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Ben Blencowe on a Technique for Monitoring Alternative Splicing

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At A Glance

Name: Benjamin Blencowe, Associate Professor, Banting and Best department of medical research, department of molecular and medical genetics, University of Toronto

Background: 1998-2002 — Assistant Professor, Banting and Best department of medical research, department of molecular and medical genetics, University of Toronto

1992-1998 — Postdoctoral Fellow and Research Fellow, Center for Cancer Research, MIT

Education: 1991 — PhD, biochemistry, University of London

1988 — BSc, microbiology, Imperial College, University of London

 

In this week’s issue of the journal Molecular Cell, a group of researchers from the University of Toronto have published a paper detailing their work on using a new technique to examine genetic material in greater detail than what current microarray technologies offer. Their system utilizes a custom-designed microarray and an advanced computer program to monitor alternative splicing in mammalian tissues. It was developed by Benjamin Blencowe and Timothy Hughes of the university’s Banting and Best Department of Medical Research and the Department of Medical Genetics and Microbiology, in collaboration with Professor Brendan Frey of the Department of Electrical and Computer Engineering. In this week’s issue of BioArray News, Blencowe explains the technique and its potential advancements over current gene expression techniques.

Did your research derive from using traditional microarrays?

We started out trying robotic, spotted oligo arrays and found that we weren’t obtaining quite the sensitivity and specificity we needed to get the system to work. So, what we’ve done is use the Agilent inkjet array platform to order the custom arrays. We design all the probe sequences in-house using a program that optimizes the probe sequence characteristics. A data analysis tool, which employs machine learning and a Bayesian network, is then used to generate alternative splicing levels from the microarray data.

So, there’s nothing different about the chip itself, it’s the software?

We’ve fine-tuned the design of oligo probes and combined sets of oligos specific for exons and splice-junctions, which is important for obtaining quantitative information. The more novel aspect is the data analysis tool that was developed by Brendan Frey’s group here at the University of Toronto.

What kind of information are you hoping this system will provide that researchers currently cannot get?

It delivers quantitative information on alternative splicing levels. We can measure the levels of inclusion of individual exons in transcripts. Previous systems for analyzing splicing are not able to deliver the level of quantitative information we can obtain with our system.

What are the applications for this system and the information it provides?

In our paper, we used the system to generate insights into how alternative splicing is regulated on a global level. For example, we’re able to observe which alternative exons are skipped at weak to moderate to high levels across different mammalian tissues — so we can obtain an idea of what types and proportions of exons undergo different inclusion levels. We have also used the system to look at how alternative splicing contributes to tissue specificity, and the quantitative information was useful in obtaining some new insights into this question.

The system should also be very useful for screening for alternative splicing events implicated in certain diseases. For example, if the level of inclusion of an exon decreases by 30 percent in disease versus non-disease individuals, our system generally would be able to detect that kind of change. Having a quantitative system gives you more detailed information.

What kind of instrumentation is required beside the Agilent arrays?

For the main equipment one needs a microrray scanner and a good computer for analyzing the data. That’s really about it.

Has anyone outside of your department used the technique yet?

No. This is the first paper we’ve published using our system. We suspect people will use the system once they find out about it. We have a lot of different applications planned now that we have the system set up. Next year will be an exciting year for us.

Have you talked with any commercial entities yet about your work?

Yes. We’ve had some discussions with a few companies about making this technology more accessible to individuals. Particularly the software tool that Brendan Frey’s group developed in the collaboration.

Would you expect to transfer the technology to a commercial entity in the near future?

Yes. We want to do that as quickly as possible. [The timeframe] depends on how fast they move.

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