focus on the effect of mutations on protein function. Chen et al. Carcinogenesis. 2016;44:D279–D85. PLoS One. Mutat Res. Xia JF, Zhao XM, Song J, Huang DS. However, a growing body of evidence suggests that synonymous mutations—either alone or in conjunction with other mutations—have nonnegligible impacts on cells. 2011;12:32–42. Cite this article. Oncogene. I-set domain is not only frequent in cell adhesion protein, but also appears in many other types of proteins [50]. 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. The leucine-rich repeat as a protein recognition motif. SFAPS: an R package for structure/function analysis of protein sequences based on informational spectrum method. Nature. Illustration of analysis procedure of cancer associated synonymous mutations. In 1000G, Ala is the most frequently mutated amino acid due to G → A transition. 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. PubMed  Synonymous Mutations Are Selected for in a Tissue-Specific Manner The frequency of missense mutation in individual oncogenes is not evenly distributed across tissues. 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. Deng SP, Huang DS. As shown in Fig. We found that C:G → T:A transitions were the most frequent single-base substitutions, and leucine underwent the largest number of synonymous mutations in TCGA due to prevalent C → T transition, which induced the transformation between optimal and non-optimal codons. BMC Genomics. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites. Several researchers have taken another approach, attempting to express wild-type MDR1 and the haplotype in order to mimic the effect found in clinical samples. Parmley JL, Chamary J, Hurst LD. Article  Gynecol Oncol. All authors read and approved the final manuscript. Synonymous mutations, however, are intuitively thought to be functionally silent and evolutionarily neutral. 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. 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). Due to ultraviolet light and deamination processes, the majority of SKCA mutations are C:G → T:A transitions [22]. List of non-hotspot synonymous mutations of HMCGs in TCAGA dataset. 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. 1993;10:512–26. volume 20, Article number: 190 (2019) 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). 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]. Google Scholar. PubMed  However, the analysis of synonymous mutation distribution in Ion_trans domain is opposite with the previous analysis of missense mutations [46], which may be due to the different pathogenic mechanisms of synonymous and non-synonymous mutations. The full contents of the supplement are available online at https://bmcmedgenet.biomedcentral.com/articles/supplements/volume-20-supplement-2. The correlation between the percentages of mutation and the codon numbers of amino acids in TCGA (r2 = 0.67) is stronger than that in 1000G (r2 = 0.54) (Additional file 1: Figure S2). Mutational signatures of synonymous mutations in TCGA and 1000G. Firstly, it needs more experimental work to investigate the effects of these hotspots on protein folding, RNA splicing, stability and folding, and whether they are drivers in cancers, and the relationship with cancer clinical outcome or treatment response. 1997;40:297–301. Synonymous mutations have been identified to play important roles in cancer development, although they do not modify the protein sequences. 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). Manage cookies/Do not sell my data we use in the preference centre. Table S2. The majority of statistical analyses in this work were completed by using R (https://www.r-project.org/), e.g., the distributions of synonymous variants across different cancer types, nucleotide substitutions and amino acids. Cheung LWT, Yu S, Zhang D, Li J, Ng PKS, Panupinthu N, Mitra S, Ju Z, Yu Q, Liang H, et al. 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]. Comparison of RS scores between the datasets of hotspots and neutral synonymous mutations, non-hotspots. CAS  The RS score of hotspot mutation dataset is significant higher than that neutral synonymous mutation dataset (p-value <2e-16). 