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In this paper, we explore the pattern of Type I functional divergence (i.e., altered functional constraints or site-specific rate difference) in the caspase gene family that is important for apoptosis (programmed cell death) and cytokine maturation. By taking advantage of substantial experimental data of caspases, the functional/structural basis of our posterior predictions from sequence analysis has been extensively studied. Our results are as follows. (1) Phylogenetic analysis shows that the evolution of major caspasemediated pathways has been facilitated by gene duplications. (2) Type I functional divergence (altered functional constraints) is statistically significant between two major subfamilies, CED-3 and ICE. (3) 4 of 21 predicted amino acid residues (for site-specific 1 Graduate student and Assistant professor, respectively, Department of Zoology and Genetics, Center for Bio informatics and Biological Statistics, Iowa State University. 2 Author for correspondence

Functional divergence and age distribution of vertebrate gene families