id_1014. EVOLUTION AND DEVELOPMENT OF THE HUMAN BRAIN THROUGH THE LENS OF PROTEIN N-GLYCOSYLATION
Thomas S. Klarić1,2, Ivan Gudelj1,2,3, Gabriel Santpere1,4, Mislav Novokmet2, Frano Vučković2, Shaojie Ma1, Hannah M. Doll5,6, Ryan Risgaard5,6, Shveta Bathla7, Amir Karger8, Angus C. Nairn7, Victor Luria1,9, Ivona Bečeheli2, Chet C. Sherwood10, John J. Ely11,12, Patrick R. Hof13, André M. M. Sousa5,6, Djuro Josić3,14, Gordan Lauc2,15, Nenad Sestan1,7,16
1 Department of Neuroscience, Yale School of Medicine; New Haven, CT, USA.
2 Genos Glycoscience Research Laboratory; Zagreb, Croatia.
3 Department of Biotechnology, University of Rijeka; Rijeka, Croatia.
4 Hospital del Mar Research Institute, Barcelona, Catalonia, Spain.
5 Waisman Center and Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin Madison; Madison, WI, USA.
6 Department of Neuroscience, University of Wisconsin Madison; Madison, WI, USA.
7 Department of Psychiatry, Yale School of Medicine; New Haven, CT, USA.
8 Harvard Medical School, IT Research Computing, Boston, MA, USA.
9 Boston Children’s Hospital, Division of Genetics and Genomics, Harvard Medical School, Boston, USA.
10 Department of Anthropology, The George Washington University; Washington, District of Columbia, USA.
11 Center for the Advanced Study of Human Paleobiology, The George Washington University; Washington, District of Columbia, USA.
12 MAEBIOS; Alamogordo, NM, USA.
13 Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai; New York, NY, USA.
14 Warren Alpert Medical School, Brown University; Providence, RI, USA.
15 University of Zagreb Faculty of Pharmacy and Biochemistry; Zagreb, Croatia.
16 Departments of Genetics and Comparative Medicine, Kavli Institute for Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, and Yale Child Study Center, Yale School of Medicine; New Haven, CT, USA.
INTRODUCTION: Although numerous comparative “omics” studies have revealed unique aspects of human neurobiology, the contribution of protein glycosylation (post-translational sugar modifications) has not been extensively explored. Likewise, little is known about the trajectory of the brain's glycome during human neurodevelopment.
AIM(S): To identify human-specific features of brain N-glycosylation and to characterize the spatiotemporal dynamics of N-glycosylation during human brain development.
METHOD(S): 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 bulk tissue and single-nucleus glycotranscriptomic data. We also performed a multi-regional comparison of the prenatal and adult human brain N-glycomes.
RESULTS: In primates, the brain N-glycomes have diverged more rapidly than the underlying transcriptomic frameworks, which implies that N-glycosylation provides a means for rapidly generating interspecies diversity at the molecular level. We uncovered numerous phylogenetic trends in brain protein N-glycosylation as well as several human-specific adaptations. Moreover, interspecies differences in the cell type expression pattern of key glycogenes were identified, including some human-specific differences, which may underpin this evolutionary divergence. Regarding glycosylation during human brain development, we uncovered both global and region-specific N-glycome maturation pathways that together lead to distinct neuroanatomical N-glycosylation profiles and thus contribute to the spatial molecular diversity of the mature brain.
CONCLUSIONS: Brain N-glycome evolution in hominids has been characterized by an overall increase in complexity coupled with a shift toward increased usage of α(2-6) linked N-acetylneuraminic acid. Also, region-specific neurodevelopmental pathways lead to distinct spatial N-glycosylation profiles in the mature brain.
FINANCIAL SUPPORT: NIH grants MH124619, MH116488, DA053628, and R01HG010898-01. Instituto de Salud Carlos III grant MS20/00064. Agencia Estatal de Investigación grant PID2019-104700GA-I00/AEI/10.13039/501100011033. The European Union Seventh Framework Programme (FP7 2007 2013) under grant agreement no. 291823 Marie Curie FP7-PEOPLE-2011-COFUND (The New International Fellowship Mobility Programme for Experienced Researchers in Croatia NEWFELPRO). We acknowledge the National Chimpanzee Brain Resource (funded by NIH grant NS092988) for contributing brain specimens used in this study.