The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Most genomic variation is attributable to single nucleotide polymorphisms (SNPs), which therefore offer the highest resolution for tracking disease genes and population history. It has been proposed that a dense map of 30,000-500,000 SNPs can be used to scan the human genome for haplotypes associated with common diseases. Here we describe a simple but powerful method, called reduced representation shotgun (RRS) sequencing, for creating SNP maps. RRS re-samples specific subsets of the genome from several individuals, and compares the resulting sequences using a highly accurate SNP detection algorithm. The method can be extended by alignment to available genome sequence, increasing the yield of SNPs and providing map positions. These methods are being used by The SNP Consortium, an international collaboration of academic centres, pharmaceutical companies and a private foundation, to discover and release at least 300,000 human SNPs. We have discovered 47,172 human SNPs by RRS, and in total the Consortium has identified 148,459 SNPs. More broadly, RRS facilitates the rapid, inexpensive construction of SNP maps in biomedically and agriculturally important species. SNPs discovered by RRS also offer unique advantages for large-scale genotyping.

Methanogenesis, the biological production of methane, plays a pivotal role in the global carbon cycle and contributes significantly to global warming. The majority of methane in nature is derived from acetate. Here we report the complete genome sequence of an acetate-utilizing methanogen, Methanosarcina acetivorans C2A. Methanosarcineae are the most metabolically diverse methanogens, thrive in a broad range of environments, and are unique among the Archaea in forming complex multicellular structures. This diversity is reflected in the genome of M. acetivorans.

We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. These SNPs were primarily discovered by two projects: The SNP Consortium and the analysis of clone overlaps by the International Human Genome Sequencing Consortium. The map integrates all publicly available SNPs with described genes and other genomic features. We estimate that 60,000 SNPs fall within exon (coding and untranslated regions), and 85% of exons are within 5 kb of the nearest SNP. Nucleotide diversity varies greatly across the genome, in a manner broadly consistent with a standard population genetic model of human history. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy.

We report results using a microdevice for DNA sequencing using samples from chromosome 17, obtained from the Whitehead Institute Center for Genome Research (WICGR) production line. The device had an effective separation distance of 11.5 cm and a lithographically defined injection width of 150 µm. The four-color raw data were processed, base-called by the sequencing software Trout, and compared to the corresponding ABI 377 sequence from WICGR. With a criteria of 99% accuracy, we achieved average continuous reads of 505 bases in 27 min with 3% linear polyacrylamide (LPA) at 150 V/cm, and 460 bases in 22 min with 4% LPA at 200 V/cm at a temperature of 45°C. In the best case, up to 565 bases could be base-called with the same accuracy in <25 min. In some instances, Trout allowed for accurate base-calling down to a resolution R as low as R = 0.35. This may be due in part to the high signal-to-noise ratio of the microdevice. Unlike many results reported on capillary machines, no additional sample cleanup other than ethanol precipitation was required. In addition, DNA fragment biasing (i.e., discrimination against larger fragments) was reduced significantly through the unique sample injection mechanism of the microfabricated device. This led to increased signal strength for long fragments, which is of great importance for the high performance of the microdevice.Significant advancement in the technology of DNA analysis is expected from the use of microfabricated electrophoretic devices for sequencing and genotyping. In this approach photolithography, combined with wet-etching and thermal wafer bonding, is used to construct enclosed intricate microchannel structures in glass and fused-silica substrates; these structures are then utilized for electrophoresis (Harrison et al. 1993). It has been speculated that these devices will allow DNA separations approaching the theoretical limits of electrophoresis and in a format that will reduce analysis time and extend parallelism and automation (Freemantle 1999), which might hence increase throughput well beyond current capillary array machines. For example, in recent experiments we have demonstrated genotyping at 10-to 100-fold reduced analysis times on microdevices when compared to capillaries and slab gels, respectively (Schmalzing et al. 1997. DNA sequencing of single-color pGEM and four-color M13 DNA standard sequencing samples has been demonstrated on 3.5-, 11.5-, and 7-cm-long microdevices (Woolley et al. 1995;Schmalzing et al. 1998;Liu et al. 1999). The feasibility of ultra-high sample throughput has been proven through still modest multiplexing up to 96 microchannels (Simpson et al. 1998;Koutny et al. 1999). However, to the best of our knowledge, all published studies on DNA sequencing by microdevices have been performed using DNA standard samples such as M13 or pGEM. Practical sequencing must deal with additional factors such as variable salt and template concentrations Salas-Solano et al. 1998), highly samplespecific compression regions, and the interplay between electr...