Comparisons of complete genome sequences allow the most objective and compr
ehensive descriptions possible of a lineage's evolution. This communication
uses the completed genomes from four major euryarchaeal taxa to define a g
enomic signature for the Euryarchaeota and, by extension, the Archaea as a
whole. The signature is defined in terms of the set of protein-encoding gen
es found in at least two diverse members of the euryarchaeal taxa that func
tion uniquely within the Archaea; most signature proteins have no recogniza
ble bacterial or eukaryal homologs. By this definition, 351 clusters of sig
nature proteins have been identified. Functions of most proteins in this si
gnature set are currently unknown. At least 70% of the clusters that contai
n proteins from all the euryarchaeal genomes also have crenarchaeal homolog
s. This conservative set, which appears refractory to horizontal gene trans
fer to the Bacteria or the Eukarya, would seem to reflect the significant i
nnovations that were unique and fundamental to the archaeal "design fabric.
" Genomic protein signature analysis methods may be extended to characteriz
e the evolution of any phylogenetically defined lineage. The complete set o
f protein clusters for the archaeal genomic signature is presented as suppl
ementary material (see the PNAS web site, www.pnas.org).