Publication costs are funded by the grants from the National Natural Science Foundation of China (61672037 and 21601001), the Anhui Provincial Outstanding Young Talent Support Plan (gxyqZD2017005), the Young Wanjiang Scholar Program of Anhui Province, the China Postdoctoral Science Foundation Grant (2018 M630699) and the Anhui Provincial Postdoctoral Science Foundation Grant (2017B325). At 5-methylcytosine in CpG dinucleotides, C:G → T:A transitions and C → A transversion are associated with the most common epigenetic modifications of DNA [34, 35]. We observed that non-CpG-island GC transition sequence context was positively selected across most of cancer types, and different sequence contexts under which hotspot mutations occur could be significance for genetic differences and functional features. The functions of these domains are different from each other. However, there are some differences for proportions of mutational nucleotide changes between TCGA and 1000G datasets. In a previous study, it was reported that A/T-rich sequence could affect gene expression and be more important for cancer development [43]. T125 in TP53 is the most prevalently occurred mutation in nine different cancer types. Schaafsma GC, Vihinen M. Large differences in proportions of harmful and benign amino acid substitutions between proteins and diseases. 2010;5:e13574. The codon usage bias is related to various biological processes, such as gene expression level, protein structure, mutation frequency and GC composition [45]. Synonymous mutations can affect protein conformation and function by affecting post-transcriptional processing and regulation of RNA, altering the local and global structure of the mRNA … Mutational signatures of synonymous mutations in TCGA and 1000G. The MDR1 … Firstly, we investigated the differences by performing a one-sample t-test, and the average proportion of each substitution in 1000G dataset was used as hypothetical value. Synonymous mutations in human CFTR exon 12 induce exon skipping. We also found that the hotspots were more conserved than neutral mutations of hotspot-mutation-containing-genes and frequently happened at leucine. I would say that silent mutations, as they have been defined, are a subset (or perhaps even same as) of synonymous mutations.However, the term, "silent mutation", is not used so much these days. 7b). Copyright © 2021 Elsevier B.V. or its licensors or contributors. Nucleic Acids Res. The same goes for nonsense mutations that introduce pre-mature stop codons into CDSs (coding sequences). Synonymous codons of amino acids with optimal and non-optimal codons for human genome. Article We investigated the nucleotide-based and amino acid-based features of synonymous mutations across 15 cancer types from The Cancer Genome Atlas (TCGA), and revealed novel driver candidates by identifying hotspot mutations. Meanwhile, we nominated 97 hotspot mutations in 86 genes in TCGA as potential drivers by considering their mutational rates across different mutational subtypes. Hum Genet. It is now known that synonymous mutations can either reduce or enhance protein synthesis. Therefore, it is proposed that the cancer related synonymous mutations prefer to influence the gene expression and are more pathogenic than neutral ones in TCGA. 3a). Deng SP, Huang DS. Furthermore, the efficient codon replacing with a less efficient one could affect protein synthesis. Wan X, Xu D, Kleinhofs A, Zhou J. Quantitative relationship between synonymous codon usage bias and GC composition across unicellular genomes. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites. Cancer associated synonymous mutations have the tendency to become A/T-rich. © 2021 BioMed Central Ltd unless otherwise stated. The common and diverse mutational signatures of hotspots across different cancer types may promote the understanding of the positive selection in the human genome, and facilitate the cancer target therapy [26]. Genome Res. Mol Biol Evol. SKCA contains the largest proportion of C → T transitions than other cancer types, owing to the signatures of ultraviolet light exposure and deamination processes [22]. For the comprehensiveness of analysis, this study not only highlights the nucleotide level preferences, but also amino acids level, and especially hotspot mutations. In this work, RS scores were extracted from the nucleotide bases that belong to hotspot mutations, neutral synonymous mutations of HMCGs in 1000G and non-hotspot mutations of HMCGs in TCGA, respectively. We reported hotspot mutations in amino acid position with adjusted p-values < 0.05 corrected by false discovery rate. Melanoma's high C>T mutation rate: is deamination playing a role? Moreover, due to the overabundance of synonymous sites involved in CpG dinucleotides, the mutation rate in exons is 30~60% higher than that in the non-coding regions [41]. PF00001, 7tm_1 domain; PF00383, dCMP_cyt_deam_1 