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.

The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the ∼120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes ∼13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.

PipMaker (http://bio.cse.psu.edu) is a World-Wide Web site for comparing two long DNA sequences to identify conserved segments and for producing informative, high-resolution displays of the resulting alignments. One display is a percent identity plot (pip), which shows both the position in one sequence and the degree of similarity for each aligning segment between the two sequences in a compact and easily understandable form. Positions along the horizontal axis can be labeled with features such as exons of genes and repetitive elements, and colors can be used to clarify and enhance the display. The web site also provides a plot of the locations of those segments in both species (similar to a dot plot). PipMaker is appropriate for comparing genomic sequences from any two related species, although the types of information that can be inferred (e.g., protein-coding regions andcis-regulatory elements) depend on the level of conservation and the time and divergence rate since the separation of the species. Gene regulatory elements are often detectable as similar, noncoding sequences in species that diverged as much as 100–300 million years ago, such as humans and mice, Caenorhabditis elegans andC. briggsae, or Escherichia coli andSalmonella spp. PipMaker supports analysis of unfinished or “working draft” sequences by permitting one of the two sequences to be in unoriented and unordered contigs.

BackgroundThe third, or wobble, position in a codon provides a high degree of possible degeneracy and is an elegant fault-tolerance mechanism. Nucleotide biases between organisms at the wobble position have been documented and correlated with the abundances of the complementary tRNAs. We and others have noticed a bias for cytosine and guanine at the third position in a subset of transcripts within a single organism. The bias is present in some plant species and warm-blooded vertebrates but not in all plants, or in invertebrates or cold-blooded vertebrates.ResultsHere we demonstrate that in certain organisms the amount of GC at the wobble position (GC3) can be used to distinguish two classes of genes. We highlight the following features of genes with high GC3 content: they (1) provide more targets for methylation, (2) exhibit more variable expression, (3) more frequently possess upstream TATA boxes, (4) are predominant in certain classes of genes (e.g., stress responsive genes) and (5) have a GC3 content that increases from 5'to 3'. These observations led us to formulate a hypothesis to explain GC3 bimodality in grasses.ConclusionsOur findings suggest that high levels of GC3 typify a class of genes whose expression is regulated through DNA methylation or are a legacy of accelerated evolution through gene conversion. We discuss the three most probable explanations for GC3 bimodality: biased gene conversion, transcriptional and translational advantage and gene methylation.