Human-specific features and developmental dynamics of the brain N-glycome

Abstract

Comparative "omics" studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. Here, we performed multi-regional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry, then integrated these data with complementary glycotranscriptomic data. We found that in primates the brain N-glycome has evolved more rapidly than the underlying transcriptomic framework, providing a mechanism for generating additional diversity. We show that brain N-glycome evolution in hominids has been characterized by an increase in complexity and α(2-6)-linked N-acetylneuraminic acid along with human-specific cell type expression of key glycogenes. Finally, by comparing the prenatal and adult human brain N-glycome, we identify region-specific neurodevelopmental pathways that lead to distinct spatial N-glycosylation profiles in the mature brain.

A draft of human N-glycans of glycoRNA

“…The isotopic envelope fingerprinting map, annotated MS/MS spectrum with the matched fragment ions, and graphical fragmentation map of each N-glycan identified from the 12 human organs are provided in Supplementary information 2-13 (PDF files, 12 in total, one for each organ). Furthermore, the number of distinct compositions for these Nglycan linkages varied as well, ranging from 17 in the heart to 118 in the spleen, and with different numbers for other organs, including brain (32), lung (39), liver (43), stomach (79), kidney (89), intestine (89), colon (75), testis (60), fat (20), and muscle (20). These variations can be attributed to the presence of sequence isomers, wherein the same composition is linked to different structural arrangements.…”

“…The human brain is a remarkably complex organ with a dynamic N-glycome. By comparison with the brain N-glycome of protein in rat, macaque, chimpanzee and human, Klaric et al 20 found that a progressively more intricate N-glycan landscape and 2,6-linked Nacetylneuraminic acid increased with the evolution. Our glycoRNA analysis in humans mirrors these findings, as complex and hybrid types of N-glycans dominate, comprising 96% of the glycoRNA N-glycome.…”

Functional associations of evolutionarily recent human genes exhibit sensitivity to the 3D genome landscape and disease

“…As in other studies (80,133), we retrieved 19,334 human annotated proteins from the Ensembl 89 database (www.ensembl.org), keeping the oldest and longest isoform per proteincoding gene. Additionally, we used 2,102 human unannotated protein sequences that are proteogenomically confirmed (74)(75)(76)(77).…”