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Your personal genome sequenced: Where do you go from here?
We are living in a period of great change for the medical sciences. Technological advances in DNA sequencing and information technology will, for the first time, make it possible for an individual to not only have their genome sequenced for less than $1,000, but also to have that information made available to their physician through cloud-based storage and software tools. The democratization of DNA sequencing, data storage and analysis promises to have a positive impact on the diagnosis and treatment of a myriad of genetically based human diseases, some of which will be detected and treated early through newborn screenings. These advancements will also have profound effects on continued medical research by further deepening our understanding of biology.
Sequencing a patient's DNA must include a method to store the information within a robust and secure environment, either at a hospital/medical system, or in a cloud-based storage system. Once approved users access this data, software tools will perform sophisticated analyses, including comparisons to private or publicly available data on other patients' DNA sequences, clinical presentations and drug responsiveness. The end product of this will be a simplified report that summarizes the key findings from the sequencing test and provides recommendations for treatment based on outcomes data from a pool of patients.
Many of the patients with the same disease will share a group of common DNA variations, and measurement of them will become the basis for diagnostic tests. These new diagnostics will be used to inform any number of decisions, including differential diagnosis, treatment selection (medical versus surgical) and drug/dosage selection.
Treatment decisions made by patients and physicians who are guided by DNA variation information will be a major advance for the medical sciences. But what about the DNA variation for which no information is available? For example, a variation in the open reading frame of a gene with no known function could be found to be predicative of disease severity, but in the absence of understanding the function of the protein, no effective treatment targeting it would be created. Such poorly annotated DNA variants will represent the vast majority of findings enabled through next-generation sequencing.
Rapid, informative and inexpensive DNA variation annotation represents the future for much of medical research, and will continue to serve as the basis for significant technology development in academic and industry settings. Associations between DNA variants and protein function, pathway homeostasis, cell growth and viability, or organism growth and health can be most easily identified when the differences between normal and variant genes are identified in cells or animals where all other variables are identical.
Manipulation of chromosomal DNA sequence through a molecular technique known as "gene editing" will allow for this type comparison. The editing process can begin with inexpensive and highly accurate DNA synthesis, followed by the creation of full-length genes. These synthetic genes, containing either the normal or the variant DNA sequence of interest, can then be introduced into cells. With appropriate molecular engineering technologies, the synthetic DNA can replace the existing DNA sequence in each of the two chromosomes of the cell.
Alternatively, the recent revolution in gene-editing technology allows for direct replacement of one DNA sequence for another at specific regions within each chromosome without requiring the synthesis of full-length genes. This technology promises to transform biological research, as gene editing will no longer be expensive or inefficient. Creating cells with identical genomes, except for the region which has been edited, will remove many of the non-informative differences commonly seen between cells that are not as closely related—differences that are often incorrectly attributed to the impact of the genetic variation instead of other DNA sequence differences in the cells that have not been detected.
Ultimately, information on DNA variants discovered through next-generation sequencing experiments will need to have more than cell culture data if the genetic variants are to be used for clinical decision making. For this, in-vivo studies are paramount. This can be accomplished by introducing specific DNA variation into one or both copies of a gene within an animal to compare its growth and health to a matched control. There are two major avenues for this approach.
The first involves developing induced pluripotent stem (iPS) cells from animal disease models containing complex genetic backgrounds that have been shown to be useful for studying disease pathophysiology and drug efficacy. These iPS cells can be generated from various cell types, and then used as targets for gene editing using the technologies discussed above.
Once editing is confirmed through DNA sequence analysis, the cells can be used to derive animals containing the DNA variant in their germ line, and ultimately to generate animals that are either homozygous or heterozygous for the variant.
The second avenue is to perform gene editing directly on embryonic stem cells, which are cells derived from non-disease model animals. These edited cells would be used to generate animals that are either homozygous or heterozygous for the variant. In both of these examples, scientists could ascertain the impact of the DNA variation on normal or disease model animal growth and health, and thus obtain highly useful biological annotation of the genetic variant.
Combined, advances in next-generation sequencing, information technology and gene editing will help transform medicine in the 21st century. DNA variants that are well annotated will contribute to the first wave of this transformation. This will be followed by the exponential growth of newly annotated DNA variants, which will lead to even more advances. It can be anticipated that the interpretation of an individual's genome sequence will become more actionable with time, a reality that will change the question about personal sequence information from "where do you go from here?" to "what is your decision?"