2013;4:312. Cell. Download : Download high-res image (129KB)Download : Download full-size image. PubMed  By using this website, you agree to our 2004;22:346–53. statement and 1, with regard to synonymous mutation proportion (blue bar), SKCA is the largest and HLTU the smallest. Sharp PM, Averof M, Lloyd AT, Matassi G, Peden JF. The effects of sSNVs on molecular functionality of the corresponding genes/prot… 1-3 It was reported that some synonymous mutations could affect messenger RNA (mRNA) splicing 4 and the splicing patterns might consequently affect the biological processes. Hearing silence: non-neutral evolution at synonymous sites in mammals. In summary, the present study would help to better understand the function of synonymous mutations in different cancer types and depicting their roles in carcinogenesis. There is none synonymous mutation under Met and Trp due to the lack of synonymous codons. It is similar with the character of pathogenic missense mutations, the substitutions under L are also the most frequent [46]. The TP53 LSDB paradigm. CAS  Synonymous mutations change the sequence of a gene without directly altering the sequence of the encoded protein. We also investigated the domain compositions of the proteins, under which hotspot mutations, neutral synonymous mutations of HMCGs in 1000G and non-hotspot mutations of HMCGs in TCGA occurred. Hum Mutat. We use cookies to help provide and enhance our service and tailor content and ads. 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. Genomes Project Consortium. Hum Mutat. Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Google Scholar. The distributions of the hotspot and neutral synonymous mutations are quantitatively similar to those of missense mutations published previously [46]. The substrate specificity of the tRNA to the rare codon can affect the timing of translation, and … 2005;571:19–31. For the proportion of tumor samples (yellow bar), BRCA is the most and UTCA the fewest. Synonymous mutations, which occur in the gene-coding regions without changing the encoded amino acids, have long been supposed to be silent for the fitness of organisms and neutral during evolution [].However, this conservative concept begins to be rebutted by two lines of evidence: first one is the understanding of synonymous mutational effect on protein synthesis and folding; second, … Sanchez MI, Grichnik JM. In summary, NC_GCts sequence context is positively selected across most cancer types, and different sequence contexts on which hotspots happen are significant for considering their genetic differences and functional features. Synonymous variations, in particular, are assumed to be functionally neutral both in clinical diagnosis and when measuring evolutionary dis-tances between species. Institutes of Physical Science and Information Technology, School of Computer Science and Technology, Anhui University, Hefei, 230601, Anhui, China, Yannan Bin, Xiaojuan Wang, Le Zhao, Pengbo Wen & Junfeng Xia, You can also search for this author in (Upper) The nucleotide and amino acid composition (in one letter code) of part of the human CFTR exon 12 (hCF). In this study, we documented the full repertoire of cancer associated synonymous mutations, especially synonymous hotspot mutations, to investigate the mutational signatures in cancer. Almost every research paper that I have read pertaining to this topic has always used the term "synonymous mutation" irrespective of whether or not it has a phenotypic effect. 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. DNA sequence evolution: the sounds of silence. 2016;17:249–62. Question: Synonymous Mutations And Their Effect On Splice Site. PLoS Comput Biol. Synonymous changes may not be neutral because certain codons are translated more efficiently (faster and/or more accurately) than others. The conservation of nucleotide sequence for each gene was assessed by rejected substitution (RS) score, computed by GERP++ [27]. Genetic mutations. 2. Supek F, Miñana B, Valcárcel J, Gabaldón T, Lehner B. Synonymous mutations frequently act as driver mutations in human cancers. 2006;39:2293–300. While synonymous mutations were long thought to be without phenotypic consequences, there is growing evidence they can affect gene expression, protein … Synonymous mutations are those mutations in the coding sequence (CDS) that do not change the amino acids (AAs). https://doi.org/10.1016/j.cell.2014.01.051. Because the abundance of cognate tRNAs involved in preferred codons are available within the cell, the use of efficient codons could increase the gene expression [6]. Genome Res. HSP70 domain is strongly upregulated by heat stress and toxic chemicals, particularly heavy metals. Nature. PubMed  Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, et al. Redundancy of the genetic code provides some protection against the effect of mutations. Identifying stages of kidney renal cell carcinoma by combining gene expression and DNA methylation data. Figure S2. Human MDR1 can be expressed in various organisms and cell lines. In a rather general sense, a gain in understanding of the association between genetic variation and its phenotypic effects is therefore a step toward grasping how nature act… Junfeng Xia. CAS  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. The observation could add perspective to understand cancer-related synonymous mutations. Google Scholar. The codon usage bias is related to various biological processes, such as gene expression level, protein structure, mutation frequency and GC composition [45]. California Privacy Statement, In summary, it is possible that synonymous mutations under L may have more important effect on gene expression and protein production than the mutations of other amino acids during biological processes. But there is no significant different between hotspot and non-hotspot datasets (p-value = 0.93) for RS score. 