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Genetics: Decades of Decoding

Since the 1970s, scientists at MGH and elsewhere have made great strides to decipher the information embedded in the human genome.

By Lauren Ware // The MGH Research Issue 2011

Frederick Sanger and colleagues at the University of Cambridge in England and Allan Maxam and Walter Gilbert at Harvard University develop the first methods to sequence DNA rapidly.

MGH geneticist James Gusella and colleagues use linkage analysis to narrow the location of Huntington’s disease gene to chromosome 4.

With Gusella, Rudy Tanzi of MGH identifies the gene that codes for amyloid precursor protein, the source of brain plaques in patients with Alzheimer’s disease that are thought to be most responsible for the disease’s pathology.

The U.S. Department of Energy and the National Institutes of Health launch the Human Genome Project to identify the precise sequence of the 3.2 billion nucleotides that make up human DNA and to map what are now known to be the roughly 25,000 genes of the human genome.

MGH geneticist Marcy MacDonald, working with Gusella and colleagues in the international Huntington’s Disease Collaborative Research Group, identifies the precise mutation responsible for Huntington’s disease.

Two additional Alzheimer’s genes strongly connected with the disease’s onset, presenilin 1 and presenilin 2, are identified by Tanzi and colleagues.

The Human Genome Project announces that it has a working-draft sequence of the human genome, comprising 90% of human DNA and estimated to be 99.9% accurate.

MGH creates the Center for Human Genetic Research, a cross-departmental, interdisciplinary center, with Gusella as director, to promote the use of genetic strategies in basic, translational and clinical research.

The Human Genome Project publishes a finished sequence of the human genome; more detailed analysis continues to this day.

454 Life Sciences launches the first “next generation” DNA sequencer, which anchors fragments of DNA to tiny resin beads in a plate to generate nucleotide sequences, dramatically speeding up the process of sequencing a genome.

Solexa, acquired by Illumina in 2006, debuts a sequencing technology that increases accuracy by amplifying the signal from the DNA fragments. At the same time, a competitor, Applied Biosystems, introduces Sequencing by Oligonucleotide Ligation and Detection, or SOLiD, technology, which improves accuracy by reading every base twice. Both sequence far more quickly and cheaply than 454 technology.

Geneticist Mark Daly, David Altshuler, an endocrinologist with the Center for Human Genetic Research and the Broad Institute, and colleagues, as well as international collaborators, complete the second phase of the International HapMap Project. This major effort to describe up to 95% of common, single-letter genetic variations (in which one base in the sequence is altered) in the 3 billion base pairs of human DNA lays the groundwork for understanding the genetic basis of many medical disorders.

Tanzi and colleagues at the MassGeneral Institute for Neurodegenerative Disease locate four new genes implicated in Alzheimer’s disease.

Daly, Gusella and colleagues at MGH, the Broad Institute, and the Boston-based Autism Consortium, examining the DNA of more than 3,000 people, identify a rare missing segment on chromosome 16 that accounts for at least 1% of cases of autism and related disorders.

Pamela Sklar, a geneticist then at MGH, and Shaun Purcell of MGH and the Stanley Center for Psychiatric Research, part of the Broad Institute, in collaboration with other investigators in the United States and Europe, complete the largest genome-wide investigation of schizophrenia to date. They report that rare deletions and duplications of genetic material are 15% more common in the DNA of patients with schizophrenia than those without, and discover two large areas of deletions on chromosomes 1 and 15 that greatly elevate the risk of developing the disorder.

An international research consortium announces the 1000 Genomes Project, co-chaired by Altshuler, which will sequence the genomes of many people to create a comprehensive resource of genetic variation.

Pacific Biosciences introduces yet another “next generation” DNA sequencing technology, which reads more than one base per second, instead of one base every 20 minutes. Oxford Nanopore Technologies offers a new technology to sequence DNA by cutting bases apart one by one and passing them through a tiny pore that allows them to be read in real time. The process has the potential to sequence an entire genome in hours, if not minutes, compared with more than a week with the Illumina method. Both technologies are not yet in widespread use.

MGH creates the Analytic and Translational Genetics Unit, with Daly as chief, to develop tools for interpreting individual human genomes, discover the genetic underpinnings of human disease and apply that knowledge to clinical decision-making.

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