domain; PF02492, cobW domain; PF00012, HSP70 domain; PF00520, Ion_trans domain; PF07679, I-set domain; PF00055, Laminin_N domain; PF03062, MBOAT domain; PF09773, Meckelin domain. Gustafsson C, Govindarajan S, Minshull J. Codon bias and heterologous protein expression. Dees ND, Zhang Q, Kandoth C, Wendl MC, Schierding W, Koboldt DC, Mooney TB, Callaway MB, Dooling D, Mardis ER. The mutational characters of 97 hotspot mutations across 14 cancer types were also investigated under different sequence contexts, including ATts, ATtv, C_GCts, C_GCtv, NC_GCts and NC_GCtv six subtypes. Google Scholar. Ion_trans domain contains sodium, potassium and calcium ion channels, and a loop flanked by two helices determines ion selectivity. There is none hotspot mutation in HLTU due to the lowest mutation frequency (Fig. 1988;78:151–5. Other statistical analyses were performed by GraphPad Prism 5 (GraphPad Software). ATts, AT transition (coral bar in a and b); ATtv, AT transversion (blue bar in a and b); C_GCts, CpG-island GC transition (yellow bar in a and b); C_GCtv, CpG-island GC transversion (rose bar in a and b); NC_GCts, non-CpG-island GC transition (green bar in a and b); NC_GCtv, non-CpG-island GC transversion (grey bar in a and b). Nat Rev Genet. Neutral selection is essentially driven by mutation and genetic drift and implies an equal number of synonymous versus nonsynonymous substitutions; the ω values will be approximately 1. 2004;4:1–11. Third nucleotide positions are numbered according to their location in the exon. Trends Biotechnol. However, a growing body of evidence suggests that synonymous mutations—either alone or in conjunction with other mutations—have nonnegligible impacts on cells. Analysis of mutation distribution in protein domains. a Venn diagram showing the number of domain types for the multiple intersections among hotspot mutations, neutral synonymous mutations and non-hotspot mutations. Moreover, noisy synonymous mutations can affect how fast and how accurately an mRNA molecule is translated. Hum Mutat. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. Synonymous Mutations Frequently Act as Driver Mutations in Human Cancers. Redundancy of the genetic code provides some protection against the effect of mutations. Yannan Bin and Xiaojuan Wang contributed equally to this work. DNA methylation in glioblastoma: impact on gene expression and clinical outcome. Except Met (M) and Trp (W), all amino acids are encoded by two or more codons. 2013;110:13481–6. Now researchers know that the optimized synonymous codon usage … 2017;38:839–48. The distributions of single-base mutational nucleotide changes in TCGA dataset are significant different from those in 1000G datasets (p-value < 0.001) except T → G transversion at pos3 (p-value = 0.8066). The vast majority of human genomic variation is accounted for by Single Nucleotide Variants (SNVs) (Bromberg et al., 2013). 2006;314:1930–3. The various codon arrangements had no apparent effects on flgM mRNA stability or predicted mRNA secondary structures. Next-generation sequencing technology has enabled the systemic analyses of huge variants in large cohorts of cancer cases, e.g., The Cancer Genome Atlas (TCGA) [15] and International Cancer Genome Consortium [16]. To investigate the differences across cancers, we compared the number of synonymous hotspot mutations in different cancer types. Cookies policy. Google Scholar. 2011;12:32–42. Freigang J, Proba K, Leder L, Diederichs K, Sonderegger P, Welte W. The crystal structure of the ligand binding module of axonin-1/TAG-1 suggests a zipper mechanism for neural cell adhesion. Additionally, it has been reported that the mutations occur at methylated CpG dinucleotide, majority of which are C:G → T:A transitions, would significantly cause human genetic diseases [34]. Gut. However, relatively little research has specifically delineated the functionality of synonymous mutations in cancer. Cell. DNA methylation in endometrial cancer. 2003;13:838–44. In addition, we mapped hotspots, neutral and non-hotspot mutations of hotspot-mutation-containing-genes to their respective protein domains and found ion transport domain was the most frequent one, which could mediate the cell interaction and had relevant implication for tumor therapy. Positive selection implies an excess of nonsynonymous versus synonymous substitutions with change of residue at a given position. Table S1. While synonymous mutations were long thought to be without phenotypic consequences, there is growing evidence they can affect gene expression, protein … GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Galphaq-p63RhoGEF-rho GTPase pathway. Bin, Y., Wang, X., Zhao, L. et al. Figure S3. Etcheverry A, Aubry M, de Tayrac M, Vauleon E, Boniface R, Guenot F, Saikali S, Hamlat A, Riffaud L, Menei P, et al. In addition, some studies have identified that synonymous mutations frequently act as driver mutations in human cancers [10, 11] and can affect clinical outcome or treatment response [12,13,14]. 