Degeneration of an Intracellular Ion Channel in the Primate Lineage by Relaxation of Selective Constraints

Ion channel genes are highly conserved and are rarely degenerated in the primate lineage leading to humans. So far, the only well-characterized ion channel known to be degenerated in primates is the plasma membrane transient receptor potential channel TRPC2, possibly due to changes in the pheromone signaling. Here, by analyzing the sequence data from ten primate species, we have determined the degeneration process of the TPC3 gene that encodes a member of the two-pore channel (TPC) family recently implicated in Ca(2+) release by nicotinic acid adenine dinucleotide phosphate from intracellular acidic stores in animals. We show that degeneration of TPC3 likely began in the common ancestors of Apes and Old World monkeys through a conserved inactivating mutation, followed by additional deleterious mutations resulting in the generation of a TPC3 pseudogene in the descendant catarrhine lineage. Located at a chromosome recombination hot spot, catarrhine TPC3 pseudogenes underwent a series of lineage-specific rearrangements, including exon deletion and duplication. In contrast, we identify near full-length TPC3 sequences in New World monkeys and Prosimians and show that the gene is subjected to strong purifying selection and therefore likely functional. Our data provide the first evidence for relaxed functional constraints for an intracellular ion channel in primates and shed novel insights into the evolution and regulation of Ca(2+) signaling in the primate lineage.