A Second Uniquely Human Mutation Affecting Sialic Acid Biology

Abstract

Siglecs are immunoglobulin superfamily member lectins that selectively recognize different types and linkages of sialic acids, which are major components of cell surface and secreted glycoconjugates. We report here a human Siglec-like molecule (Siglec-L1) that lacks a conserved arginine residue known to be essential for optimal sialic acid recognition by previously known Siglecs. Loss of the arginine from an ancestral molecule was caused by a single nucleotide substitution that occurred after the common ancestor of humans with the great apes but before the origin of modern humans. The chimpanzee Siglec-L1 ortholog remains fully functional and preferentially recognizes N-glycolylneuraminic acid, which is a common sialic acid in great apes and other mammals. Reintroducing the ancestral arginine into the human molecule regenerates the same properties. Thus, the single base pair mutation that replaced the arginine on human Siglec-L1 is likely to be evolutionarily related to the previously reported loss of N-glycolylneuraminic acid expression in the human lineage. Siglec-L1 and its chimpanzee Siglec ortholog also have a different expression pattern from previously reported Siglecs because they are found on the lumenal edge of epithelial cell surfaces. Notably, the human genome contains several Siglec-like pseudogenes that have independent mutations that would have replaced the arginine residue required for optimal sialic acid recognition. Thus, additional changes in the biology of sialic acids may have taken place during human evolution.

Comparing the human and chimpanzee genomes: Searching for needles in a haystack

“…A related approach is to assume that a major change in a single gene is likely to affect the evolution of other genes that are functionally connected. For example, following up on the discovery of the CMAH mutation affecting synthesis of one type of sialic acid (Chou et al 1998), multiple functional genetic differences in the biology of sialic acids have been identified between humans and great apes (Angata et al 2001;Gagneux et al 2003;Sonnenburg et al 2004). Since <60 genes are directly involved in all of the major processes of sialic acid biology, it is reasonable to suggest that this system underwent multiple related changes at some point(s) in human evolution.…”

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

“…All functional Siglecs have a conserved essential arginine residue in the Ig1 that is required for optimal Sia recognition (4). We previously noted that human Siglec-XII has a cysteine residue at this position, thus abrogating Sia recognition (32). Because the chimpanzee ortholog cSiglec-12 has arginine at this position and is bound preferentially to Neu5Gc in vitro, this replacement of arginine may be a rare event that was selected for following the human loss of Neu5Gc expression (32).…”

“…We previously noted that human Siglec-XII has a cysteine residue at this position, thus abrogating Sia recognition (32). Because the chimpanzee ortholog cSiglec-12 has arginine at this position and is bound preferentially to Neu5Gc in vitro, this replacement of arginine may be a rare event that was selected for following the human loss of Neu5Gc expression (32). Surprisingly, we found that the baboon Siglec-6 and chimpanzee Siglec-5 orthologs also have the essential arginine residue changed to leucine (R111L) and histidine (R119H), respectively.…”

Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact

“…It is well documented that human CD22 recognizes ligands with both N-acetylneuraminic acid and N-glycolylneuraminic acid, whereas murine CD22 prefers NeuGc, expressed abundantly on murine but not human cells (42,43). We used murine CD22-specific probe (NeuGc␣2-6Gal-PAA) (37) but saw no difference in the masking of CD22 on B cells of WT and CD45-null mice (Fig.…”