title: Identification of novel mammalian caspases reveals an important role of gene loss in shaping the human caspase repertoire.
abstract: Proteases of the caspase family play central roles in apoptosis and inflammation. Recently, we have described a new gene encoding caspase-15 that has been inactivated independently in different mammalian lineages. To determine the dynamics of gene duplication and loss in the entire caspase gene family, we performed a comprehensive evolutionary analysis of mammalian caspases. By comparative genomics and reverse transcriptase-polymerase chain reaction analyses, we identified 3 novel mammalian caspase genes, which we tentatively named caspases-16 through -18. Caspase-16, which is most similar in sequence to caspase-14, has been conserved in marsupials and placental mammals, including humans. Caspase-17, which is most similar to caspase-3, has been conserved among fish, frog, chicken, lizard, and the platypus but is absent from marsupials and placental mammals. Caspase-18, which is most similar to caspase-8, has been conserved among chicken, platypus, and opossum but is absent from placental mammals. These gene distribution patterns suggest that, in the evolutionary lineage leading to humans, caspase-17 was lost after the split of protherian and therian mammals and caspase-18 was lost after the split of marsupials and placental mammals. In the canine genome, the number of caspases has been reduced by the fusion of the neighboring genes caspases-1 and -4, resulting in a single coding region. Further lineage-specific gene inactivations were found for caspase-10 in murine rodents and caspase-12 in humans, rabbit, and cow. Lineage-specific gene duplications were found for caspases-1, -3, and -12 in opossum and caspase-4 in primates. Other caspases were generally conserved in all mammalian species investigated. Using the positions of introns as stable characters during recent vertebrate evolution, we define 3 phylogenetic clades of caspase genes: caspases-1/-2/-4/-5/-9/-12/-14/-15/-16 (clade I), caspases-3/-6/-7/-17 (clade II), and caspases-8/-10/-18/CFLAR (clade III). We conclude that gene inactivations have occurred in each of the 3 caspase clades and that gene loss has been as critical as gene duplication in the evolution of the human repertoire of caspases.
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria. leopold.eckhart@meduniwien.ac.at
authors.forename: Leopold
authors.initials: L
authors.lastname: Eckhart
authors.forename: Claudia
authors.initials: C
authors.lastname: Ballaun
authors.forename: Marcela
authors.initials: M
authors.lastname: Hermann
authors.forename: John L
authors.initials: JL
authors.lastname: VandeBerg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sipos
authors.forename: Aumaid
authors.initials: A
authors.lastname: Uthman
authors.forename: Heinz
authors.initials: H
authors.lastname: Fischer
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053148:Caspase 3 / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics; D020169:Caspases / Q000145:classification / Q000235:genetics*; D002645:Chickens; D030541:Databases, Genetic; D019143:Evolution, Molecular; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D007438:Introns; D008322:Mammals / Q000235:genetics*; D008969:Molecular Sequence Data; D009893:Opossums; D010802:Phylogeny; D010987:Platypus; D009626:Terminology as Topic; D014714:Vertebrates / Q000235:genetics
chemical_list: D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases