Evolutionary rate covariation is pervasive between glycosylation pathways and points to potential disease modifiers.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Congenital Disorders of Glycosylation*/genetics ; Congenital Disorders of Glycosylation*/metabolism ; Evolution, Molecular*; Glycosylation ; Humans ; Animals ; Mutation ; Glycosylphosphatidylinositols/metabolism ; Glycosylphosphatidylinositols/genetics ; Phenotype

Mutations in glycosylation pathways, such as N-linked glycosylation, O-linked glycosylation, and GPI anchor synthesis, lead to Congenital Disorders of Glycosylation (CDG). CDG typically present with seizures, hypotonia, and developmental delay but display large clinical variability with symptoms affecting every system in the body. This variability suggests modifier genes might influence the phenotypes. Because of the similar physiology and clinical symptoms, there are likely common genetic modifiers between CDG. Here, we use evolution as a tool to identify common modifiers between CDG and glycosylation genes. Protein glycosylation is evolutionarily conserved from yeast to mammals. Evolutionary rate covariation (ERC) identifies proteins with similar evolutionary rates that indicate shared biological functions and pathways. Using ERC, we identified strong evolutionary rate signatures between proteins in the same and different glycosylation pathways. Genome-wide analysis of proteins showing significant ERC with GPI anchor synthesis proteins revealed strong signatures with ncRNA modification proteins and DNA repair proteins. We also identified strong patterns of ERC based on cellular sub-localization of the GPI anchor synthesis enzymes. Functional testing of the highest scoring candidates validated genetic interactions and identified novel genetic modifiers of CDG genes. ERC analysis of disease genes and biological pathways allows for rapid prioritization of potential genetic modifiers, which can provide a better understanding of disease pathophysiology and novel therapeutic targets.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Thorpe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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R01 HG009299 United States HG NHGRI NIH HHS; R35 GM124780 United States GM NIGMS NIH HHS; T32 DK110966 United States DK NIDDK NIH HHS

0 (Glycosylphosphatidylinositols)

Date Created: 20240911 Date Completed: 20240924 Latest Revision: 20240925

20240925

PMC11419382

10.1371/journal.pgen.1011406

39259723