Lindley Robyn A, Hall Nathan E
GMDxCo Pty Ltd, Melbourne Vic, Australia; Department of Clinical Pathology, Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne Vic, Australia.
GMDxCo Pty Ltd, Melbourne Vic, Australia.
Mutat Res. 2018 Jul;810:33-38. doi: 10.1016/j.mrfmmm.2018.03.008. Epub 2018 Jun 22.
Cytosine and adenosine deamination events (DNA, RNA substrates) account for most codon-context Targeted Somatic Mutation (TSM) patterns observed in immunoglobulin (Ig) somatic hypermutation (SHM), and in cancer exomes following Ig-SHM-like responses. TSM refers to the process of somatic mutagenesis involving deamination events that results on a dominant type of mutation (e.g., C-to-T), and co-incident at a particular motif (e.g., WRC), and preferentially targeting the first, second or third nucleotide position within the mutated codon (e.g. MC1, MC2 or MC3, read 5-prime to 3-prime). It is now widely accepted that if left uncorrected, the accumulation of uncorrected TSMs involving the deaminases, may lead to a diagnosis of cancer or other degenerative disease. Our hypothesis is that many missense, nonsense and synonymous single nucleotide polymorphisms (SNPs) associated with clinically significant diseases may have arisen in the population by similar highly targeted deamination events. The OMIM database was searched for disease-associated SNPs on the X chromosome, and for all chromosomes. The nucleotide substitution patterns for disease-associated SNPs were analyzed by the TSM method to identify the likely deaminase source for C-to-U (C-to-T/G-to-A) and A-to-I (A-to-G/T-to-C) derived gene mutations preferentially targeting known sequence motifs associated with the deaminases: AID, APOBEC3G, APOBEC3B and ADAR 1/2. Of the 789 OMIM SNPs analysed. In both data sets, the mutation targeting preferences within the mutated codon reveal a statistically significant bias (p < 0.001). The results imply that a deamination of C-site and A-site targets are written into the human germline for the chromosome wide exomic SNPs analysed. This is consistent with previously observed mutation patterns arising in cancer genomes and hypermutated Ig genes during SHM. The results imply that similar types of deaminase-mediated molecular processes that occur in somatic hypermutation and cancer, may be contributing causative drivers of human exomic SNPs.
胞嘧啶和腺苷脱氨基事件（DNA、RNA底物）构成了在免疫球蛋白（Ig）体细胞超突变（SHM）以及Ig-SHM样反应后的癌症外显子组中观察到的大多数密码子上下文靶向体细胞突变（TSM）模式。TSM是指涉及脱氨基事件的体细胞诱变过程，该过程导致一种主要的突变类型（例如，C到T），并在特定基序（例如，WRC）处同时发生，且优先靶向突变密码子内的第一、第二或第三核苷酸位置（例如MC1、MC2或MC3，从5'端到3'端读取）。现在人们普遍认为，如果不加以纠正，涉及脱氨酶的未纠正TSM的积累可能会导致癌症或其他退行性疾病的诊断。我们的假设是，许多与临床重大疾病相关的错义、无义及同义单核苷酸多态性（SNP）可能是通过类似的高度靶向脱氨基事件在人群中产生的。在OMIM数据库中搜索了X染色体及所有染色体上与疾病相关的SNP。通过TSM方法分析疾病相关SNP的核苷酸替换模式，以确定优先靶向与脱氨酶（AID、APOBEC3G、APOBEC3B和ADAR 1/2）相关的已知序列基序的C到U（C到T/G到A）和A到I（A到G/T到C）衍生基因突变的可能脱氨酶来源。在分析的789个OMIM SNP中。在两个数据集中，突变密码子内的突变靶向偏好显示出统计学上的显著偏差（p＜0.001）。结果表明，对于所分析的全染色体外显子组SNP，C位点和A位点靶点的脱氨基已写入人类种系。这与先前在癌症基因组和SHM期间超突变的Ig基因中观察到的突变模式一致。结果表明，在体细胞超突变和癌症中发生的类似类型的脱氨酶介导的分子过程，可能是人类外显子组SNP的致病驱动因素。
