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Large-scale Sequencing Research Network Sets Its Sights On Disease Targets

Date:
October 18, 2005
Source:
NIH/National Human Genome Research Institute
Summary:
In what promises to be a significant step forward in the genome era, the National Human Genome Research Institute (NHGRI), one of the National Institutes of Health (NIH), today announced plans to devote a portion of its large-scale sequencing capacity to efforts aimed at identifying the genetic roots of specific diseases that have long eluded gene hunters.
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BETHESDA, Md., Mon., Oct. 17, 2005 - In what promises to be asignificant step forward in the genome era, the National Human GenomeResearch Institute (NHGRI), one of the National Institutes of Health(NIH), today announced plans to devote a portion of its large-scalesequencing capacity to efforts aimed at identifying the genetic rootsof specific diseases that have long eluded gene hunters.

The National Advisory Council for Human Genome Research (NACHGR)recently approved a plan for NHGRI's Large-Scale Sequencing Networkthat, for the first time, includes a portfolio of "medical sequencing"projects. Projects given the highest priority will use large-scalesequencing over the next few years to identify the genes responsiblefor dozens of relatively rare, single-gene (autosomal Mendelian)diseases; sequence all of the genes on the X chromosome from affectedindividuals to identify those involved in sex-linked diseases; and tosurvey the range of variants in genes known to contribute to somecommon diseases. The launch of each project will depend on a number offactors, including the strategic selection of specific diseases and theavailability of patient samples with appropriate informed consent.

In addition to the new focus on medical sequencing, the plancontinues NHGRI's emphasis on using comparative genomic sequencinganalysis to understand the structure and function of the human genomeand the biological processes at work in human health and disease. Thestrategy includes a mix of whole genome sequencing, genome mapping andsequencing of genomic regions chosen for their scientific merits.Additionally, NACHGR approved the refinement of several existing draftgenome sequences and targeted a group of seven additional non-mammalianorganisms for sequencing.

"Medical sequencing has the potential to make asubstantial impact on both biological and medical research. While manyof the genes we will initially be pursuing are responsible for raredisorders, what we learn from rare disorders often has profoundconsequences for our understanding of more common conditions. Thus weexpect the cumulative impact of this acceleration in disease genediscovery to be profound, as many of the discoveries will shed newlight on the biological pathways involved in human health and disease,"said NHGRI Director Francis S. Collins, M.D., Ph.D.

The first medical sequencing project, predicted tobegin in the next year, will be a demonstration project to find thegenetic variations responsible for seven rare, autosomal Mendeliandisorders. The demonstration project will establish the best proceduresfor obtaining quality samples, for determining the minimum number ofaffected and control samples needed, and for deciding how the data willbe released to the biomedical research community.

Among the demonstration projects under considerationare those to identify the genes responsible for the familial forms ofatrial fibrillation, a major risk factor for heart failure and stroke;thoracic aortic aneurysms, which are life-threatening tears in themajor artery of the heart; and dominant restrictive cardiomyopathy,another heart disorder. By understanding the familial forms of thesediseases, scientists can apply what they learn to uncover the geneticcomponents underlying the more common types of these heart disorders inthe human population.

The other demonstration projects will target the genes for four otherrare disorders: paroxysmal kinesigenic choreoathetosis, a neurologicalcondition; neovascular inflammatory vitreoretinopathy, a blindingdisorder; lymphedema-cholestasis syndrome, a hereditary disordercausing jaundice and leg swelling; and Joubert syndrome, a rare brainand physical development disorder.

NHGRI estimates that there are at least 50 to 100 additionalprojects in the scientific community that could benefit from the bruteforce and specialized tools of large-scale sequencing. In order to makean accurate assessment and gather community input into this program,NHGRI has issued a Request for Information to seek additional examplesof such diseases from investigators around the world. The deadline forresponses is Nov. 4. NHGRI will also hold an open discussion on Oct. 28during the upcoming meeting of the American Society for Human Geneticsin Salt Lake City to seek additional input from the human geneticscommunity. NHGRI will analyze the input from these sources anddetermine the ultimate size of this aspect of medical sequencing aswell as the best way to select those projects that offer the mostpromise.

