What's the difference between shotgun sequencing and clone based sequencing?

What's the difference between shotgun sequencing and clone based sequencing?

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In a lecture during my undergraduate degree we were introduced to the race to complete the human genome. Celera were competing with Sanger and collaborators to sequence the human genome. Celera wanted to patent some sequences, whilst Sanger et al. wanted to keep their findings in the public domain. Celera knew they couldn't compete with Sanger et al. with conventional cloning techniques which required a lot of man-power, "so instead opted for shotgun sequencing".

To me it seems like both clone based sequencing and shotgun sequencing could have been used together, however the lecturers semantics were a bit vague (… okay, I wasn't paying close enough attention!) and I didn't ask for clarification at the time.

Whilst I appreciate this is a large topic, what are the main differences between Celera's shotgun sequencing and Sanger's clone based sequencing during the late 1990s? Are "shotgun cloning" and "clone based sequencing" actually mutually exclusive terms?

The v short answer is that in shotgun sequencing, the sequencer is fed a set of random sequences from the target. This can be done for instance by mechanically shearing DNA and then building a set of shotgun sequencing jobs which are then compiled back together by a genome assembler (i.e. in whole genome sequencing projects) into a full sequence.

In clone based sequencing, the DNA to be sequenced is specifically sectioned off into sequence copied into of plasmids (BACs - bacterial artificial chromosome) to divide the sequencing job into sections- a divide and conquer strategy. BACs can be 150 kb long just to give you an idea.

These are not mutually exclusive terms; clone-based sequencing projects usually use the large clone libraries to section the project into a set of shotgun sequencing projects.

In short: the basis of the process is the same in both, the difference relies that in the clone based sequencing you make DNA library of the pieces of DNA clones you got from the sequence you used in first place. Like that, data management and the mounting of DNA contigs will be a lot easier computationally speaking. In shotgun sequencing the same is done but without the cloning and libraries, you directly mount contigs from sequenced sequence pieces, thus better computers are needed.

Also I think your terminology is wrong: shotgun strictly means the sequencing based on the random shearing and consecutive construction of contigs. I think you better mean whole genome shotgun sequencing with "shotgun sequencing"(as the clone based sequencing also is a shotgun sequencing method).

"To me it seems like both clone based sequencing and shotgun sequencing could have been used together,"

I believe they were. The public project cut up the genome into BACs and shotgunned every BAC, and then put the BACs together, while Venter used some sequence position information from the public effort to help him place his shotgun pieces.


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