A mutation in human CMP-sialic acid hydroxylase occurred after theHomo-Pandivergence

Abstract

Sialic acids are important cell-surface molecules of animals in the deuterostome lineage. Although humans do not express easily detectable amounts of N-glycolylneuraminic acid (Neu5Gc, a hydroxylated form of the common sialic acid N-acetylneuraminic acid, Neu5Ac), it is a major component in great ape tissues, except in the brain. This difference correlates with lack of the hydroxylase activity that converts CMP-Neu5Ac to CMP-Neu5Gc. Here we report cloning of human and chimpanzee hydroxylase cDNAs. Although this chimpanzee cDNA is similar to the murine homologue, the human cDNA contains a 92-bp deletion resulting in a frameshift mutation. The isolated human gene also shows evidence for this deletion. Genomic PCR analysis indicates that this deletion does not occur in any of the African great apes. The gene is localized to 6p22-p23 in both humans and great apes, which does not correspond to known chromosomal rearrangements that occurred during hominoid evolution. Thus, the lineage leading to modern humans suffered a mutation sometime after the common ancestor with the chimpanzee and bonobo, potentially affecting recognition by a variety of endogenous and exogenous sialic acid-binding lectins. Also, the expression of Neu5Gc previously reported in human fetuses and tumors as well as the traces detected in some normal adult humans must be mediated by an alternate pathway.

Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms

“…This evolutionary change occurred in the human lineage after our last common ancestor with the chimpanzee and bonobo (10,11), allowing recognition of N-acetylneuraminic acid, which, being a precursor to Neu5Gc accumulates at higher levels in humans (12). These data favor the hypothesis that CD33rSiglecs function primarily as self-recognition receptors for endogenous Sia ligands.…”

Local Inhibition of Complement Improves Mesenchymal Stem Cell Viability and Function After Administration

“…Humans cannot make Neu5GC because of an inactivating mutation in the gene encoding CMP-N-acetylneuraminic acid hydroxylase, the rate-limiting enzyme in the synthesis of Neu5GC in mammalian cells. 24 But because of exposure to Neu5GC from different sources, including animal meat consumption, most humans develop antibodies against Neu5GC. Thus, our two major findings from this study-the identification of Neu5GC on MSCs that had been expanded in vitro and the observation that MSCs with reduced levels of Neu5GC showed correspondingly decreased levels of IgG/IgM binding and reduced cell damage after contact with serumboth suggest that the Neu5GC incorporated onto MSCs during in vitro propagation, potentially from xenoproteins in the culture medium, is integrally involved in the mechanism by which complement recognizes and attacks MSCs after their administration.…”

Inactivation of the EGF‐TM7 receptor EMR4 after the Pan‐Homo divergence

“…It makes EMR4 one of the very few genes [27][28][29] and, to our knowledge, the only one encoding an individual molecule involved in immunity that, on current evidence, are nonfunctional in humans but still might be active in chimpanzees. The only biochemically characterized gene that became inactive after divergence from chimpanzee is the cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac) hydroxylase gene (CMAH), which contains a 92-nt deletion in humans [30]. Consequently, the great apes, but not humans, express high levels of the sialic acid derivative N-glycolylneuraminic acid (Neu5Gc).…”