2014;26:479–94. Cell. 2006;7:98–108. This position has proven contentious, not least because of the absence of a viable mechanism. 2011;12:683–91. The hotspot mentioned in this work is not the hotspot in protein-protein interfaces [24], and is defined as the mutation that occurs significantly more frequently than the background frequency characterized by genes, cancer types and mutation subtypes. Synonymous codon suppressors that corrected the effect of a translation-defective synonymous flgM allele were restricted to two codons flanking the translation-defective codon. Supek F, Miñana B, Valcárcel J, Gabaldón T, Lehner B. Synonymous mutations frequently act as driver mutations in human cancers. Synonymous mutations also significantly cluster in known oncogenes (Figure 3E) and even more so in the top-16 oncogene set, where a synonymous mutation is more likely to occur within five codons of another synonymous-mutated site (OR = 1.74, p = 10 −6; Figure 3E), an effect size similar to the missense-missense clustering in the same genes (OR = 1.92; Figure 3F). 2000;79:18–22. HSP70 domain is strongly upregulated by heat stress and toxic chemicals, particularly heavy metals. 2005;26:916–22. Finn RD, Coggill P, Eberhardt RY, Eddy SR, Mistry J, Mitchell AL, Potter SC, Punta M, Qureshi M, Sangrador-Vegas A. But there is no significant different between hotspot and non-hotspot datasets (p-value = 0.93) for RS score. Synonymous mutations change the sequence of a gene without directly altering the sequence of the encoded protein. Moreover, the most frequently substituted bases are C and G, and the most frequently mutated to bases are T and A. The x-axis represents the cancer types and the y-axis represents the 12 mutation patterns. 2016;17:249–62. The cancer related synonymous mutations in TCGA were downloaded from COSMIC v79 (Catalogue of Somatic Mutations in Cancer) [25]. In coding regions of genes, single nucleotide polymorphisms (SNPs) are categorized as either synonymous (also called ‘silent’) for those that do not change amino acid sequence or missense for those that do. In this study, two haplotypes of Igf1r with four synonymous mutations in the coding sequences of IGF-1R ECD between large pigs (LP) and Bama pigs (BM) were stably expressed in the Igf1r-knockout MC3T3-E1 cells and named as MC3T3-LP cells (LP group) and MC3T3-BM cells (BM group), respectively. Single-tailed unpaired t-test was used to test significantly difference between hotspot mutations, neutral synonymous mutations and non-hotspot mutations. Genome Res. PLoS Comput Biol. Netherlands. Nature. Nevertheless, there are growing evidences that the significant impact of synonymous mutations on RNA splicing, stability and folding [3, 4], translation or co-translational protein folding [5,6,7,8]. As an important target for tumor therapy [51], Ion_trans domain is critical for cell-to-cell communication and regulates multiple biological processes. As a complex genetic disease, cancer was affected by a large number of variants. In human genes, roughly 99.8% of DNA sequence variations do not alter the primary sequences of proteins (1), and synonymous SNPs show a higher frequency than both missense SNPs and the SNPs in the non-coding regions (1,2). Human MDR1 can be expressed in various organisms and cell lines. Mutational landscape and significance across 12 major cancer types. Methods. However, this does not mean that synonymous mutations are free from natural selection. Besides nucleotide level, the analysis of synonymous mutations was also performed at the amino acid level. PubMed Central Losi L, Baisse B, Bouzourene H, Benhattar J. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Synonymous mutations can affect transcription, splicing, mRNA transport, and translation, any of which could alter phenotype, rendering the synonymous mutation non-silent. Additionally, more recent studies have indicated that different substitution types, codon usage bias and hotspot mutational positions in base sequence could be associated with different biological processes and cancer types [2, 22, 23]. However, for neutral mutation dataset, the most frequent substitutions are under Ala (14.44%), which is largely tolerated outside functional site as the smallest residues can be fitted into structures easily. Soussi T, Taschner PE, Samuels Y. Synonymous somatic variants in human cancer are not infamous: a plea for full disclosure in databases and publications. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. For the proportion of tumor samples (yellow bar), BRCA is the most and UTCA the fewest. Junfeng Xia. Porta-Pardo E, Garcia-Alonso L, Hrabe T, Dopazo J, Godzik A. a Hotspot mutations; b Neutral synonymous mutations of HMCGs in 1000G dataset; c Non-hotspot mutations of HMCGs in TCGA dataset. By contrast, HLTU has none hotspot and THCA has only one hotspot mutation in ILF3 (N192). From TCGA, we obtained 373,434 synonymous mutations of 5749 tumor samples from 15 types of cancer. Epigenetics. All authors read and approved the final manuscript. