Abstract The lengths of orthologous protein families in Eukarya are almost double the lengths found in Bacteria and Archaea. Here we examine protein structures in 745 genomes and show that protein length differences between superkingdoms arise as much shorter prokaryotic nondomain linker sequences. Eukaryotic, bacterial, and archaeal linkers are 250, 86, and 73 aa residues in length, respectively, whereas folded domain sequences are 281, 280, and 256 residues, respectively. Cryptic domains match linkers (P < 0.0001) with probabilities ranging between 0.022 and 0.042; accordingly, they do not affect length estimates significantly. Linker sequences support intermolecular binding within proteomes and they are probably enriched in intrinsically disordered regions as well. Reductively evolved linker sequence lengths in growth rate maximized cells should be proportional to proteome diversity. By using total in-frame coding capacity of a genome [i.e., coding sequence (CDS)] as a reliable measure of proteome diversity, we find linker lengths of prokaryotes clearly evolve in proportion to CDS values, whereas those of eukaryotes are more randomly larger than expected. Domain lengths scarcely change over the entire range of CDS values. Thus, the protein linkers of prokaryotes evolve reductively whereas those of eukaryotes do not. http://www.pnas.org/content/108/29/11954.abstract?etoc -- Prof. Dr. Klaas Vandepoele Tel. 32 (0)9 33 13822 VIB Department of Plant Systems Biology, Ghent University Technologiepark 927, 9052 Gent, Belgium E-mail: Klaas.Vandepoele@psb.vib-ugent.be Website: http://bioinformatics.psb.ugent.be/cig/ ---------------------------------------------------------