Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N‐Glycolylneuraminic Acid

Abstract

About 2–3 million years ago, Alu‐mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans, possibly through a stepwise process of selection by pathogen targeting of the CMAH product (the sialic acid Neu5Gc), followed by reproductive isolation through female anti‐Neu5Gc antibodies. Loss of CMAH has occurred independently in some other lineages, but is functionally intact in Old World primates, including our closest relatives, the chimpanzee. Although the biophysical and biochemical ramifications of losing tens of millions of Neu5Gc hydroxy groups at most cell surfaces remains poorly understood, we do know that there are multiscale effects functionally relevant to both sides of the host–pathogen interface. Hominin CMAH loss might also contribute to understanding human evolution, at the time when our ancestors were starting to use stone tools, increasing their consumption of meat, and possibly hunting. Comparisons with chimpanzees within ethical and practical limitations have revealed some consequences of human CMAH loss, but more has been learned by using a mouse model with a human‐like Cmah inactivation. For example, such mice can develop antibodies against Neu5Gc that could affect inflammatory processes like cancer progression in the face of Neu5Gc metabolic incorporation from red meats, display a hyper‐reactive immune system, a human‐like tendency for delayed wound healing, late‐onset hearing loss, insulin resistance, susceptibility to muscular dystrophy pathologies, and increased sensitivity to multiple human‐adapted pathogens involving sialic acids. Further studies in such mice could provide a model for other human‐specific processes and pathologies involving sialic acid biology that have yet to be explored.

Human-like Cmah inactivation in mice increases running endurance and decreases muscle fatigability: implications for human evolution

“…The ramifications of this major change in cell surface biochemistry continue to be explored in mouse models of disease [25], and there is evidence for other significant phenotypic effects, including a human-like increase in sensitivity to certain muscular dystrophy pathologies [26][27][28][29]. Although initial muscle studies showed no major differences in the ex vivo force frequency relationship between WT and Cmah null muscle itself [26,27], independent gene expression studies pointed towards alterations in redox biology [30,31], and several transcription factors (cyclic AMP-responsive element-binding protein 1 (CREB1), CCAAT-enhancerbinding protein b (C/EBPb) and CCAAT-enhancer-binding protein a (C/EBPa)) linked to metabolism and inflammation [26].…”

Human species-specific loss of CMP- N -acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms

“…phenotypes (20), are more susceptible to develop glucose intolerance (21), and have hyperreactive macrophages (22), T cells (23), and B cells (24).…”

N -glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils

“…Potential scenario for the role of Neu5Gc loss and female anti-Neu5Gc immunity in the origin of the genus Homo via interplay of natural and sexual selection acting on cell-surface Sias. There are many known pathogens that recognize and exploit Neu5Gc (blue diamond) as a receptor on host target cells (9). Natural selection by such pathogens may have selected for rare CMAH null alleles that abolish Neu5Gc expression in homozygote individuals (12).…”

“…There are many known and possible biological consequences of human Neu5Gc loss, discussed in detail elsewhere (9). Following loss of Neu5Gc biosynthesis, the human immune system also recognizes Neu5Gc-bearing glycans as foreign and antigenic molecules (10,11).…”