Another medical sequencing project will be an effort toidentify the genetic changes that result in diseases known as X-linkeddisorders. The human genome consists of 22 matching pairs ofchromosome, referred to as autosomal chromosomes, plus a non-matchingpair referred to as the sex chromosomes. The sex chromosomes, which arecalled X and Y, determine whether a person is female (XX) or male (XY).Any defects in genes on the X chromosome are often more apparent inmales than females because the Y chromosome does not carrycorresponding genes to compensate.

While researchers have identified the genes responsible for anumber of X-linked disorders, the precise genetic basis forapproximately 130 of these disorders remains to be determined. Thestudy would entail completely sequencing all genes on the X chromosomesof individuals affected with the disorders, and looking for variationsthat consistently correlate with each disorder.

The other medical sequencing project given priority willattempt to characterize the entire spectrum of variation, both rare andcommon, in a significant number of candidate genes for common diseases.Genes known to influence high blood pressure, cholesterol and bodyweight will be targeted. Samples would be sequenced from hundreds tothousands of individuals from existing large cohort studies examiningspecific diseases, such as atherosclerosis or diabetes.

As part of the effort to select medical sequencing projects,NHGRI has included a working group to examine the ethical, legal andsocial issues relevant to the new medical sequencing projects. Many ofthese issues, which include obtaining informed consent from volunteerswho plan to donate samples or who have already donated samples forother research projects, protecting the privacy of such volunteers, andunderstanding when, or how to report clinically relevant results backto volunteers, are similar to those encountered in much of humangenetics research. The group will also address data release andintellectual property procedures.

In addition to the new focus on medical sequencing, NHGRI iscontinuing its ongoing effort to sequence other organisms' genomes,with the aim of deepening our understanding of human biology andevolution. Since the human genome and that of other mammalian andnon-mammalian genomes have all evolved from a common ancestor,scientists can use the genome sequences of the non-mammalian animals tolearn more about how, when and why the genomes of humans and othermammals came to be composed of certain DNA sequences. Such studies alsoprovide new insights into the function of those sequences, theorganization of genomes, and expand our understanding of the biologicalbasis of certain infectious diseases.

NHGRI has selected seven non-mammalian organisms or groupsof organisms for the next round of sequencing. Three of the organismshave been targeted for "high-quality draft" sequencing. They are: thegreen anole lizard (Anolis carolinensis), zebra finch (Taeniopygiaguttata) and body louse (Pediculus humanus). Researchers will alsoconstruct physical genetic maps and do some targeted genomic sequencingof two sandflies (Lutzomyia longipalpis and Phlebotomus papatasi), andwill obtain a low coverage sequence of the Africanized honey bee (Apismellifera scutellata) for comparison with the honey bee genomesequence. Finally, the genomes of 100 bacteria cultured from the normalhuman gut will be sequenced.

"We are continuing to focus on those organisms that willreveal the greatest amount of information about the major biologicalinnovations that have occurred throughout evolution, with emphasis onlearning more about our own genome. Genomic information from a widearray of species is proving useful in many areas of biomedicalresearch," said Mark S. Guyer, Ph.D., director of NHGRI's Division ofExtramural Research.

The green anole lizard will be the first reptile to have itsgenome sequenced. Sequencing this reptile will provide a valuablecomparison to the chicken, human and other mammalian genomes. The greenanole lizard is also a well-established experimental model forneurobiology, endocrinology and reproduction.

Selected for physical mapping earlier this year, the zebrafinch will now be sequenced to a high-quality draft. The zebra finchwas chosen because it is a major model system for understanding braindevelopment, learning and memory. Because it is related to the chicken,whose genome has already been sequenced, it will be possible toleverage the chicken genome to get more insight from the zebra finchgenome sequence.

