8 new human genomes offer large-scale picture of genetic variation
Projects give view of structural differences among individuals and find previously unknown human DNA
Thursday, 01 May 2008
A nationwide consortium led by the University of Washington in Seattle has completed the first sequence-based map of structural variations in the human genome, giving scientists an overall picture of the large-scale differences in DNA between individuals. The project gives researchers a guide for further research into these structural differences, which are believed to play an important role in human health and disease. The results appear in the May 1 issue of the journal Nature.
The project involved sequencing the genomes of eight people from a diverse set of ethnic backgrounds: four individuals of African descent, two of Asian descent, and two of European background. The researchers created what's called a clone map, taking multiple copies of each of the eight genomes and breaking them into numerous segments of about 40,000 base pairs, which they then fit back together based on the human reference genome. They searched for structural differences that ranged in size from a few thousand to a few million base pairs. Base pairs are one of the basic units of information on the human genome.
Most previous studies of the genome have focused on small genetic variations called SNPs (pronounced "snips"), or single-nucleotide polymorphisms – changes on the scale of a single base pair. More recent research on the human genome has shown, however, that larger-scale differences may account for a great deal of genetic variation among individuals. Structural variation in the human genome has already been linked to individual differences in susceptibility to conditions like coronary heart disease, HIV, schizophrenia, autism, and mental retardation.
In addition to millions of smaller differences, the researchers identified 1695 regions of structural variation in the genome. They also provided a detailed look at the sequence for 261 regions of the genome, revealing an unprecedented view of the complexity of the genetic differences among different humans. The large-scale differences that the researchers were looking for can come in many forms, such as the deletion of a large swath of DNA, or the insertion of an out-of-place string of genetic code. Others simply appear as a different number of copies of a gene or DNA sequence.
Until now, there has not been a comprehensive study to sequence these variations systematically in multiple individuals. As part of their study, the authors also discovered 525 segments of DNA that were previously unknown to the human genetics community.
"There is a perception that the human genome is essentially completely understood," explained the project's leader, Dr. Evan Eichler, UW associate professor of genome sciences and an investigator for the Howard Hughes Medical Institute.
"The sequences we have identified range in size from a few thousand to hundreds of thousands of base pairs, and are not part of the published human genome reference sequence. We found that many of these are highly variable in copy and content between individuals. This represents uncharted territory that can now be examined in more detail to determine the function of these new segments of the human genome with respect to disease and gene activity."
Eichler expects that the structural variation map will give scientists a much better picture of genetic variations, and help them better understand these areas of the genome that are prone to large-scale changes over time. Even more research is needed on structural variations, the scientists argue in the article, to help get a more accurate picture of the human genome than what we already have in the reference genome constructed by the Human Genome Project.
"The important point here is that we could not have found these differences without sequencing more human genomes from individuals of diverse ancestry to a high-quality standard," Eichler added.
The project will also serve as a sound resource for the science community, said Eichler, since the researchers have preserved the many segments of DNA used for the project. As new genomes are studied, someone might find a new sequence or new area of variation, and the researchers can revisit that particular segment of DNA to study it more closely.
In addition to Eichler, several UW researchers in the UW Departments of Genome Sciences and Medicine worked on the project, including Jeffrey Kidd, a graduate student in genome sciences, and Maynard Olson, professor of medicine and genome sciences and director of the UW Genome Center.
The project also included researchers at Agencourt Bioscience Corp. in Beverly, Mass.; Agilent Technologies in Santa Clara, Calif.; Washington University School of Medicine in St. Louis; the National Human Genome Research Institute in Bethesda, Md.; the University of Wisconsin, in Madison; the Broad Institute of MIT and Harvard, in Cambridge, Mass.; and Illumina, Inc. in San Diego. The researchers were supported by the National Science Foundation, the Jane Coffin Childs Memorial Fund, Merck, and the National Human Genome Research Institute, part of the National Institutes of Health.
See also:
International Human Genome Project Launched
CellNEWS - Wednesday, 23 January 2008
.........
