全外显子组测序研究卵巢早衰特异性变异关联的生物学过程  

Whole exome sequencing to study the biological processes associated with specific mutations in premature ovarian failure

作　　者：占雷 吴志南[1] 宋晓雪[1] 周安稳[1] 伯乐[1] 茅彩萍[1] Zhan Lei;Wu Zhinan;Song Xiaoxue;Zhou Anwen;Bo Le;Mao Caiping(Reproductive Medicine Center,the First Affiliated Hospital of Soochow University,Suzhou 215006,China)

机构地区：[1]苏州大学附属第一医院生殖医学中心,215006

出　　处：《中华生殖与避孕杂志》2020年第5期400-406,共7页Chinese Journal of Reproduction and Contraception

基　　金：江苏省社会发展项目(BE2015642);江苏省妇幼健康“生殖医学”重点学科项目(FXK201749);江苏省“科教强卫”医学重点人才项目(ZDRCA2016044)。

摘　　要：目的研究卵巢早衰(POF)特异性变异关联的生物学过程。方法通过对来自2个家系的3个POF患者和7个健康对照的全外显子组测序数据进行生物信息学分析。对筛选获得的POF特异性单核苷酸变异(SNVs)以及对应的基因进行生物学功能富集与蛋白互作分析。结果262个疾病特异性变异对应基因显著富集在多个GO功能条目下,如在生物学过程集合中的嗜同性细胞黏附(P=1.28E-3)、细胞黏附(P=3.56E-3)、转录的正调节(P=9.41E-3)、消化道发育(P=0.011)、Notch信号通路(P=0.018)、钙离子跨膜转运(P=0.021)、细胞对氧气水平降低的反应(P=0.026)等,在细胞组分集合中的质膜(P=2.58E-4)、细胞前缘(P=0.014)、中心粒(P=0.016)、动力蛋白复合物(P=0.033)、突触后致密区(P=0.035),在分子功能集合中的转录因子活性(P=5.04E-3)、肌动蛋白结合(P=6.03E-3)、钙离子结合(P=0.008)、核小体组蛋白结合(P=0.039)、碳水化合物结合(P=0.048)等。其次262个基因显著富集在多个KEGG生物信号通路中,如背腹轴形成(P=4.09E-4)、甲状腺激素信号通路(P=0.017)、血管加压素调节的水重吸收(P=0.020)、Notch信号通路(P=0.025)、亨廷顿病(P=0.042)。另外对262个基因编码的蛋白进行蛋白互作网络分析,结果显示MYC、FOXO1、CREBBP、NOTCH2及HES1等包含在互作网络中的核心基因组成的较强网络簇中。结论POF特异性的遗传学变化可能通过导致卵巢发育生物学过程及卵巢发育相关的信号通路的活性改变,从而促进POF的发生。这些证据可以为POF的遗传发病机制进一步研究提供坚实的理论依据。Objective To study the biological processes associated with the premature ovarian failure(POF)-specific variants from the genome level.Methods Bioinformatics analysis was performed by whole exome sequencing data from 3 POF patients and 7 healthy controls from 2 families.POF-specific single nucleotide variants(SNVs)and corresponding genes were used to execute biological function enrichment and protein interaction analysis.Results Totally 262 disease-specific mutations were significantly enriched in multiple GO functional items,such as homophilic cell adhesion(P=1.28E-3),cell adhesion(P=3.56E-3),positive regulation of transcription(P=9.41E-3),digestive tract development(P=0.011),Notch signaling pathway(P=0.018),calcium ion transmembrane transport(P=0.021)and cellular response to decreased oxygen levels(P=0.026)in the set of biological processes;plasma membrane(P=2.58E-4),cell leading edge(P=0.014),centriole(P=0.016),dynein complex(P=0.033),postsynaptic density(P=0.035)in the set of cell component;transcription factor activity(P=5.04E-3),profilin binding(P=6.03E-3),calcium ion binding(P=0.008),nucleosomal histone binding(P=0.039),carbohydrate binding(P=0.048)in the set of molecular function.A total of 262 genes were significantly enriched in multiple KEGG biological signaling pathways,such as dorso-ventral axis formation(P=4.09E-4),thyroid hormone signaling pathway(P=0.017),vasopressin-regulated water reabsorption(P=0.020),Notch signaling pathway(P=0.025)and Huntington's disease(P=0.042).In addition,262 genes encode proteins sets were performed to protein interaction network analysis,the result showed that MYC,FOXO1,CREBBP,NOTCH2,and HES1 were involved in the strong network clusters composed of core genes in the interaction network.Conclusion POF-specific genetic changes may contribute to the development of POF by causing changes in the biological processes and activity of the signaling pathway of ovarian development.These evidence can provide a solid theoretical basis for further research on the heredity pathogenes

关 键 词：全外显子测序 卵巢早衰 功能富集 信号通路 蛋白互作 

分 类 号：R711[医药卫生—妇产科学]