Computational identification and characterization of constrained elements in the human genome is 1 of the major goals of the next phase of the human genome project (Collins et al. 2003). To generate the requisite comparative sequence data, the sequencing centers will generate whole genome sequence from a number of mammals chosen primarily for their large diversity in terms of neutral substitutions. Currently existing, in production, or scheduled for production are at least 8 mammalian genomes at high coverage and 8 mammalian genomes at 2x coverage (www.genome.gov/12511858). This proposal focuses on the detection and annotation of constrained elements on the basis of global sequence alignments and high-resolution estimates of evolutionary rates. In short, we propose to generate the data that provided the justification for making a large investment in comparative sequencing of diverse mammals.