The body louse, which possesses the smallest measured insectgenome, is a vector for Rickettsia prowazekii, a category Bbioterrorism agent that causes typhus. The two sand flies targeted forsequencing are major vectors of leishmaniasis, a parasitic diseaseresponsible for disfiguring skin lesions and damage to the spleen,liver and bone marrow. It is estimated that 12 million people areinfected worldwide and that this disease causes more than 60,000 deathseach year. In fact, approximately 1,200 soldiers deployed during theGulf War have contracted the skin lesions caused by leishmaniasis.Sequencing the genomes of the sandflies will give researchers a betterunderstanding of this disease and possibly aid the development ofvaccines.

The human gut microbiome project represents an exciting newresearch area for NHGRI, which, except for the bacterium E. coli, hasfocused its large-scale sequencing program on higher organisms ratherthan bacteria. But there are more bacterial cells in the human gut thanthere are human cells in the entire human body. Furthermore, human gutmicrobes have a profound effect on many human physiological processes,such as digestion and drug metabolism, and play a vital role in diseasesusceptibility. Sequencing the genomes of these 100 microorganismsfound in the human gut, which represent a significant, but unknownfraction of all microbes in the human gut, is expected to provide amuch more complete picture of this aspect of human biology than hasever been available previously. It is hoped this new information couldlead to improved diagnostic tools for monitoring human health.

The latest NHGRI sequencing plan will also support therefinement of the rat, chicken and dog genomes. All are important modelorganisms, and their genomes are used to identify features that aresimilar, or conserved, among the genomes of the human and othermammals. Sequences that have been conserved throughout evolution oftenreveal important functional regions of the human genome. To learn moreabout the field of comparative genomic analysis, go to: www.genome.gov/10005835.

Sequencing efforts will be carried out by the NHGRI-supportedLarge-Scale Sequencing Research Network, which consists of fivecenters: Agencourt Bioscience Corp., Beverly, Mass.; Baylor College ofMedicine, Houston; the Broad Institute of MIT and Harvard, Cambridge,Mass.; the J. Craig Venter Science Institute, Rockville, Md.; andWashington University School of Medicine, St. Louis. Assignment of eachorganism to a specific center or centers will be determined at a laterdate.

NHGRI's process for selecting sequencing targets begins withthree working groups comprised of experts from across the researchcommunity. Each of the working groups is responsible for developing aproposal for a set of genomes to sequence that would advance knowledgein one of three important scientific areas: to identify areas ingenetic research where the application of high-throughput sequencingresources would rapidly lead to significant medical advances,understanding the human genome and understanding the evolutionarybiology of genomes. A coordinating committee then reviews the workinggroups' proposals, helping to fine-tune the suggestions and integratethem into an overarching set of scientific priorities. Therecommendations of the coordinating committee are reviewed and approvedby NHGRI's advisory council, which in turn forwards its recommendationsto NHGRI leadership. For more on the selection process, go to: www.genome.gov/Sequencing/OrganismSelection.

The genomes of a number of organisms have been or are being sequencedby the large-scale sequencing capacity developed by the Human GenomeProject. A complete list of organisms and their sequencing status canbe viewed at www.genome.gov/10002154.

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High-resolution photos of many of the organisms being sequenced in the Large-Scale Sequencing Program are available at: www.genome.gov/10005141.

NHGRI is one of the 27 institutes and centers at NIH, an agencyof the 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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Materials provided by NIH/National Human Genome Research Institute. Note: Content may be edited for style and length.


Cite This Page:

NIH/National Human Genome Research Institute. "Large-scale Sequencing Research Network Sets Its Sights On Disease Targets." ScienceDaily. ScienceDaily, 18 October 2005. <www.sciencedaily.com/releases/2005/10/051018222733.htm>.
NIH/National Human Genome Research Institute. (2005, October 18). Large-scale Sequencing Research Network Sets Its Sights On Disease Targets. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2005/10/051018222733.htm
NIH/National Human Genome Research Institute. "Large-scale Sequencing Research Network Sets Its Sights On Disease Targets." ScienceDaily. www.sciencedaily.com/releases/2005/10/051018222733.htm (accessed March 28, 2024).

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