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

We have characterized the phylogenetic distribution of the CMAH gene. Among nondeuterostomes, the gene is present in two green algae and in a handful of bacteria and archaea. Within deuterostomes, potentially functional CMAH homologs are present in 184 of the 323 genomes studied. Mapping the presence and absences of putatively functional CMAH homologs onto the deuterostome phylogeny allowed us to infer a total of 31 independent gene loss or pseudogenization events (figs. 1-4). Our inferred gene trees (supplementary figs. S1-S3, Supplementary Material online) do not contradict the species tree (figs. 1-4), indicating that lateral gene transfer does not account for the observed phylogenetic distribution. A few of these events had already been described, including those in the human (Chou et al. 1998) and platypus (Schauer et al. 2009 ) lineages, an ancestor of New World monkeys (Springer et al. 2014) , and an ancestor of pinnipeds and musteloids (Ng et al. 2014) . The other 27 events represent new discoveries. At one point, our results contradict a prior hypothesis. Based on the observations that Neu5Gc is rare in reptiles and birds, and that CMAH is absent in birds, Schauer et al. (2009) suggested that CMAH may have been lost in an ancestor of Sauropsida. Our analyses, however, identified a putatively functional CMAH sequence in the green anole lizard A. carolensis, implying that the most recent common ancestor of Sauropsida had a functional CMAH gene, which was then lost both in the snake lineage and in an ancestor of turtles, crocodilians, and birds ( fig. 3 ). The fact that CMAH was lost so many times during the evolution of deuterostomes strongly suggests that the gene is not essential. However, given the relevance of Neu5Gc (e.g., as part of the ancestral SAMP; Varki 2011), its loss probably needs to be compensated by adjustments in sialic acid biology.