Human Genome Project

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Initially biologists were content to clone and sequence genes on a one by one basis which required large amounts of labor and time. As technology improved in the 1980s, some scientists such as Craig Venter and Leroy Hood believed that the focus should shift to sequencing whole genomes and they advocated a era of big science epitomised by the Human Genome Project (HGP). Their goal was to automate the mapping and sequencing to produce resources that give science a valuable shortcut to addressing the biology of the genome.

Leroy Hood designed DNA sequencing machines to automate the process and thus massively reduce the cost of large scale sequencing. The chemistry of dideoxy sequencing devised by Frederick Sanger in 1977 was still the primary tool but new fluorescent labeling techniques, polymerase chain reaction (PCR) and genomic BAC/YAC libraries were technological advances that made automation possible. Craig Venter advocated a random approach to sequencing rather than the traditional and slower target driven approach. Initially this was in the form of sequencing a massive number of randomly picked expressed sequence tags (EST's). Each tag represented a cDNA clone and the whole collection represented a catalog of expressed genes in a genome. This approach transitioned to sequencing random BAC's from the whole genome and was coined shotgun sequencing.

The HGP started out as an academic pursuit that used a methodological tactic of establishing unique genetic markers, breaking the DNA into smaller bits which were then sequenced and, using the markers as a guide, reassembled. The public consortium was joined by a private effort at Celera Genomics that used the shotgun sequencing approach and a race to finish the project ensued. With the use of computers the vast number of fragments from Celera were assembled using the framework established by the HGP and in June of 2000, the completion of the draft sequence was announced by the leaders of the public and private projects.

One example of the impact on understanding the biological basis for schizophrenia, was reported in Scientific American.[1]

The researchers determined which affected genes were likely to cause damage—and where in the body that damage that might occur. The flawed genes in the schizophrenia patients were overwhelmingly linked to changes in pathways responsible for communication between and within nerve cells. In fact, one gene, ERBB4, is known to code for a receptor that interacts with neuregulin 1, a protein that's been associated with the illness for a decade. "The silver lining is that these new findings show us … that we were already on the right track," Sebat says."

References

  1. Nikhil Swaminathan, A New, Genetic Model for Schizophrenia Scientific American 2008, March 28.