Last Friday we had a seminar from David I. Smith, who was in town to run the St. Louis marathon. Evidently his goal is to run a marathon in every state. He gave us a seminar of next-gen sequencing applications at the Mayo Clinic, which include gene expression profiling, rearrangement/CNV detection (with paired-end), chip-seq, methylation, microbial genomics, and characterization of large genes.
Their main focus, however, is using next-gen sequencing for rare variant detection. The goal is to develop clinical assays for early detection of cancer from blood, saliva, stool, or urine samples by looking for somatic mutations carried by a small number of cancer cells. The ratio of mutant to wild type signal is presumably low at early cancer stages, but theoretically detectable with sufficient cancer coverage.
Another clinical application of this approach is the detection of “heteromorphisms” in mitochondrial DNA. Here, the idea is to detect diseases associated with mitochondrial mutations (encephalopathies, neuropathies, oxidative phosphorylation disorders, etc.). Apparently mtDNA has a high mutation rate and propensity to accumulate somatic mutations due in part to poor DNA repair mechanisms. While the population size within a single patient is large, the genome is small enough (16kb) to be covered at high depth by next-gen technologies.
Finally, Dr. Smith presented some of the work done at Mayo on a transcriptional profiling technique that uses 454 sequencing of 3′ tags. They’ve developed approaches to profile both the polyadenylated and the non-polyA transcriptome at a cost of around $3,000 per sample.
Overall, I found Dr. White to be an engaging speaker. He also seemed very knowledgeable of the current state of various next-gen platforms, and by dropping names such as Eland, Maq, and SSAHA, convinced me that (while they only have a couple of machines) they’re pretty serious about next-gen sequencing informatics at the Mayo Clinic.