新型冠状病毒复制依赖基因MTHFD1的表达及功能

Expression and Function of Novel Coronavirus Replication-Dependent MTHFD1 Gene

【目的】研究新型冠状病毒(SARS-CoV-2)复制依赖基因MTHFD1在人群间的功能差异以及该基因与病毒蛋白的相互作用关系。【方法】使用千人基因组计划和gnomAD数据库,系统分析MTHFD1基因的重要功能变异(包括有害错义变异和eQTL变异)在世界不同人群间的分布。并进一步通过蛋白互作数据库STRING和IntAct,以及手工文献检索,寻找与MTHFD1蛋白有相互作用的其他蛋白。【结果】MTHFD1基因上有419个错义突变,其中有害变异195个;大部分的有害变异都是低频的,唯一的例外是变异位点rs10813,它在全世界总人群中等位基因频率大于0.01且该位点在物种间具有保守性。此外,在肺组织中发现了1个MTHFD1基因的eQTL变异(rs57087457),该位点在东亚人群中具有更低的等位基因频率,说明在东亚人群中MTHFD1基因可能具有较高表达水平。通过蛋白相互作用研究,发现GGH,ACSL3,MAT2B,ARF6,CUL2,BRD4等6个蛋白与MTHFD1蛋白存在蛋白互作。【结论】在不同人群中,MTHFD1存在天然抗性变异,这些变异的等位基因频率在人群间存在差异,可能对新型冠状病毒的易感性和感染后症状有影响;蛋白互作研究结果则提示MTHFD1基因在新型冠状病毒感染细胞中发挥了多种功能。

[Purposes]To investigate the functional differences of novel coronavirus(SARS-CoV-2)replication-dependent MTHFD1 gene between human populations and the interaction of this gene with viral proteins.[Methods]The distribution of important functional variants(including deleterious missense variants and eQTL variants)of the MTHFD1 gene among different populations in the world was systematically analyzed by using the 1 000 Genomes Project and the gnomAD database.Other proteins that interact with MTHFD1 were further searched by protein interaction databases STRING,IntAct,and manual literature searches.[Findings]It was found that there were 419 missense mutations and 195 deleterious variants in the MTHFD1 gene,most of the deleterious variants were low-frequency variants.The only exception was rs10813,which had an allele frequency greater than 0.01 in the total population worldwide and this locus was conserved between species.In addition,an eQTL variant(rs57087457)in the MTHFD1 gene was found in lung tissue,which has a lower allele frequency in East Asian population,indicating that MTHFD1 might have a higher expression level in East Asian population.Through protein interaction studies,six proteins GGH,ACSL3,MAT2 B,ARF6,CUL2,and BRD4 were found to interact with MTHFD1.[Conclusions]There are natural resistance variants of MTHFD1 gene in different populations and the allele frequencies of these variants vary among populations,which may have an effect on the susceptibility and post-infectious symptoms of SARS-CoV-2.At the same time,it is found that MTHFD1 gene have played a variety of functions in SARS-CoV-2 cell infection by protein interaction studies.