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Personalized genome around the corner?

In 1990, scientists in the United States and around the world initiated the Human Genome Project to provide a complete DNA sequence of the human genome within a 15-year time span. In the United States, the overall budget allocated to this effort was around $3 billion, which included the ambitious task of developing improved DNA sequencing technologies and methods for analyzing the vast amount of DNA sequence data created in order for the project to be successful. Although a far-reaching goal was to apply the new knowledge to understanding disease and improving health, the principal intent of the project was to reveal the actual DNA sequence.

For the past several years, the speed of DNA sequencing and the amount of DNA sequence that can reasonably be mapped in one experiment has gradually and methodically increased. Most clinical DNA sequencing uses these older methodologies, and diagnostic sequencing of one or a few genes can cost in the neighborhood of $l,000-$5,000. Larger testing panels that sequence two or three dozen genes can exceed the $5,000 mark.

In 2009, researchers began using newly developed DNA sequencing technologies that go be yond the methods used in the Human Genome Project, collectively referred to as "next-generation" (or NextGen) DNA sequencing methods. The NextGen methods have vastly increased the amount of DNA sequence that can be studied. Although the scientific community has known that NextGen platforms were in the pipeline, the past 1.5 years have shown how much these approaches have matured.

For the internist, this information will remain clinically irrelevant for a little while longer, but several papers published in the last 12 months have described the use of NextGen techniques in human disease. Researchers used whole-exome NextGen DNA sequencing technology to identify causative mutations in Bartter, Miller, and Freeman-Sheldon syndromes, which are rare human genetic conditions (Proc. Natl. Acad. Sci. U S A 2009;106:19096-101; Nat. Genet. 2009;42:30-5; Nature 2009; 461:272-6).

In these studies, the researchers decided to avoid the whole genome, remembering that only l%-2% of our DNA is occupied by known genes. The summed region containing genes is called the "exome," in reference to the "exons" that are the main components of genes. Ignoring the remaining 98% of the human genome, the investigators applied NextGen sequencing to identify the genetic causes of these rare conditions. In a sense, this strategy reduced the needle-in-a-haystack approach from a 3 billion base-pair "haystack" into something more manageable (although a large amount of computer power still was required to find the proverbial "needle," the genetic mutation).

This approach, termed "exome sequencing," was used successfully to identify the genetic cause of disease, proving that this technique could discover previously unknown causes of genetic disease without the need for large family studies and laborious genetic mapping projects. The power of this approach to detect single genetic defects is impressive, but it remains to be determined if it will work for other genetic conditions.

Although this technology might be considered to be a tool only for research scientists, these studies tackled problems directly related to human health and disease.

It is likely that the NextGen methods also will generate new tools for studying the interaction of environmental factors with an individual's genetic background.

This application can be seen in a study of acute myeloid leukemia (AML) in which a sample of DNA from a patient's AML cancer was compared with DNA derived from her normal, non-cancerous skin. Using whole-genome sequencing methods, the investigators identified eight genetic mutations present only in the AML cancer likely caused by environmental mutagens and Continued on following page representing potential causative steps in the development of her AML (Nature 2008;456:66-72).

Already, research companies are offering "full-genome" sequencing for costs of $25,000-$50,000, a far cry from the $3 billion that was initially budgeted for the first human DNA sequence. While $25,000 per DNA sample is still beyond the budget of most genetic researchers, the cost continues to drop. Just as some commercial companies now offer genetic testing of hundreds or even hundreds of thousands of genetic markers for less than $1,000, similar "price points" for NextGen DNA sequencing are probably not far off (see also Genetics in Your Practice, "Direct-to-Consumer Genetic Analysis," Internal Medicine News, Oct. 1, p. 32).

Medically indicated exome or whole-genome sequencing is probably still several years away, as the technology needs to meet the standards of clinical utility and a host of cost-effectiveness measures.

However, as is the case with other genetic or genomic technologies, a "personalized genome" NextGen assay probably will be available in the marketplace before the critical clinical validation studies are completed, and the internist will do well to become familiar with these technologies and their evolving limitations.

DR. TAYLOR is associate professor and director of adult clinical genetics at the Health Sciences Center of the University of Colorado, Aurora. To provide feedback or suggest future topics of interest, write to Dr. Taylor at our editorial offices or
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Title Annotation:PRACTICE TRENDS
Publication:Internal Medicine News
Geographic Code:1USA
Date:Mar 1, 2010
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