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Clearly, the distributions of amino acids are different for the three synonymous mutation datasets. Gynecol Oncol. Notable among these outliers are SKCA, ENAD, STAD and LUAD, which contain more than 100 synonymous mutations per sample. However, it is probable that the uses of synonymous codons in TCGA tend to be at equal frequencies, and are less affected by codon usage bias than those in 1000G. dCMP_cyt_deam_1 domain is the cytidine and deoxycytidylate deaminase zinc-binding region, which is associated with the catalytic activity of cytidine deaminase. At nucleotide level, owing to the degeneracy of genetic codons, the nucleotide substitutions of synonymous codons occur at the third codon position (pos3), except some L and R codons (only T↔C transition and A↔C transversion) vary at the first codon position (pos1) (Additional file 1: Table S1). 2002;21:7435. To further investigate the difference among hotspot mutations, neutral synonymous mutations and non-hotspot mutations of HMCGs, the distributions of amino acids under which the mutations occurred were investigated (Fig. Here we test whether synonymous mutations might be under selection owing to their effects on the thermodynamic stability of mRNA, mediated by changes … A p-value < 0.05 was considered statistically significant. A pan-cancer catalogue of cancer driver protein interaction interfaces. Mutational signatures of synonymous hotspot mutation in 15 cancer typers. Google Scholar. Nat Methods. 2004;22:346–53. Selection on synonymous mutations in oncogenes is cancer-type specific, and although the functional consequences of cancer-associated synonymous mutations may be diverse, they recurrently alter exonic motifs that regulate splicing and are associated with changes in oncogene splicing in tumors. These three datasets were applied for the further functional analyses, for example, conservation, amino acids and protein domains under which mutations occurred. To further investigate the mutational signatures of hotspot mutations, neutral synonymous mutations of HMCGs in 1000G and the non-hotspot mutation of HMCGs in TCGA were used as control datasets. Synonymous mutations in TCGA are prone to become A/T-rich. It is found that the percentage of transitions between C and T preceded that between A and G, which is known to be a general property of DNA sequence change and evolution [42]. In addition, to estimate the important synonymous mutations for pan-cancer, the distribution of hotspot mutations across different genes was analyzed (Additional file 1: Figure S3B). PubMed Kobe B, Kajava AV. https://doi.org/10.1016/j.cell.2014.01.051. The authors declare that they have no competing interests. 1), and exhibit many more or many less synonymous mutations per sample than the average number of 15 cancer types. Genetic mutations. In this work, the hotspot mutation is defined as the mutation that occurs significantly more frequently than the background frequency characterized by genes, cancer types and mutation subtypes. In addition, our analyses suggest that dosage-sensitive oncogenes have selected mutations in their 3′ UTRs. Curr Opin Struc Biol. 2014;43:D805–D11. XW, LZ and PW helped perform the analysis. synonymous and nonsynonymous mutations in coagu-lation Factor VIII illustrates a general strategy for inves-tigators to score synonymous mutations [28]. Studies have shown that nucleotide substitutions, including synonymous mutations, could be related to carcinogen exposures and DNA repair processes [35,36,37]. Cancer Res. There is none synonymous mutation under Met and Trp due to the lack of synonymous codons. In this study, we identified 97 hotspot mutations in 86 HMCGs associated with 14 cancer types (Additional file 1: Table S2). BMC Medical Genetics It has been identified to be pathogenic for its detrimental role in TP53 splicing [48]. Download : Download high-res image (129KB)Download : Download full-size image. In contrast, there is no significantly different between hotspot and non-hotspot mutations (p-value = 0.93), it is possible that the non-hotspot in TCGA might influence cancer processes, but their harmfulness is less than that of hotspots. The aim of 1000G is to discover variants with a frequency of occurrence > 1% in multiple human populations worldwide. Chamary J, Parmley JL, Hurst LD. 2013;502:333–9. And the signatures of synonymous hotspots were qualitatively similar with those of harmful missense variants. cobW domain contains a nucleotide-binding loop and a histidine-rich region that plays an important role in metal binding. The greatest frequently occurring is C → T transitional substitution (with average proportions of 44.01% across 15 cancer types), which is possible to associate with the aberrant DNA methylation [38,39,40]. Nature. Oncogene. California Privacy Statement, There are several types of mutations, some of which have no effect while others have a major effect. a Histogram of the number of hotspot mutations under different sequence contexts. Find 18 ways to say mutation, along with antonyms, related words, and example sentences at Thesaurus.com, the world's most trusted free thesaurus. