Genomic Medicine


Ambitious 1000 Genomes Project to
pave way for era of personal medicine

A major genetic sequencing initiative that will produce the most detailed map of human genetic variation will significantly speed up the identification of the genetic root of many common diseases with a view to providing new strategies for prevention, diagnosis and treatment. Middle East Health reports.

The 1000 Genomes Project, an international research consortium announced in January this year, is an ambitious initiative that will sequence the genomes of at least 1,000 people from around the world to create the most detailed and medically useful picture to date of human genetic variation.

The project will lay the groundwork for the personal genomics era of medicine, in which people routinely will have their genomes sequenced to predict their individual risks of disease and response to drugs.

The project will receive major support from the Wellcome Trust Sanger Institute in Hinxton, England, the Beijing Genomics Institute, Shenzhen (BGI Shenzhen) in China and the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH) in the United States.

Drawing on the expertise of multidisciplinary research teams, the 1000 Genomes Project will develop a new map of the human genome that will provide a view of DNA variations at a resolution unmatched by current resources. As with other major human genome reference projects, data from the 1000 Genomes Project will be made available to the scientific community through freely accessible public databases.

“The 1000 Genomes Project will examine the human genome at a level of detail that no one has done before,” said Richard Durbin, PhD, of the Wellcome Trust Sanger Institute, who is co-chair of the consortium. “Such a project would have been unthinkable only two years ago. Today, thanks to amazing strides in sequencing technology, bioinformatics and population genomics, it is now within our grasp. So we are moving forward to build a tool that will greatly expand and further accelerate efforts to find more of the genetic factors involved in human health and disease.”

Any two humans are more than 99% the same at the genetic level. However, it is important to understand the small fraction of genetic material that varies among people because it can help explain individual differences in susceptibility to disease, response to drugs or reaction to environmental factors. Variation in the human genome is organised into local neighbourhoods, called haplotypes, which are stretches of DNA that are usually inherited as intact blocks of information.

Recently developed catalogs of human genetic variation, such as the HapMap, have proved valuable in human genetic research. Using the HapMap and related resources, researchers already have discovered more than 100 regions of the genome containing genetic variants that appear to contribute to common human diseases such as diabetes, coronary artery disease, prostate and breast cancer, rheumatoid arthritis, inflammatory bowel disease and age-related macular degeneration.

However, because existing maps are not extremely detailed, researchers often must follow those studies with costly and time-consuming DNA sequencing to help pinpoint the precise causative variants. The new map would enable researchers to more quickly zero in on disease-related genetic variants, speeding efforts to use genetic information to develop new strategies for diagnosing, treating and preventing common diseases.

The scientific goals of the 1000 Genomes Project are to produce a catalog of variants that are present at 1% or greater frequency in the human population across most of the genome, and down to 0.5% or lower within genes.

“This new project will increase the sensitivity of disease discovery efforts across the genome five-fold and within gene regions at least 10- fold,” said NHGRI director Francis S. Collins, MD, PhD. “Our existing databases do a reasonably good job of cataloging variations found in at least 10% of a population. By harnessing the power of new sequencing technologies and novel computational methods, we hope to give biomedical researchers a genome-wide map of variation down to the 1% level. This will change the way we carry out studies of genetic disease.”

One use of the new catalog will be to follow up genomewide association studies. Investigators who find that a part of the genome is associated with a disease will be able to look it up in the catalog, and find almost all variants in that region. They will then be able to conduct functional studies to see whether any of the catalogued variants directly contribute to the disease. The 1000 Genomes Project builds on the human haplotype map developed by the International HapMap Project. The new map will provide genomic context surrounding the HapMap's genetic variants, giving researchers important clues to which variants might be causal, including more precise information on where to search for causal variants.

Going a major step beyond the HapMap, the 1000 Genomes Project will map not only the single-letter differences in people’s DNA, called single nucleotide polymorphisms (SNPs), but also will produce a high-resolution map of larger differences in genome structure called structural variants. Structural variants are rearrangements, deletions or duplications of segments of the human genome. The importance of these variants has become increasingly clear with surveys completed in the past 18 months that show these differences in genome structure may play a role in susceptibility to certain conditions, such as mental retardation and autism.

In addition to accelerating the search for genetic variants involved in susceptibility to common diseases, the map produced by the 1000 Genomes Project will provide a deeper understanding of human genetic variation and open the door to many other new findings of biomedical significance.

The sequencing work will be carried out at the Sanger Institute, BGI Shenzhen and NHGRI's Large-Scale Sequencing Network, which includes the Broad Institute of MIT and Harvard; the Washington University Genome Sequencing Center at the Washington University School of Medicine in St. Louis; and the Human Genome Sequencing Center at the Baylor College of Medicine in Houston. The consortium may add other participants over time.

The project depends on large-scale implementation of several new sequencing platforms. Using standard DNA sequencing technologies, the effort would likely cost more than $500 million. However, leaders of the 1000 Genomes Project expect the costs to be far lower -- in the range of $30 million to $50 million -- because of the project's pioneering efforts to use new sequencing technologies in the most efficient and cost-effective manner.

First phase

In the first phase of the 1000 Genomes Project, lasting about a year, researchers will conduct three pilots. The results of the pilots will be used to decide how to most efficiently and cost effectively produce the project's detailed map of human genetic variation.

The first pilot will involve sequencing the genomes of two nuclear families (both parents and an adult child) at deep coverage that averages 20 passes of each genome. This will provide a comprehensive dataset from six people that will help the project figure out how to identify variants using the new sequencing platforms, and serve as a basis for comparison for other parts of the effort.

