title: On the sequencing of the human genome.
abstract: Two recent papers using different approaches reported draft sequences of the human genome. The international Human Genome Project (HGP) used the hierarchical shotgun approach, whereas Celera Genomics adopted the whole-genome shotgun (WGS) approach. Here, we analyze whether the latter paper provides a meaningful test of the WGS approach on a mammalian genome. In the Celera paper, the authors did not analyze their own WGS data. Instead, they decomposed the HGP's assembled sequence into a "perfect tiling path", combined it with their WGS data, and assembled the merged data set. To study the implications of this approach, we perform computational analysis and find that a perfect tiling path with 2-fold coverage is sufficient to recover virtually the entirety of a genome assembly. We also examine the manner in which the assembly was anchored to the human genome and conclude that the process primarily depended on the HGP's sequence-tagged site maps, BAC maps, and clone-based sequences. Our analysis indicates that the Celera paper provides neither a meaningful test of the WGS approach nor an independent sequence of the human genome. Our analysis does not imply that a WGS approach could not be successfully applied to assemble a draft sequence of a large mammalian genome, but merely that the Celera paper does not provide such evidence.
authors.affiliation: Genome Sequencing Center, Washington University, Saint Louis, MO 63108, USA. bwaterst@watson.wustl.edu
authors.forename: Robert H
authors.initials: RH
authors.lastname: Waterston
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: John E
authors.initials: JE
authors.lastname: Sulston
mesh_terms: D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D003001:Cloning, Molecular; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D016045:Human Genome Project; D006801:Humans; D008957:Models, Genetic; D020161:Physical Chromosome Mapping / Q000379:methods* / Q000592:standards; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000379:methods*; D016324:Sequence Tagged Sites