Edison T. Liu, M.D.

Title: Genomic Sequencing: The Potential Impact of the Technologies on Science and Society

The success of the Human Genome Project, completed in 2003, was primarily due to the development of high throughput sequencing approaches and advanced computational capabilities. Earlier sequencing approaches relied on primer extension and fluorescent dye termination using DNA polymerase and specific nucleotides terminators (also called Sanger sequencing). The subsequent terminated fragments were then separated by capillary electrophoresis and the position of the specific nucleotide terminator deduced from the fragment sizes. The completed version of The Human Genome Project had less than 400 gaps covering 99% of the genome with an accuracy of more than 99.99% .

In the last few years, a dramatic change in sequencing technologies have allowed for improvements by five orders of magnitude in speed and reduction in cost. These “second generation” technologies have now superseded Sanger-based capillary electrophoresis sequencing and are the basis for the generation of data for genome-to-systems investigations. The fundamental shift that distinguishes this second generation sequencing is the reliance on reading the DNA code by assessing the incorporation of each individual complementary nucleotide – sequencing-by-“synthesis” (as compared with sequencing by fragment length). Alternatively, sequencing-by-hybridization is used whereupon precise sequences are deduced by specific hybridization of oligonucleotide probes. Secondly, this sequencing-by-synthesis is augmented in scale by arraying each sequencing reaction in a massively parallel fashion. What then that is limited is the length of sequencing. Until recently, the sequencing lengths have been limited from 25-250 base pairs. But here, the computational algorithms for sequence assembly allows for the “stitching” of these fragmented sequences into contiguous sequences – called “contigs”.

The advance of these sequencing technologies has allowed the timely and cost-effective sequencing of whole genomes including human genomes. Several projects such as the 1000 Genomes Project seeks to assess the complete catalogue of genetic variation in humans through whole genome sequencing. The availability of genome sequences will change the face of biomedical research and of medicine. Individual genomes that do not change in life can be assessed at one time. Therefore one’s complete genetic profile is accessible potentially as a clinical test. As with other technologies, genome sequencing of this magnitude raises clear legal and social challenges. In the same way that personal computers and the internet has changed our social activities and redefined privacy, the same will be true of personal genomic information.