Glucocerebrosidase recombinant allele: molecular evolution of the glucocerebrosidase gene and pseudogene in primates.

Glucocerebrosidase is a lysosomal enzyme that hydrolyses the beta-glycosidic linkage of glucocerebroside, a ubiquitous sphingolipid present in the plasma membrane of mammalian cells. Deleterious mutations in the glucocerebrosidase gene result in Gaucher disease, the most prevalent lysosomal storage disease. Humans have one glucocerebrosidase functional gene and pseudogene that were located 16 kb apart on chromosome 1q21 and share 96% overall sequence similarity. Recombination between the two genes creates a 'complex allele' that renders glucocerebrosidase non-functional and accounts for >20% of the total Gaucher disease mutations in some population. The glucocerebrosidase pseudogene is absent in all other mammalian species surveyed so far. In order to learn more about the molecular evolution of the glucocerebrosidase functional gene and pseudogene, we have sequenced approximately 1.1 kb of the C-terminal region of these genes that encodes the enzyme catalytic site, from PCR-amplified genomic DNA of gorilla, chimpanzee, orangutan (the great apes), and squirrel monkey (a new-world monkey). In gorilla, chimpanzee, and orangutan, there are two copies of the glucocerebrosidase gene while the squirrel monkey possesses only a single copy. Similar to human, the second copy of glucocerebrosidase gene in gorilla and chimpanzee is non-functional because of a 55-bp deletion in exon 9, while that in orangutan appears to be unaffected and may still be functional. These data suggest that the glucocerebrosidase gene duplication event occurred after squirrel monkey divergence from the great apes, and that the exon 9 deletion that rendered the second copy of the glucocerebrosidase gene non-functional occurred prior to the divergence of gorilla and chimpanzee but after the divergence of orangutan from their common ancestor to human. The two genes in each species are least similar in gorilla and chimpanzee (97.8%) and most similar in orangutan (99.5%). None of the nucleotide variations in the GBA gene among the primates correspond to known mutations in Gaucher disease. Phylogenetic tree analysis using DNAstar and PAUP4.0 software indicates that gene conversion caused the evolution of glucocerebrosidase functional gene and pseudogene to be concerted.