reason, Dr. Altshuler said, could arise from the fact that men carry only one X chromosome and so, unlike women, have no backup copy if a gene on their single X is inactivated through mutation. That puts the X chromosome under heavy pressure of natural selection when it is carried by a man, and the different pressures experienced by various ethnic groups may have forced the X chromosome to differentiate more than the other chromosomes.
The hapmap team believe they have created a powerful new tool for exploring the human genome but they advise researchers to be careful about publicizing their work, especially when exploring genetic links to human characteristics that are not medical. "We urge conservatism and restraint in the public dissemination and interpretation of such studies, especially if nonmedical phenotypes are explored," they wrote.