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

IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences PLoS Genetics Pub Date : 2024-09-11 DOI:10.1371/journal.pgen.1011406
Holly J. Thorpe, Raghavendran Partha, Jordan Little, Nathan L. Clark, Clement Y. Chow
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Abstract

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.
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糖基化通路之间普遍存在进化率协变,并指向潜在的疾病调节因子
糖基化途径(如N-连接糖基化、O-连接糖基化和GPI锚合成)中的突变会导致先天性糖基化紊乱(CDG)。先天性糖基化障碍通常表现为癫痫发作、肌张力低下和发育迟缓,但临床表现差异很大,症状会影响身体的各个系统。这种变异性表明,修饰基因可能会影响表型。由于生理和临床症状相似,CDG 之间可能存在共同的遗传修饰基因。在这里,我们以进化为工具,找出 CDG 和糖基化基因之间的共同修饰基因。从酵母到哺乳动物,蛋白质糖基化在进化上是保守的。进化速率共变(ERC)可以识别具有相似进化速率的蛋白质,这表明它们具有共同的生物功能和途径。利用ERC,我们在相同和不同糖基化途径的蛋白质之间发现了强烈的进化速率特征。对与GPI锚合成蛋白显示出显著ERC的蛋白质进行全基因组分析,发现了与ncRNA修饰蛋白和DNA修复蛋白之间的强烈特征。我们还根据 GPI 锚合成酶在细胞中的亚定位确定了强烈的 ERC 模式。对得分最高的候选基因进行的功能测试验证了基因之间的相互作用,并确定了 CDG 基因的新型基因修饰因子。通过对疾病基因和生物通路进行ERC分析,可以快速确定潜在遗传修饰因子的优先次序,从而更好地了解疾病的病理生理学和新型治疗靶点。
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来源期刊
PLoS Genetics
PLoS Genetics 生物-遗传学
CiteScore
8.10
自引率
2.20%
发文量
438
审稿时长
1 months
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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