Solving an N-dimensional puzzle: Finding chromosomal re-arrangements using genome-wide sequencing

Source: Campbell et al (2008). Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genetics 49(6): 722-729.

Without any doubt, this paper excels in portraying the power of massive parallel sequencing to address whole genome problems. The idea is elegant and simple, they nebulize the genomic DNA extracted from two lung cancer cell lines (NCI-H2171 and NCI-H1770 for which the genomic rearrangements are in part identified) while ligating adapters to the sheared ends. The resulting fragments are size selected using gel extraction (200-400bp) and then applied to massive parallel sequencing for reading the two fragment ends. They then aligned the reads back to the genome with the idea that the two end reads falling far from each other (600bp) represent chromosomal re-arrangements. This process is shown here with a figure from the original paper:
To summarize the results, they succeed in capturing the previously known re-arrangements in these two cell-lines. Using the same data, they also extract information regarding the copy-number and the structure of complex amplicons in the genome. The details do not really matter (see the original paper if you are interested); nevertheless, this paper is a perfect example of combining whole-genome experimental and computational tools to reveal the underlying biological differences.