Elucidating Human Milk Oligosaccharide Biosynthetic Genes Through Network-Based Multi-Omics Integration

Authors

Benjamin P Kellman
Anne Richelle
Jeong-Yeh Yang
Digantkumar Chapla
Austin W T Chiang
Julia A Najera
Chenguang Liang
Annalee Fürst
Bokan Bao
Natalia Koga
Mahmoud A Mohammad
Anders Bech Bruntse
Morey W Haymond
Kelley W Moremen
Lars Bode
Nathan E Lewis

Publication Date

5-4-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-29867-4

PMID

35508452

PMCID

PMC9068700

PubMedCentral® Posted Date

5-4-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Glycosyltransferases, Humans, Infant, Milk, Human, Oligosaccharides, Glycomics, Polysaccharides, Biochemical networks

Abstract

Human Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we use a systems biology framework that integrates glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we construct models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. Our model aggregation approach recovers 2 of 2 previously known gene-enzyme relations and 2 of 3 empirically confirmed gene-enzyme relations. The top genes we propose for the remaining 5 linkage reactions are consistent with previously published literature. These results provide the molecular basis of HMO biosynthesis necessary to guide progress in HMO research and application with the goal of understanding and improving infant health and development.