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Chen T, Wang Z, Zhou W, Chong Z, Meric-Bernstam F, Mills GB, Chen K. Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types. PubMed Central 2010;6:e1001025. Hotspot synonymous mutations across different cancer types in TCGA dataset. conducted a broad survey of 21,429 disease-related single nucleotide polymorphisms (SNPs) to indicate that synonymous SNPs and non-synonymous SNPs showed similar probability and effect size for human diseases [9]. Google Scholar. P Natl Acad Sci Usa. 2010;5:491–8. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. a Distribution of synonymous mutations for the 12 mutation patterns at pos1 and pos3 of codons in TCGA and 1000G. Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Huang D-S, Zhao X-M, Huang G-B, Cheung Y-M. 3b). Among these nine domains, the Ion_trans domain is the most frequent one (28 items), but the proportion of hotspots is less than those of neutral synonymous mutations and non-hotspots (Fig. Cheung LWT, Yu S, Zhang D, Li J, Ng PKS, Panupinthu N, Mitra S, Ju Z, Yu Q, Liang H, et al. PubMed Tao MH, Freudenheim JL. For example, INAD has the largest number of hotspots (39 hotspots), but ENAD and STAD only have 13 hotspots with the smallest number, and HLTU has none. Omid • 570 wrote: Hi To analysis exome sequence data sometimes people exclude synonymous mutation.BUT it might affect on splice sites depend on how far it is from splice sites. The role of ion channels and transporters in cell proliferation and cancer. Moreover, the average numbers of variants per sample across 15 cancer types are different with each other (the lower panel of Fig. Relative to nonsynonymous mutations, synonymous muta- tions are thought to face at most modest selection, and have thus been used to estimate neutral mutation rates for many decades. Article More importantly, several of the mechanisms by which synonymous mutations alter the structure, function, and expression level of proteins are now being elucidated. From the distribution of hotspot mutations across cancers (Additional file 1: Figure S3A), it was found that the number of hotspot mutations varies largely from one cancer to another, many more or many fewer mutations than average. 2017;38:339–42. 2014;35:643–53. PubMed Central A map of human genome variation from population scale sequencing. To evaluate the conservation of hotspot mutations, neutral synonymous mutations of 86 HMCGs in 1000G (235 neutral synonymous mutations were shown in Additional file 2: Table S3) and non-hotspot mutations of HMCGs in TCGA (1358 non-hotspot mutations were shown in Additional file 3: Table S4), we computed their RS scores to estimate the evolutionary constraints across different genome sites. Cell. YB performed the analysis and drafted the manuscript. PubMed Google Scholar. More information: Yogita Sharma et al, A pan-cancer analysis of synonymous mutations, Nature Communications (2019).DOI: 10.1038/s41467-019-10489-2 IGF-1R expression was lower in the BM group than in the LP group both in terms of transcription and … PubMed Identifying stages of kidney renal cell carcinoma by combining gene expression and DNA methylation data. A mutation is any type of alteration or change in DNA that is permanent. BMC Genomics. Manage cookies/Do not sell my data we use in the preference centre. Hearing silence: non-neutral evolution at synonymous sites in mammals. By chance the precision is gone because of mutation 'Simply diseases.' Table S2. MuSiC: identifying mutational significance in cancer genomes. Here we used the Hot-Driver package [26] to identify the hotspot mutations that are positively correlated with the number of mutations across all cancer samples for all 15 cancer types. Nat Rev Genet. In this study, 21,121 putatively benign synonymous mutations were derived from 1000G (the phase 3 version 5b, 20,130,502) and this dataset will be referred to as the neutral synonymous mutations dataset for the comparative analysis of cancer related synonymous mutations. Then we analyzed the distributions of hotspot, neutral synonymous and non-hotspot mutations under the nine common protein domains. PubMed Central Distribution of 12 possible mutation patterns of synonymous mutations in different cancer types. Tamura K, Nei M. Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees.
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