primer walk, shotgun

Solexa sequencing
http://awcgs.massey.ac.nz/seqserver/solexa-faq.htm

Dideoxy chain-termination sequencing depends on synthetic DNA primer sequences to initiate the reaction. These primers must match a portion of the template whose sequence we are trying to determine. This gives us a 'chicken and egg' problem of needing to know a bit of the template sequence before we can read more of it.

One way to start sequencing an unknown sequence is to make a recombinant clone, putting the unknown insert into a vector of known sequence. Then primers from the vector can be used to begin reading the sequence of the insert. Once a portion of the new insert sequence is known, we can use that to design a new primer to let us read further. This process can be repeated until the whole insert is sequenced. This 'primer walking' process is inherently sequential, since each step must be completed before the results can be used to design the primer for the next step.

Shotgun sequencing is an approach that lets us run large numbers of reactions in parallel, rather than in series. Rather than using primer walking through one large insert, we randomly fragment the insert to create a library of smaller fragments. A large number of these clones are chosen at random, and sequenced in parallel using primers matching the vector. The sequencing results are then 'assembled' on the computer into a contiguous sequence of overlapping fragments. This approach essentially trades much of the laborious laboratory work for a puzzle to be solved on the computer, and turns out to be much faster than pure primer walking.