Wang Dongyang, Cao Wen, Yang Wenqian, Jin Weiwei, Luo Haohui, Niu Xiaohui, Gong Jing
Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, Hubei 430074, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
NAR Cancer. 2022 Dec 22;4(4):zcac043. doi: 10.1093/narcan/zcac043. eCollection 2022 Dec.
Multi-nucleotide variants (MNVs) are defined as clusters of two or more nearby variants existing on the same haplotype in an individual. Recent studies have identified millions of MNVs in human populations, but their functions remain largely unknown. Numerous studies have demonstrated that single-nucleotide variants could serve as quantitative trait loci (QTLs) by affecting molecular phenotypes. Therefore, we propose that MNVs can also affect molecular phenotypes by influencing regulatory elements. Using the genotype data from The Cancer Genome Atlas (TCGA), we first identified 223 759 unique MNVs in 33 cancer types. Then, to decipher the functions of these MNVs, we investigated the associations between MNVs and six molecular phenotypes, including coding gene expression, miRNA expression, lncRNA expression, alternative splicing, DNA methylation and alternative polyadenylation. As a result, we identified 1 397 821 -MNVQTLs and 402 381 -MNVQTLs. We further performed survival analysis and identified 46 173 MNVQTLs associated with patient overall survival. We also linked the MNVQTLs to genome-wide association studies (GWAS) data and identified 119 762 MNVQTLs that overlap with existing GWAS loci. Finally, we developed Pancan-MNVQTLdb (http://gong_lab.hzau.edu.cn/mnvQTLdb/) for data retrieval and download. Pancan-MNVQTLdb will help decipher the functions of MNVs in different cancer types and be an important resource for genetic and cancer research.
多核苷酸变异（MNVs）被定义为个体中存在于同一单倍型上的两个或更多相邻变异的簇。最近的研究已经在人类群体中鉴定出数百万个MNVs，但其功能在很大程度上仍然未知。大量研究表明，单核苷酸变异可通过影响分子表型作为数量性状位点（QTLs）。因此，我们提出MNVs也可通过影响调控元件来影响分子表型。利用来自癌症基因组图谱（TCGA）的基因型数据，我们首先在33种癌症类型中鉴定出223759个独特的MNVs。然后，为了解析这些MNVs的功能，我们研究了MNVs与六种分子表型之间的关联，包括编码基因表达、miRNA表达、lncRNA表达、可变剪接、DNA甲基化和可变聚腺苷酸化。结果，我们鉴定出1397821个-MNVQTLs和402381个-MNVQTLs。我们进一步进行了生存分析，并鉴定出46173个与患者总生存相关的MNVQTLs。我们还将MNVQTLs与全基因组关联研究（GWAS）数据相联系，并鉴定出119762个与现有GWAS位点重叠的MNVQTLs。最后，我们开发了Pancan-MNVQTLdb（http://gong_lab.hzau.edu.cn/mnvQTLdb/）用于数据检索和下载。Pancan-MNVQTLdb将有助于解析MNVs在不同癌症类型中的功能，并成为遗传和癌症研究的重要资源。
