Uniquely human evolution of sialic acid genetics and biology

Abstract

Darwinian evolution of humans from our common ancestors with nonhuman primates involved many gene-environment interactions at the population level, and the resulting human-specific genetic changes must contribute to the "Human Condition." Recent data indicate that the biology of sialic acids (which directly involves less than 60 genes) shows more than 10 uniquely human genetic changes in comparison with our closest evolutionary relatives. Known outcomes are tissue-specific changes in abundant cell-surface glycans, changes in specificity and/or expression of multiple proteins that recognize these glycans, and novel pathogen regimes. Specific events include Alu-mediated inactivation of the CMAH gene, resulting in loss of synthesis of the Sia N-glycolylneuraminic acid (Neu5Gc) and increase in expression of the precursor N-acetylneuraminic acid (Neu5Ac); increased expression of α2-6-linked Sias (likely because of changed expression of ST6GALI); and multiple changes in SIGLEC genes encoding Sia-recognizing Ig-like lectins (Siglecs). The last includes binding specificity changes (in ; expression pattern changes (in Siglecs -1, -5, -6, and -11); gene conversion (SIGLEC11); and deletion or pseudogenization (SIGLEC13, SIGLEC14, and SIGLEC16). A nongenetic outcome of the CMAH mutation is human metabolic incorporation of foreign dietary Neu5Gc, in the face of circulating anti-Neu5Gc antibodies, generating a novel "xeno-auto-antigen" situation. Taken together, these data suggest that both the genes associated with Sia biology and the related impacts of the environment comprise a relative "hot spot" of genetic and physiological changes in human evolution, with implications for uniquely human features both in health and disease.genomics | Siglec | Neu5Gc | Xeno-auto-antigen

Sexual selection by female immunity against paternal antigens can fix loss of function alleles

“…The human lineage lost Neu5Gc expression due to an inactivating mutation in the CMAH gene (7). Human cell surfaces thus differ from those of most mammals because they lack Neu5Gc molecules, and instead carry an excess of Neu5Ac molecules (8).…”

“…Of the <70 known genes directly involved in Sia metabolism and recognition, over a dozen have undergone human-specific changes, possibly because the loss of Neu5Gc required subsequent reconfiguration of other aspects of human Sia biology (8). Pseudogenization of CMAH in hominins is estimated to have occurred about 3 million years ago (Mya).…”

Successful Prediction of Substrate-binding Pocket in SLC17 Transporter Sialin

“…As humans are genetically deficient in Neu5Gc synthesis, this results in the production of anti-Neu5Gc antibodies that contribute to chronic inflammation and enhanced tumor progression (19). The metabolic incorporation of Neu5Gc also alters cell-cell and cell-pathogen interactions that depend on surface sialoglycoconjugates (20).…”

Molecular Phylogeny and Functional Genomics of β-Galactoside α2,6-Sialyltransferases That Explain Ubiquitous Expression of st6gal1 Gene in Amniotes

“…Indeed, phenotypic variation in ␣2,6-sialylation of N-glycosylproteins has been observed in various animals and in particular in mammals despite genetic conservation of their translated gene sequences (24). The patterns of tissue ␣2,6-sialylation of N-glycosylproteins differ widely among mammals, even among closely related taxa, such as mice and humans, which diverged only 96 MYA (68, 96 -98), or great apes and humans, which diverged 13-14 MYA (28,96). We suggest a still on-going evolution and neofunctionalization of st6gal1 genes in mammals, which could explain differences in influenza virus infection of airway epithelial cells (24).…”

“…The position of the teleost second intron is inside a relatively well conserved protein sequence, downstream to the amino acid corresponding to the human Trp 96 . These results do not support the exon shuffling hypothesis.…”