Comparative genomics: the evolutionary history of the Bcl-2 family.

The Bcl-2 family is a huge family composed of various members, occurring in all animals, which are key regulators of apoptosis, the cell death program critical for cell survival and development, tissue homeostasis, and protection against pathogens. The members of the Bcl-2 family can be divided into pro-apoptotic and anti-apoptotic proteins. A delicate balance between these members exists in each cell and the regulations of these two groups of proteins determines whether the cell survives or undergoes apoptosis. Bcl-2 family proteins are characterized by distinct domains. All members possess at least one of the four motifs known as Bcl-2 homology domains (BH1 to BH4). Most pro-survival members which can inhibit apoptosis facing a wide variety of cytotoxic insults, contain at least BH1 and BH2 domains; those most similar to Bcl-2 have all four BH domains. All the pro-apoptosis family members possess BH3 domain which is the central domain. For the first time, a global phylogenetic analysis of all Bcl-2 family members is presented here. We have analyzed the genes known so far that have a different composition of the functional domains BH1, BH2, BH3 and BH4. The analyses were performed both on complete sequences (124 sites analyzed) and on single domains. We present the results obtained using both approaches. We have also analyzed the amino acid profile and the degree of conservation of the BH3 domains of pro- and anti-apoptotic proteins. The results of our phylogenetic analyses show that a clear-cut clustering into pro- and anti-apoptotic products, reproducible with different evolutionary methods, could also be obtained by analyzing restricted areas such as the BH1 and BH2 domains. It is noteworthy that even when the analysis is performed only on the BH3 domain, we have two clear-cut clusters. The evolutionary analysis of gene family members is a valuable tool to predict their functions and guide experimental assays to validate predictions. Once the functions of all the components are known, it will be possible to study the process in a holistic way.