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SMRT Sequencing Offers First Look at Fragile X Syndrome Repeat Expansion Disorder Sequence

Monday, February 11, 2013

Scientists at the University of California, Davis, School of Medicine have used the PacBio® RS to sequence a previously “unsequenceable” region of highly repetitive DNA on the X chromosome, providing a critical leap forward in understanding the genetic complexity of repeat expansion disorders such as Fragile X Syndrome.

Paul Hagerman, a professor of biochemistry and molecular medicine at the University of California, Davis, has spent the better part of the last 30 years trying to parse the molecular biology of Fragile X Syndrome. The FMR1 genetic mutation responsible for the syndrome is a leading cause of heritable cognitive impairment and autism, but scientists have been unable to characterize the causative CGG repeat expansion using conventional molecular
biology techniques.

But now, Hagerman has made history with the recent publication of the first reported sequence data covering a full mutation of CGG repeats in FMR1. (Loomis et al.Sequencingthe unsequenceable: Expanded CGG-repeat alleles of the fragile X gene,” Genome Research.) This major advance was made possible by single molecule, real-time (SMRT®) sequencing from Pacific Biosciences, which offers read lengths in the thousands of bases as well as other advantages, including a lack of GC bias, that were ideally suited to the challenge of the CGG repeat expansion.

“Utilizing the SMRT sequencing approach for the analysis of the CGG-repeat region of the FMR1 gene, we have demonstrated that it is possible to generate sequence data for FMR1 alleles in excess of 750 CGG repeats, which translates to over [2,250 bases] of 100% CGG-repeat DNA,” the authors write in the Genome Research paper.

With multi-kilobase average read lengths and no GC bias, the PacBio RS allowed for sequencing several samples with varying numbers of repeats. Flanking sequence accuracy approached 100 percent, while accuracy in the repeat region was generally better than 99 percent.

Hagerman and his team have big ideas for what can be done with the PacBio technology in the screening and diagnostic realms. “This approach is expected to fill a critical need for screening large populations for expanded-repeat alleles — in the current instance, for expanded CGG-repeat alleles of the FMR1 gene that are associated with neurodevelopmental, reproductive, and neurodegenerative disorders,” they write, noting that through method adaptations such as barcoding and multiplexed sequencing of samples, the approach could “eventually allow for high-throughput genotyping for population screening at a fraction of the current cost.”

As Hagerman moves forward with his Fragile X studies using SMRT sequencing, he notes that any scientist or clinician studying a repeat expansion disorder could benefit from this technology. “PacBio has the capability of doing long reads that would be essential for studying simple repeat expansions of any kind,” he says.

Read the full case study of the FMR1 sequencing effort.

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