A Journey from Exploring the tod Operon to Nucleotide Resolution Genetics of Eukaryotes

At the time the tod operon was cloned and attempts to sequence it began, Sanger based sequencing in M13 vectors was just beginning to be scaled to phage or operon sized targets. In the three decades since, DNA sequencing has undergone a revolutionary increase in capabilities which has driven science in important new directions. The initial days of the human genome project were largely based on simple automations of the original Sanger chemistry. However, as these incremental improvements piled up, they were significant enough to allow sequencing the human genome by the end of the 20th century. Next-generation sequencing developed a few years later and the capacity to sequence not one reference, but hundreds or even tens of thousands of genomes became possible. This change allowed us to begin to understand for the first time genetics (as genetic variation among individuals), including human genetics, at the nucleotide level. We have now entered into yet another generation of sequencing where very long read sequence data are showing us a very different view of the genome than has been previously possible. Overall these changes in technology have changed the way we do biology (and medicine) and understand organisms and even complex biological systems at the molecular level.