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. Clone-by-Clone Sequencing For purposes of comparison it is helpful to first outline a specific implementation of clone-by-clone sequencing. Although by no means the only one possible, this implementation is being used by several of the larger groups and seems likely to be the method of choice for the major part of the genome. One starts with a set of mapped sequence-tagged sites (STSs) (Olson et al. 1989) from a particular chromosomal region. These are screened against a bacterial artificial chromosome (BAC) (or other large bacterial clone) library (Kim et al. 1996) to obtain overlapping clusters of clones from that region. Since whole-genome mapping efforts are nearing the target density of 1 STS per 100 kb [Hudson et al
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