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When the organizers of ISMB 2013 kindly invited me to give a keynote presentation this year, I decided to use the opportunity to survey “sequence census” methods. These are functional genomics assays based on high throughput sequencing. It has become customary to append the suffix “-Seq” to such assays (e.g. RNA-Seq), and I therefore prefer the term *Seq where the * denotes a wildcard.

The starting point for preparing the talk was a molecular biology seminar I organized in the Spring of 2010, where we discussed new high-throughput sequencing based assays with a focus on the diverse range of applications being explored. At the time I had performed a brief literature search to find *Seq papers for students to present, and this was helpful as a starting point for building a more complete bibliography for my talk. Finding *Seq assays is not easy- there is no central repository for them- but after some work I put together a (likely incomplete) bibliography that is appended to the end of the post. Update: I’ve created a page for actively maintaining a bibliography of *Seq assays.

The goal for my talk was to distill what appears to be a plethora of complex and seemingly unrelated experiments (see, e.g., Drukier et al. on the *Seq list) into a descriptive framework useful for thinking about their commonalities and differences. I came up with this cartoonish figure that I briefly explain in the remainder of this post. In future posts I plan to review in more detail some of these papers and the research they have enabled.

*SeqCartoon

A typical assay first involves thinking of a (molecular) measurement to be made. The problem of making the measurement is then “reduced” (in the computer science sense of the word) to sequencing. This means that the measurement will be inferred from sequencing bits of DNA from “target” sequences (created during the reduction), and then counting the resulting fragments.  It is important to keep in mind that the small fragments of DNA are sampled randomly from the targets, but the sampling may not be uniform.

The inference step is represented in the “Solve inverse problem” box in the figure, and involves developing a model of the experiment, together with an algorithm for inferring the desired measurement from the data (the sequenced DNA reads). Finally, the measurement becomes a starting point for further (computational) biology inquiry.  Read the rest of this entry »

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