Structural Genomic Variation and Personalized Medicine (2/24/2008)

The ultimate goal of personalized medicine is to comprehensively identify genetic differences among persons and to correlate specific genetic features (or combinations of genetic features) with the differential risk of human diseases or the efficacy of certain therapeutic interventions. "This goal is likely to be achieved when we are able to identify all relevant forms of genetic variation in each person and are able to interpret this information in a clinically meaningful manner," said researchers from Harvard Medical School in their article recently published in The New England Journal of Medicine.

The Human Genome Project revealed a very high degree of similarity between the DNA sequences of any two persons. These similarities unite us as a species. On the other hand, the differences in our DNA sequences (combined with the effects of our environment) make each one of us unique. Until recently, qualitative differences in the genome - in the form of single-nucleotide polymorphisms - have enjoyed the limelight. However, a recent study published by Korbel and colleagues in Science, reinforces the notion that quantitative differences, such as delated and duplicated genomic sequences, and large-scale rearrangements (collectively referred to as structural genomic variant architecture) are just as - or more - relevant.

Korbel et al. developed an experimental and computational strategy to obtain a view of the structural genomic variant architecture of two persons. They accomplished this by taking the total DNA from each of this persons, "chopping" each DNA sample down to fragments of about 3 kb, randomly sequencing the ends of tens of millions of these fragments, and then comparing the pairs of DNA sequences obtained from each DNA fragment with the reference sequence, which was made available by the Human Genome Project.

The authors identified 761 structural genomic variants in one person and 887 structural genomic variants in another person. Approximately 65% of the variants identified were smaller than 10 kb, and 15% of the variants were larger then 100 kb. It therefore seems likely that structural genomic variants contribute more toward genetic heterogeneity than single-nucleotid polymorphisms, with several million bases of structural genomic variants differentiating the genomes of any two persons. Moreover, many of the genes affected by the identified variants were "environmental sensor" genes (i.e., genes that modulate interactions with the environment, including those involved in immunity and sensory perception). The functional effect of structural genomic variants was not limited to presumed differential levels of gene expression due to different copies of genes; rather, it was also related to the inversion of certain genes, deletions affecting specific exons or introns, and even the creation of new gene-fusion products.

This proof-of principle study elegantly showed a form of whole-genome analysis that accurately identifies structural variation. However, several tall hurdles stand between the knowledge of a person's genome and the practice of personalized medicine. First, information about whole-genome sequencing must be obtained more efficiently and in a cost-effective manner. The strategy used by Korbel et al. currently requires 8 months of continuous use of DNA-sequencing machine, at a cost of as much as $200,000, to obtain the data about structural genomic variants described in their article. Clearly, this scale of investment prohibits routine analysis. Second, human genetic variation - including the minor allele frequencies of relevant variants - needs to be more comprehensively catalogued. Toward this goal, various genomewide techniques are being applied to identify and characterize single-nucleotide polymorphisms and structural genomic variants in the DNA of thousands of healthy persons from populations around the world. With these catalogues of human genetic variations, case-control and family-based association studies can be conducted to correlate specific genetic variants with human traits, including differential susceptibility to common diseases. Indeed, such associations are already beginning to emerge for a wide range of human conditions.

Physicians may eventually be able to use a person's genetic-variation profile to determine the optimal intervention for the patient's condition, although such a strategy will depend on genetically informed clinically trials. There will continue to be a struggle to provide this type of information so that a patient and a physician can make informed health-related decisions, while minimizing its effect on insurance-related discrimination. Nevertheless, we are currently witnessing an exciting discovery phase in human genetics that will undoubtedly affect the way physicians ultimately practice medicine.

Note: This story has been adapted from a news release issued by the European Society for Medical Oncology

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