When the first draft sequence of the human genome was announced, I was a research assistant for a lab that was part of the Genome Center of Wisconsin where I created shotgun libraries of bacterial genomes for sequencing. Of course, the local news organizations were all abuzz with the news and sought opinions on what this meant for the future, including that of the lab’s PI and oddly enough, my own. While I do not recall the exact words I offered on camera, I believe they were something along the lines of this is only the first step toward the future of human genetics. Ten years later, we have not fulfilled the potential of the grandiose words used to report the first draft sequence but have gained enough knowledge of what our genome holds to only intrigue scientists even more.
The full sequence of the human genome was expected to reveal all the secrets of cancer and other diseases, making it easier to treat and even cure them and giving us the keys to the greatly desired personalized medicine; these expectations have yet to be fully realized. However, few, if any, endeavors fill the goals expressed from the onset. While many researchers have focused on studying the protein-coding genes, others have explored the vast regions of noncoding or so-called junk DNA and leveraged the genetic information for comparative sequence analysis especially as the total number of sequenced genomes has increased. Regardless of the research direction taken, scientists have discovered that sequencing the human genome has not clarified genetics but led to discovery of even more complexity.
After publishing the genome sequence, it became more obvious that the DNA sequence is not the answer but merely a stepping stone in understanding the underlying design of human beings. Functional genomics, which encompasses all levels of gene expression including transcription, translation and protein:protein interactions, has been a major focus of research after the human genome sequence was completed. The regulation of expression, feedback loops, activation and suppression of coding regions have made analysis increasingly complex, trying to encompass all the influences on a gene or gene pathway. For example, the noncoding regions are not all junk DNA as first characterized. Rather, they can be transcribed into microRNAs (miRNAs), modulating the level of protein translation in the cell, and noncoding pseudogene transcripts, which can be used as decoy targets for miRNAs, thus regulating expression of the functional gene. Epigenetics, the study of inheritable changes in phenotype that do not rely on the DNA sequence, has also made great progress and adds to the elaborate web of gene expression regulation.
The sequence of the human genome as well as genomes of other organisms has been placed in public databases. With this easy access, scientists can use the information to help design experiments and explore hypotheses. The study of molecular evolution has grown by leaps and bounds because of the publicly available genome sequences. The human genome was certainly not the first to be made available, but over time, more and more genomes have been sequenced and placed in databases, making comparative studies of genes across genera, families and kingdoms easier.
And let us not forget the advances in sequencing technology. While we are not to the point of the film GATTACA where a hair can be submitted for genetic sequencing and the entire genome turned around in minutes, sequencing has both decreased in cost and increased in throughput since the draft human genome. These are no longer the painstaking days of Sanger sequencing with slab gel electrophoresis and 96-well plate capillary electrophoresis on ABI PRISM® 3700 instruments. Sequencing has become so much quicker, more individual human genomes are being added yearly to those first published. In fact, Ozzy Osbourne will soon join this exclusive club to see what can be learned from his genome. While sequencing a genome costs around $20,000USD, anyone can submit samples via mail-order kits at a more modest cost to analyze relatedness for fleshing out a family tree or learn what disease genes we might carry and be at higher risk for developing. Companies like 23andme sprang up as a result of the human genome project and subsequent study of the various genes and loci for human identification and estimation of the probability of a disease state.
My legacy from my work in a sequencing facility is my name on a couple of papers, some footage of me pipetting at my lab bench and an appreciation that a sequence is just a bunch of code written with four letters until we understand its meaning and the influences on expression. Even now, ten years after sequencing the human genome, we are only just starting to understand the complexity of our genetic code.