Individual genomes on the horizon.

Physicians have long recognized that pinpointing specific causes of disease in individual patients enables therapies that are the most likely to confer benefit with the fewest adverse effects. We also recognize the potential for disease prevention through identification of specific risk factors and mitigation of their effects. For a century, we have known that many of these risk factors are genetic. In the past 20 years, the genomic revolution has translated this knowledge into a new understanding of disease: mutations that cause more than 2000 mendelian diseases have been identified, which has led to the rewriting of textbooks of pathophysiology of every organ system and the identification of rational targets for therapeutic intervention. Genes also play a major role in risk for virtually every common disease, affording the possibility of identifying persons who have a specific inherited predisposition. The field has been driven by saltatory leaps in technology. The development of complete genetic maps of the human genome fueled the mapping and identification of genes underlying mendelian traits in nuclear families. Subsequently, the ability to inexpensively genotype hundreds of thousands of common sequence variants across the genome enabled the discovery of common variants contributing to common diseases in large cohorts of case patients and controls. Building on the complete sequence of the human genome, spectacular reductions in the cost of DNA sequencing now point to a coming era of genomics based on identification of rare variants that confer disease risk in individual patients. When the sequencing of the first human genome was initiated, the cost to produce 1 million bases of sequence was $100,000. The development of new technologies that permit simultaneous sequencing of hundreds of millions of DNA templates has recently driven the cost to sequence 1 million bases to under $1. This advance creates myriad opportunities for the use of DNA sequencing in gene discovery. For example, the discovery of the comprehensive set of somatic mutations in cancer1 and suspected de novo mutations underlying diseases ranging from congenital malformations to autism become tractable goals. Similarly, common variants have explained only a small fraction of the inherited risk for most common diseases, findings that suggest a role for rare variants with relatively large effect,2,3 which can be discovered by sequencing large cohorts. Finally, thousands of known and suspected mendelian traits that have thus far eluded understanding will most likely be solvable with the use of high-throughput sequencing. Genome sequencing will also have a role in translating these discoveries into clinical diagnosis. Traditionally, the genetic diagnosis of a mendelian disorder relied on the establishment of a clinical diagnosis followed by the sequencing of previously implicated genes. Practical limitations of this approach include frequent diagnostic uncertainties, which thwart efforts to define a short list of genes for sequencing. Similar limitations arise for diseases in which mutations in many genes can cause the same disease. Sequencing these genes one by one is cumbersome and limits the number that can be efficiently examined. Supplanting this approach with routine sequencing of all the genes is consequently attractive and, more importantly, scalable. Although daunting challenges, such as distinguishing clinically significant mutations from nonconsequential variation, remain, the cost to