Selenocysteine (Sec), the 21st amino acid, is incorporated into proteins through 
the recoding of a termination codon, an inefficient translational process 
mediated by a complex molecular machinery. Sec is a rare amino acid in extant 
proteins, chemically similar to cysteine (Cys), found in homologous position to 
Cys of nonselenoprotein families. Selenoproteins account for the dependence of 
vertebrates on environmental selenium (Se) and have an important role in several 
Se-deficiency diseases. Selenoproteins are poorly characterized enzymes and 
reports on the functional exchangeability of Sec with Cys are limited and 
controversial. Whether the unique role of Sec in some selenoenzymes illustrates 
the broader contribution of Se to protein function is unknown (Gromer S, 
Johansson L, Bauer H, Arscott LD, Rauch S, Ballou DP, Williams CH Jr, Schirmer 
RH, Arnér ES. 2003. Active sites of thioredoxin reductases: why selenoproteins? 
Proc Natl Acad Sci USA. 100:12618-12623). Here, we address this question from an 
evolutionary perspective by the simultaneous identification of the patterns of 
divergence in almost half a billion years of vertebrate evolution and diversity 
within the human lineage for the full complement of enzymatic Sec residues in 
these proteomes. We complete this analysis with data for the homologous Cys 
residues in the same genomes. Our results indicate concerted purifying selection 
across Sec and Cys sites in all selenoproteomes, consistent with a unique role 
of Sec in protein function, low exchangeability, and an unknown degree of 
functional divergence with Cys homologs. The distinct biochemical properties of 
Sec, rather than the geographical distribution of Se, global O(2) levels or Sec 
metabolic cost, appear to play a major role in driving adaptive changes in 
vertebrate selenoproteomes. A better understanding of the selenoproteomes and 
neutral evolutionary patterns in other taxa will be necessary to fully assess 
the generality of this conclusion.