The second pilot will involve sequencing the genomes of 180 people at low coverage that averages two passes of each genome. This will test the ability to use lowcoverage data from new sequencing platforms to identify sequence variants and to put them in their genomic context.

The third pilot will involve sequencing the coding regions, called exons, of about 1,000 genes in about 1,000 people. This is aimed at exploring how best to obtain an even more detailed catalog in the approximately 2% of the genome that is comprised of protein-coding genes.

During its two-year production phase, the 1000 Genomes Project will deliver sequence data at an average rate of about 8.2 billion bases per day, the equivalent of more than two human genomes every 24 hours. The volume of data – and the interpretation of those data – will pose a major challenge for leading experts in the fields of bioinformatics and statistical genetics.

“This project will examine the human genome in a detail that has never been attempted – the scale is immense. At 6 trillion DNA bases, the 1000 Genomes Project will generate 60-fold more sequence data over its three-year course than have been deposited into public DNA databases over the past 25 years,” said Gil McVean, PhD, of the University of Oxford in England, one of the co-chairs of the consortium’s analysis group. “In fact, when up and running at full speed, this project will generate more sequence in two days than was added to public databases for all of the past year.”

The first thousand samples for the 1000 Genomes Project will come from those used for the HapMap and from additional samples in the extended HapMap set, which used the same collection processes. No medical or personal identifying information was obtained from the donors, and the samples are labeled only by the population from which they were collected. The donors’ anonymity was enhanced by recruiting more donors than were actually used. Similar processes will be used for collecting additional samples for the 1000 Genomes Project.

Among the populations whose DNA will be sequenced in the 1000 Genomes Project are: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Chinese in Beijing; Utah residents with ancestry from northern and western Europe; Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Toscani in Italy; Gujarati Indians in Houston; Chinese in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States.

The data generated by the 1000 Genomes Project will be held by and distributed from the European Bioinformatics Institute and the US National Center for Biotechnology Information. There will also be a mirror site for data access at BGI Shenzhen. In addition to a catalog of variants, the data will include information about surrounding variation that can speed identification of the most important variants.

● Website: The 1000 Genomes Project -
www.1000genomes.org





Physicians not ready for genomic medicine – study

Although advances in genomic medicine for common adult chronic diseases such as heart disease, diabetes, and cancer hold promise for improved prevention, diagnosis and treatment, health professionals and the public are not prepared to effectively integrate these new tools into practice, according to a recent study. Middle East Health reports.

Physicians and patients are optimistic about the health benefits that genetic testing might provide, but neither group is well informed about genetics and there are likely too few experts available to meet growing demands for genetic testing, according to the study by researchers from the United States Department of Veterans Affairs and the RAND Corporation, a US - based multinational nonprofit research organisation. The research was published in the 19 March edition of the Journal of the American Medical Association.

“Genetic testing increasingly will be available to aid in the diagnosis, prevention and treatment of common chronic diseases, not just rare genetic diseases,” said Dr Maren Scheuner, lead author of the study and a natural scientist at RAND. “What requires attention now is how we will provide these services to an increasing number of patients.”

Researchers say the findings demonstrate a need for a largescale effort to educate both health professionals and the public about genomic medicine, and to develop and evaluate new ways to deliver genetic services.

Researchers from RAND Health and the Department of Veterans Affairs reviewed all studies published from January 2000 to February 2008 about the delivery of genomic medicine for common chronic diseases. The authors synthesized the findings from 68 relevant studies to develop a picture of the status of the delivery of genomic medicine in developed countries to diagnose, prevent and treat common chronic adult illnesses.

The studies consistently found that primary care physicians feel “woefully underprepared” to integrate genetics into their practice. This includes having neither the time nor the skill necessary to obtain and interpret family histories that might detect disease patterns that merit a referral for genetic testing or specialty consultation.

“Primary care clinicians are on the front lines of patient care and they are going to need to be prepared to incorporate genetics into their practices,” Scheuner said. “Training and educating the healthcare workforce about the role of genetics in their clinical practice and increasing the size of the genetics specialty workforce are potential solutions to barriers we identified.”

While consumers report having unclear notions about the value of genetic testing for common chronic diseases, they were interested in the prospect that the tests might help identify those people who are at greater risk for chronic illnesses that are preventable.

Adverse consequences

However, consumers are worried about the prospect of adverse consequences to genetic testing – particularly loss of privacy and discrimination by health insurers or employers among those found to be predisposed to disease, according to the study. Despite this concern, researchers found there have been no well-documented cases of health insurers asking for or using presymptomatic genetic test results to define eligibility for coverage.

Researchers also found little research describing health outcomes associated with genetic testing for common chronic diseases. Most of the research to date has focused on patients’ well-being after genetic testing, not on whether the testing prevented disease, changed treatment or extended lives. Well-designed studies that evaluate impacts on death and illness will be necessary to estimate the value that genetic tests add to health services delivery.

Researchers also found that scant research has been done to determine what might be the best system for providing genetic services for chronic adult illnesses.

Several studies in the United Kingdom found that using a nurse geneticist incorporated into a primary care practice resulted in high patient satisfaction and lower costs since fewer people required referral to a genetics specialist. But more research is needed about both the organisation and the cost of systems to expand use of genetic medicine, according to researchers.

The study outlines several promising electronic tools that may offer benefits, including genetic consultation done via videoconference, disclosing genetic test results via telephone, and imbedding clinical support tools for physicians in electronic health records.

Researchers also found that most medical geneticists believe that there are too few trained specialists to adequately provide genetic services and that most directors of genetic laboratories support creation of more rigorous national standards for genetic tests to ensure quality of such testing.


 Date of upload: 23rd July 2008

                                  
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