The Human Genome Mapping Project set out to unravel the secrets of the genes by determining the primary sequence of the human genome, but it has become clear that this information is insufficient. Determination of functional and coding sequences in a primary genome sequence depends on an a priori knowledge of gene function and on statistics, and so the information obtained is incomplete and probabilistic. In the May 15 Nature, Manolis Kellis and colleagues at the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research develop and apply a general approach to determining regions of significance in primary sequence by whole genome comparison of several related species. They reasoned that evolution would conserve protein coding and regulatory elements and that comparison of more than two genomes would increase the signal:noise ratio by highlighting changes that were not due to chance (Nature 423:241-254, 2003).

Kellis et al. compared...

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