A central and long-standing issue in evolutionary theory is the origin of t
he biological variation upon which natural selection acts'. Some hypotheses
suggest that evolutionary change represents an adaptation to the surroundi
ng environment within the constraints of an organism's innate characteristi
cs(1-3). Elucidation of the origin and evolutionary relationship of species
has been complemented by nucleotide sequence(4) and gene content(5) analys
es, with profound implications for recognizing life's major domains(4). Und
erstanding of evolutionary relationships may be further expanded by compari
ng systemic higher-level organization among species. Here we employ multiva
riate analyses to evaluate the biochemical reaction pathways characterizing
43 species. Comparison of the information transfer pathways of Archaea and
Eukaryotes indicates a close relationship between these domains. In additi
on, whereas, eukaryotic metabolic enzymes are primarily of bacterial origin
(6), the pathway-level organization of archaeal and eukaryotic metabolic ne
tworks is more closely related. Our analyses therefore suggest that during
the symbiotic evolution of eukaryotes,(7-9) incorporation of bacterial meta
bolic enzymes into the proto-archaeal proteome was constrained by the host'
s pre-existing metabolic architecture.