Exploring Our Genes

Abstract Our genomes can be explored in many ways. The least precise, but nonetheless highly useful, is the family history. The most precise, but with important caveats, is DNA sequencing. Both methods, and others of varying degrees of precision, clearly document that an important contributor to individuality is our genome. Each of us has several hundred thousand sequence variants in our chromosomes that differ from the human reference genome. Nearly all these variants are harmless. Some contribute, to some degree and in combination with other sequence variants, to our risk for common diseases. A few variants cause serious diseases, some evident at birth and others that develop throughout the lifespan. From a clinical perspective, DNA analysis may involve visualization of chromosomes. Much more frequently, DNA sequencing is employed. This may involve sequencing of an individual gene, of a panel of genes known to cause a specific condition, of the protein coding sequence of all genes, or of the entire 6.2 billion nucleotides that constitute our genome. Variants found on DNA analysis are classified in five categories: benign, likely benign, likely pathogenic, pathogenic, and variant of unknown significance (VUS). The VUS provokes the most concern for both the clinician and the patient. Long-term follow-up is often necessary to determine if new information leads to reclassification of the VUS. In some cases, in an analysis done for a specific reason, an important unexpected variant is found, the incidental finding. Patients must be counseled ahead of analysis that this is a possibility.