Conference Summary

Clinical Applications for Technological Advances in Genetic Testing

Shelley D. Smith, PhD


December 11, 2009

In This Article

The Challenges in Identifying Causal Variants

Jay Shendure[9] of the University of Washington in Seattle described his group's experience with sequencing exomes, which involves the isolation and sequencing of the coding regions and splice sites of genes. Mutations in exons are more likely to have major effects on disease but may individually be rare. When they sequenced the human exome, they found about 17,000 SNPs, but less than 10% were unique to a single individual. However, when they sequenced exomes of individuals with several common disorders and filtered the SNPs they discovered to omit the common SNPs, they found SNPs that appeared to be causal. This technique could work well to identify genes that contribute to a disorder as long as the disorder is genetically fairly homogeneous.

Elaine Mardis[10] of Washington University in St Louis, Missouri, described her group's work with whole genome sequencing in a patient with acute myeloid leukemia and found several mutations in new genes. By conducting similar studies in patients with different subtypes of acute myeloid leukemia, they plan to use their results to determine genetic differences behind the subtypes.

However, because sequencing such large regions may discover so many mutations the bioinformatics needed to determine which mutations are actually deleterious is a major undertaking and can be as expensive as the sequencing itself. Mardis and colleagues described several approaches, including: removing any previously reported SNPs; selecting for those in coding, regulatory, or conserved regions, and comparing sequences in normal and tumor tissue to determine mutations that are unique to the tumor; and sequencing matched controls to detect mutations in individuals that may create susceptibility to cancer. Finally, sequencing complementary DNA transcripts can detect variants that produce abnormal gene products.

All of these studies underscore the need to determine which rare variants are deleterious and which ones are benign. The 1000 Genomes Project, discussed by Gil McVean[11] of Oxford University in Oxford, United Kingdom, will sequence entire genomes of 1000 subjects. The sample will be divided into subpopulations across the globe, with at least 100 people per subpopulation, allowing researchers to catalog genetic variation, including rare variants. By identifying and determining the frequencies of variants in these populations, the significance of variants in a population selected for disease can be determined more easily.

This project is in progress, starting with a pilot of 60 unrelated individuals representing the 3 primary ethnic groupings in the HapMap studies: Caucasians (CEPH families), Yoruban (Nigerian), and Asian (Japanese and Han Chinese). To date, they have identified 17.2 million SNPs, 9.2 million of which had not been identified previously, as well as deletions, insertions, and novel sequences. At least 200 Europeans have been sequenced, and the data are being made available to researchers as they are obtained.


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