The National Human Genome Research Institute (NHGRI), one of the National Institutes of Health (NIH), has 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.
The National Advisory Council for Human Genome Research (NACHGR) recently approved a plan for NHGRI's Large-Scale Sequencing Network that, for the first time, includes a portfolio of "medical sequencing" projects.
Projects given the highest priority will use large-scale sequencing over the next few years to identify the genes responsible for dozens of relatively rare, single-gene (autosomal Mendelian) diseases; sequence all of the genes on the X chromosome from affected individuals to identify those involved in sex-linked diseases; and to survey the range of variants in genes known to contribute to some common diseases.
In addition to the focus on medical sequencing, the plan continues NHGRI's emphasis on using comparative genomic sequencing analysis to understand the structure and function of the human genome and the biological processes at work in human health and disease.
The strategy includes a mix of whole genome sequencing, genome mapping and sequencing of genomic regions chosen for their scientific merits.
Additionally, NACHGR approved the refinement of several existing draft genome sequences and targeted a group of seven additional non-mammalian organisms for sequencing.
“Medical sequencing has the potential to make a substantial impact on both biological and medical research,” said NHGRI Director Francis S. Collins, M.D., Ph.D.
“While many of the genes we will initially be pursuing are responsible for rare disorders, what we learn from rare disorders often has profound consequences for our understanding of more common conditions.”
“Thus we expect the cumulative impact of this acceleration in disease gene discovery to be profound, as many of the discoveries will shed new light on the biological pathways involved in human health and disease.”
The first medical sequencing project, predicted to begin in the next year, will be a demonstration project to find the genetic variations responsible for seven rare, autosomal Mendelian disorders.
The demonstration project will establish the procedures for obtaining quality samples, for determining the minimum number of affected and control samples needed, and for deciding how the data will be released to the biomedical research community.
Among the demonstration projects under consideration are those to identify the genes responsible for the familial forms of atrial fibrillation, thoracic aortic aneurysms, and dominant restrictive cardiomyopathy.
By understanding the familial forms of these diseases, scientists can apply what they learn to uncover the genetic components underlying the more common types of these heart disorders in the human population.
The other demonstration projects will target the genes for four other rare disorders: paroxysmal kinesigenic choreoathetosis, neovascular inflammatory vitreoretinopathy, lymphedema-cholestasis syndrome and Joubert syndrome.
The deadline for responses is Nov. 4. NHGRI will also hold an open discussion on Oct. 28 during the upcoming meeting of the American Society for Human Genetics in Salt Lake City to seek additional input from the human genetics community.
NHGRI will analyze the input from these sources and determine the ultimate size of this aspect of medical sequencing as well as the best way to select those projects that offer the most promise.
The other medical sequencing project given priority will attempt to characterize the entire spectrum of variation, both rare and common, in a significant number of candidate genes for common diseases.
Genes known to influence high blood pressure, cholesterol and body weight will be targeted.
Samples would be sequenced from hundreds to thousands of individuals from existing large cohort studies examining specific 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 and social issues relevant to the medical sequencing projects.
NHGRI has selected seven non-mammalian organisms or groups of organisms for the next round of sequencing.
Researchers will also construct physical genetic maps and do some targeted genomic sequencing of two sandflies ("Lutzomyia longipalpis" and "Phlebotomus papatasi"), and will obtain a low coverage sequence of the Africanized honey bee ("Apis mellifera scutellata") for comparison with the honey bee genome sequence.
Finally, the genomes of 100 bacteria cultured from the normal human gut will be sequenced.
"We are continuing to focus on those organisms that will reveal the greatest amount of information about the major biological innovations that have occurred throughout evolution, with emphasis on learning more about our own genome,” said Mark S. Guyer, Ph.D., director of NHGRI's Division of Extramural Research.
“Genomic information from a wide array of species is proving useful in many areas of biomedical research.”