ZenMaster
For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/ and
http://www.geocities.com/giantfideli/index.html
Friday, 2 May 2008
Large-scale Genetic Differences in Humans II
Large-scale Genetic Differences in Humans I
Researchers produce first sequence map of large-scale structural variation in human genome Map will boost efforts to explore role of structural variants in disease Thursday, 01 May 2008 A nationwide team of researchers, funded in part by the National Human Genome Research Institute (NHGRI), one of the National Institutes of Health (NIH), has produced the first sequence-based map of large-scale structural variation across the human genome. The work, published today in the journal Nature, provides a starting point to examine how such DNA variation contributes to human health and disease. Other recently created maps, such as the HapMap, have catalogued the patterns of small-scale variations in the genome that involve single DNA letters, or bases. However, the scientific community has been eagerly awaiting the creation of additional types of maps in light of findings that larger scale differences account for a great deal of the common genetic variation among individuals and between populations, and may account for a significant fraction of disease. While previous work has identified structural variation in the human genome, a sequence-based map provides much finer resolution and location information. Large-scale structural variations are differences in the genome among people that range from a few thousand to a few million DNA bases. Some are gains or losses of stretches of genome sequence. Others appear as re-arrangements of stretches of sequence. Already, some structural variations have been linked to individual differences in susceptibility to the human immunodeficiency virus (HIV), risk of coronary heart disease, as well as to schizophrenia and autism. Researchers hope the new map will open the door to uncovering the functions of structural variants in even more conditions. “It is important that we understand how changes in the human genome, both small and large, contribute to individual differences in susceptibility to diseases,” said Francis Collins, M.D., Ph.D. “This map is a valuable starting point for researchers studying the normal patterns of structural variation and how differences in those patterns affect human health.” Researchers constructed the structural variation map by partially sequencing the genomes of eight people: four people of African descent, two of Asian descent and two of European descent. The samples were collected as part of the International HapMap Project. No medical or personal identifying information was obtained from the donors, but the samples were labelled by population group. Sequence data were collected from each end of roughly 1 million random small pieces of DNA from each individual’s genome. These end sequences were compared to the reference sequence of the human genome completed in 2003. Where precise matches did not occur, the scientists inferred that there was a structural difference between the volunteer’s sample and the reference sequence of the human genome. In addition to revealing new variations, the map also provides a more detailed look at the locations of nearly 1,700 structural variations – half of which had not been previously described. About half of the structural variations were found in at least two of the eight genomes analyzed. The work also uncovered 525 new regions of large-scale structural variation in the human genome. The large-scale differences came in many forms, including deletions and out-of-place insertions of long stretches of DNA. Almost half of the new variations consist of differences in how many copies individuals have of a certain gene, which researchers refer to as a copy number variant. "The structural variation map will give us a much better picture of genetic variation between each individual, and help us better understand these areas of the genome that are prone to large-scale changes over time," said Evan Eichler, Ph.D., of the University of Washington, who led the research. About the project: Sequence data from the structural variation map are publicly available through the NIH’s National Center for Biotechnology Information Trace Archive. Mapping data are also freely available from the University of Washington. In addition to Eichler and his colleagues at the University of Washington, the project included researchers at Agencourt Bioscience Corp., Beverly, Mass.; Agilent Technologies, Santa Clara, Calif.; Washington University School of Medicine, St. Louis; Division of Intramural Research, NHGRI, Bethesda, Md.; the University of Wisconsin, Madison; the Broad Institute of MIT and Harvard, Cambridge, Mass.; and Illumina, Inc., San Diego. NHGRI is one of 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Extramural Research supports grants for research and for training and career development at sites nationwide. The National Institutes of Health — "The Nation's Medical Research Agency" — includes 27 institutes and centers, and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. See also: International Human Genome Project Launched CellNEWS - Wednesday, 23 January 2008 ......... ZenMaster
For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html
New Approaches to Islet Transplantation
