Genome-Analysis Strategy Discovers Possible Gene-Disease Links

By saving time and lowering expenses, the approach makes it feasible for scientists to search for disease-causing genes in people with the same inherited disorder but without any family ties to each other.

The strategy might be extended to common medical conditions with complex genetics by making it more cost-effective and efficient to study the genomes of large groups of people. Such large-scale studies have not been undertaken because they have been expensive, cumbersome, and time-consuming to sequence, compare, and interpret entire human genomes.

University of Washington (UW; Seattle, WA, USA) scientists have successfully developed the novel genome-analysis strategy for more rapid, lower cost discovery of possible gene-disease links. The strategy might be extended to common medical conditions with complex genetics by making it more cost-effective and efficient to study the genomes of large groups of people.

Scientists conducted a study as a proof-of-concept to see if a more targeted analysis and newer technology could identify candidate genes for diseases such as cystic fibrosis or sickle cell anemia. These conditions are caused by a mutation in a single gene and are passed along through generations in a simple inheritance pattern. In this study, the rare Mendelian disorder chosen to evaluate the strategy was the Freeman-Sheldon syndrome, a rare form of multiple congenital contracture (MCC) syndromes.

The study's senior author, Jay Shendure, UW assistant professor of genome sciences, explained the team's approach: "We decided to focus only on the one percent of the human genome which codes for proteins. This portion is called the exome. In other words, we determined the genetic variation in these areas, and ignored the rest. We used new technologies to capture these specific regions in the genomes of 12 people, 4 of who were affected by the same Mendelian disorder. None of the subjects were relatives. We then decoded these selected parts of the genome through massively parallel DNA sequencing, a technology that allows one to sequence hundreds of millions of DNA fragments in parallel." Intersecting these data found that only a single gene, MYH3, contained novel mutations in the exomes of all four affected individuals.

To make progress in disease genetics, new strategies such as this are vital. Shendure gave an example: "The genetics of thousands of rare diseases remains unsolved because sufficient numbers of families with individuals affected by those disorders are not easily available. Even with such families, mapping and identifying the causative gene can take many years."

From attempts to determine the genetics of cancer, diabetes, and heart disease, scientists now realize that common variations in the human genome account for only a small fraction of the risk of these common diseases. The new strategy allows scientists to investigate the contributions of rare variants and might be extended to larger population studies to untangle the complex genetics underlying the leading causes of death and disability.

The study was published on August 18, 2009 in the journal Nature.

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