After the development of recombinant DNA technology in the 1970s, research laboratories typically undertook the cloning and sequencing of one gene at a time, and then only after having had first found out something interesting about that gene from a classic mutational analysis. The steps in proceeding from the classical genetic map of a locus to isolating the DNA encoding a gene (cloning) to determining its sequence were often numerous and time consuming. In the 1980s, some scientists realized that a large team of researchers making a concerted effort could clone and sequence the entire genome of a selected organism. Such genome projects would then make the clones and the sequence publicly available resources. One appeal of having these resources available is that, when researchers become interested in a gene of a species whose genome has been sequenced, they need only find out where that gene is located on the map of the genome to be able to zero in on its sequence and potentially its function. By this means, a gene could be characterized much more rapidly than by cloning and sequencing it from scratch, a project that at the time could take several years to carry out. This quicker approach is now a reality for all model organisms.

Similarly, the Human Genome Project aimed to revolutionize the field of human genetics. The availability of human genome sequences, and the ability to sequence the genomes of patients and their relatives, has greatly aided the identification of disease-causing genes. Similarly, the ability to determine gene sequences in normal and diseased tissues (for example, cancers) has been a great catalyst to the understanding of disease processes, and pointed the way to new therapies.

From a broader perspective, the genome projects had the appeal that they could provide some glimmer of the principles on which genomes are built. The human genome contains 3 billion base pairs of DNA. Having the entire sequence raised questions such as: How many genes does it contain? How are they distributed and why? What fraction of the genome is coding sequence? What fraction is regulatory sequence? How is our genome similar to or different from other animals? Although we might convince ourselves that we understand a single gene of interest, the major challenge of genomics today is genomic literacy: How do we read the storehouse of information enciphered in the sequence of complete genomes?

The basic techniques needed for sequencing entire genomes were already available in the 1980s (see Chapter 10). But the scale that was needed to sequence a complex genome was, as an engineering project, far beyond the capacity of the research community then. Genomics in the late 1980s and the 1990s evolved out of large research centers that could integrate these elemental technologies into an industrial-level production line. These centers developed robotics and automation to carry out the many thousands of cloning steps and millions of sequencing reactions necessary to assemble the sequence of a complex organism. Just as important, advances in information technology aided the analysis of the resulting data.

511

The first successes in genome sequencing set off waves of innovation that led to faster and much less expensive sequencing technologies. Now, individual machines can produce as much sequence in a day as centers used to accomplish in months. New technologies can now obtain more than 100 billion bases of sequence in a working day on a single instrument. This figure represents an approximately 100,000-fold increase in throughput over earlier instruments used to obtain the first human genome sequence.

Genomics, aided by the explosive growth in information technology, has encouraged researchers to develop ways of experimenting on the genome as a whole rather than simply one gene at a time. Genomics has also demonstrated the value of collecting large-scale data sets in advance so that they can be used later to address specific research problems. In the last sections of this chapter, we will explore some ways that genomics now drives basic and applied genetics research. In subsequent chapters, we will see how genomics is catalyzing advances in understanding the dynamics of mutation, recombination, and evolution.