Studies test new approaches to islet transplantation Friday, 02 May 2008 Researchers from 11 medical centers in the United States, Canada, Sweden, and Norway have begun testing new approaches to transplanting clusters of insulin-producing islets in adults with difficult-to-control type 1 diabetes. The clinical studies, funded by the National Institutes of Health (NIH), will determine whether changes to current methods of islet transplantation lead to improved, long-lasting control of blood glucose with fewer side effects. In islet transplantation, clusters of islets are extracted from a donor pancreas and infused into the recipient’s liver. In a successful transplant, the islets become embedded in the liver and begin producing insulin. “A major goal of the NIH research program in type 1 diabetes is to develop therapies that replace the insulin-producing cells destroyed by the autoimmune process,” said NIH Director Elias A. Zerhouni, M.D. “These studies, which build on advances in immunology and transplantation research, may open the door to more widespread use of islet transplantation for patients with severe type 1 diabetes.” About 5 percent to 10 percent of the nearly 21 million people with diabetes have type 1, formerly known as juvenile onset diabetes or insulin-dependent diabetes. In type 1 diabetes, a person’s own immune cells attack and destroy pancreatic beta cells, which produce the hormone insulin needed for survival. Beta cells, along with several other types of cells that work together to balance blood glucose, reside in islets, also known as islets of Langerhans, in the pancreas. Three or more insulin injections a day or treatment with an insulin pump are often needed to maintain blood glucose control, but most people with type 1 diabetes still develop complications, including damage to the heart and blood vessels, eyes, nerves, and kidneys. Despite steady improvements in managing the disease, type 1 diabetes cuts lives short by about 15 years, with early deaths due mainly to heart attacks and strokes. In 2000, a research team led by Dr. James Shapiro at the University of Alberta in Edmonton, Canada, reported sustained insulin independence in seven patients transplanted with islets from two to four donor pancreases and treated with an immunosuppressive regimen that omitted glucocorticoids, thought to be toxic to islets. In the next few years, other researchers replicated the “Edmonton protocol,” and most centers adopted this approach to islet transplantation. The protocol greatly benefits some patients with severe type 1 diabetes, but two or more infusions of islets are usually needed, and the islets tend to lose their insulin-producing function over time. Participating in an islet transplant study is appropriate for people with severe hypoglycaemia (dangerously low levels of blood sugar) and for those with type 1 diabetes who have had a kidney transplant to treat kidney failure, a complication of diabetes. Since the Edmonton advance, scientists have been working to lengthen the survival of donor islets and reduce the side effects — such as anaemia, nerve and kidney damage, and vulnerability to infection — of drugs that prevent the body’s destruction of donor islets. In the new studies, the researchers will culture islets before transplantation to enhance their viability. They will also compare specific anti-rejection drugs for the ability to maximize islet survival while reducing toxicity. As the procedure becomes safer and new sources of beta cells become available, more people are likely to benefit. The researchers are conducting pilot, or phase 1/2, studies of experimental agents as well as phase 3 studies that modify the Edmonton protocol. If the phase 3 studies succeed in safely controlling blood glucose levels, the investigators may ask the Food and Drug Administration to approve the procedure for people with poorly controlled type 1 diabetes. “If these approaches are successful in prolonging islet function with less drug toxicity, type 1 diabetes patients with severe problems controlling their blood glucose may have another treatment option for controlling their diabetes,” said study chair Dr. Camillo Ricordi of the University of Miami. The studies are enrolling individuals with type 1 diabetes who have serious difficulty controlling their blood glucose despite intensive medical therapy and who suffer from episodes of severe hypoglycaemia (dangerously low levels of blood glucose). Also eligible are patients with severe hypoglycaemia and hypoglycaemia unawareness, who cannot sense a drop in blood glucose and may lose consciousness without warning. In addition, researchers are accepting type 1 diabetes patients who have had a kidney transplant and are already taking immunosuppressive drugs. The following researchers are conducting the studies: Dr. Camillo Ricordi, study chair University of Miami Dr. Christian Larsen, Emory University, Atlanta Dr. Dixon Kaufman, Northwestern University, Chicago Dr. Bernhard Hering, University of Minnesota, Minneapolis Dr. Ali Naji, University of Pennsylvania, Philadelphia Dr. Peter Stock, University of California, San Francisco Dr. James Shapiro, University of Alberta, Edmonton, Canada Dr. Jose Oberholzer, University of Illinois at Chicago Dr. Aksel Foss, University Hospital Rikshospitalet, Oslo, Norway Dr. Olle Korsgren, Uppsala University Hospital, Uppsala, Sweden Dr. Annika Tibell, Karolinska University Hospital, Stockholm, Sweden Dr. William Clarke, oversees the Consortium’s Data Coordinating Center at the University of Iowa About: For more information about the studies see the Clinical Islet Transplantation (CIT) Consortium. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Allergy and Infectious Diseases (NIAID), components of the NIH, are sponsoring the studies. The studies are funded by a special Congressional funding program for type 1 diabetes research, recently extended through fiscal year 2009, which supplements the regular NIH appropriation for diabetes research. The NIDDK conducts and supports research in diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies. The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. ......... ZenMaster
For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html
Posts
