Against a Whole-Genome Shotgun

The human genome project is entering its decisive final phase, in which the genome sequence will be determined in large-scale efforts in multiple laboratories worldwide. A number of sequencing groups are in the process of scaling up their throughput; over the next few years they will need to attain a collective capacity approaching half a gigabase per year to complete the 3-Gb genome sequence by the target date of 2005. At present, all contributing groups are using a clone-by-clone approach, in which mapped bacterial clones (typically 40-400 kb in size) from known chromosomal locations are sequenced to completion. Among other advantages, this permits a variety of alternative sequencing strategies and methods to be explored independently without redundancy of effort. Although it is not too late to consider implementing a different approach, any such approach must have as high a probability of success as the current one and offer significant advantages (such as decreased cost). I argue here that the whole-genome shotgun proposed by Weber and Myers satisfies neither condition.