Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

Peri, Sateesh; Kulkarni, Asmita; Feyertag, Felix; Berninsone, Patricia M; Alvarez-Ponce, David

In addition to humans, CMAH has also been reported or suggested to be inactivated or lost in other animal lineages independently. New World monkeys underwent inactivation of CMAH $30 Ma due to inversion of exons 4-13 and loss of exons 4-8 and 10-13. This may explain why they are susceptible to certain human pathogens, such as P. falciparum (Springer et al. 2014 ). In the ferret genome, the first nine exons of the gene have been lost, and PCR analyses did not detect conserved portions of the gene in a number of pinnipeds and musteloids, indicating that CMAH was inactivated in an ancestor of pinnipeds and musteloids (Ng et al. 2014) . Sequence similarity searches against the genomes of chicken and zebra finch did not detect any CMAH homolog (Schauer et al. 2009 ) and southern-blot analysis did not detect expression of the gene in chicken liver (Kawano et al. 1995) . Consistently, Neu5Gc has been shown to be rare in birds and reptiles (Fujii et al. 1982; Schauer and Kamerling 1997; Ito et al. 2000; Schauer et al. 2009 ). These observations led to the hypothesis that the CMAH gene may have been lost in an ancestor of Sauropsida (reptiles and birds) (Schauer et al. 2009 ). According to this hypothesis, the low amounts of Neu5Gc detected in some reptiles and birds may have been incorporated from the diet. Analysis of the platypus genome did not reveal any CMAH homolog, and Neu5Gc was not detected in platypus muscles or liver (Schauer et al. 2009 ), or in the milk of the Australian spiny anteater echidna (Kamerling et al. 1982) , suggesting that CMAH was also lost in an ancestor of extant monotremes.