Box 2. Box 2 Technology development

The Human Genome Project was aided by several 'breakthrough' technological developments, including Sanger DNA sequencing and its automation, DNA-based genetic markers, large-insert cloning systems and the polymerase chain reaction. During the project, these methods were scaled up and made more efficient by 'evolutionary' advances, such as automation and miniaturization. New technologies, including capillary-based sequencing and methods for genotyping single-nucleotide polymorphisms, have recently been introduced, leading to further improvements in capacity for genomic analyses. Even newer approaches, such as nanotechnology and microfluidics, are being developed, and hold great promise, but further advances are still needed. Some examples are:

• Sequencing and genotyping technologies to reduce costs further and increase access to a wider range of investigators
• Identification and validation of functional elements that do not encode protein
• In vivo, real-time monitoring of gene expression and the localization, specificity, modification and activity/kinetics of gene products in all relevant cell types
• Modulation of expression of all gene products using, for example, large-scale mutagenesis, small-molecule inhibitors and knock-down approaches (such as RNA-mediated inhibition)
• Monitoring of the absolute abundance of any protein (including membrane proteins, proteins at low abundance and all modified forms) in any cell
• Improved imaging methods that allow non-invasive molecular phenotyping
• Correlating genetic variation to human health and disease using haplotype information or comprehensive variation information
• Laboratory-based phenotyping, including the use of protein affinity reagents, proteomic approaches and analysis of gene expression
• Linking molecular profiles to biology, particularly pathway biology to disease