1988;78:151–5. YB performed the analysis and drafted the manuscript. Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. synonymous and nonsynonymous mutations in coagu-lation Factor VIII illustrates a general strategy for inves-tigators to score synonymous mutations [28]. Nat Methods. By chance the precision is gone because of mutation 'Simply diseases.' PubMed Central  The authors thank all members of our laboratory for their valuable discussions. 2004;4:1–11. And this transition is associated with two of four Ala’s codons, but independent of the transformation between optimal and non-optimal codons [10]. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Galphaq-p63RhoGEF-rho GTPase pathway. As seen in the upper panel of Fig. Similar to SilVA, by integrating characteristics at the level of DNA and/or RNA alongside more conventional variables, this tool is uniquely equipped to assess this class of genetic variant. Laminin_N domain is extracellular matrix molecule and MBOAT domain contains various acyltransferase enzymes. The procedure is illustrated in Additional file 1: Figure S1. 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]. 2010;5:e13574. From the distribution of hotspot mutations under different subtypes of sequence contexts (Fig. 2017;38:839–48. Front Physiol. The Hot-Driver suite assigns mutations to six subtypes: AT transition (ATts), AT transversion (ATtv), non-CpG-island GC transition (NC_GCts), non-CpG-island GC transversion (NC_GCtv), CpG-island GC transition (C_GCts) and CpG-island GC transversion (C_GCtv). CAS  A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency. 2014;156:1324–35. It is found that nine domain types are common to hotspot, neutral synonymous and non-hotspot mutations (Fig. Pfeifer GP, You YH, Besaratinia A. Mutations induced by ultraviolet light. PubMed Central  PubMed  2006;7:98–108. Clearly, the distributions of amino acids are different for the three synonymous mutation datasets. Cell. a miscopied DNA nucleotide that only changes one base pair in the RNA copy of the DNA. A map of human genome variation from population scale sequencing. Similar with the distributions of mutational types in TCGA dataset, the most frequency mutational nucleotide changes in 1000G dataset are also C → T and G → A transitions (Fig. Gustafsson C, Govindarajan S, Minshull J. Codon bias and heterologous protein expression. Nature. The aim of 1000G is to discover variants with a frequency of occurrence > 1% in multiple human populations worldwide. The authors declare that they have no competing interests. The MDR1 … The datasets supporting the conclusions of this article are included within the article and its additional files. IEEE/ACM Trans Comput Biol Bioinform. 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. If we add the possibility of weak effects of translational rate/accuracy and an otherwise mysteriouseffectofsynonymousnucleotidecontentonmRNA levels,(47) mediated at either the transcriptional or RNA- Hotspot synonymous mutations across different cancer types in TCGA dataset. The functions of these domains are different from each other. P Natl Acad Sci Usa. Bioinformatics. PubMed Central  Huang D-S, Zhao X-M, Huang G-B, Cheung Y-M. As rhodopsin-like receptor, 7tm_1 domain comprises the group of G protein-coupled receptor and encompasses a wide range of functions such as various autocrine, paracrine, and endocrine processes. More information: Yogita Sharma et al, A pan-cancer analysis of synonymous mutations, Nature Communications (2019).DOI: 10.1038/s41467-019-10489-2 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. Generally there should not be any effect as the introns are spliced out. 5, the RS scores of hotspot mutations are significantly higher than those of neutral synonymous mutations in 1000G (p-value <2e-16). 2013;502:333–9. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Curr Opin Struc Biol. Notable among these outliers are SKCA, ENAD, STAD and LUAD, which contain more than 100 synonymous mutations per sample. And it is also the most prevalent sequence context in nine cancer types (CEAD, CNST, ENAD, INAD, KICA, PRAD, SKCA, STAD and THCA). We got 373,434 cancer related synonymous mutations obtained from 5749 tumor samples across 15 types of cancer: breast cancer (BRCA), central nervous system tumor (CNST), cervical adenocarcinoma (CEAD), endometrial adenocarcinoma (ENAD), haematopoietic and lymphoid tumor (HLTU), kidney carcinoma (KICA), large intestine adenocarcinoma (INAD), liver carcinoma (LICA), lung adenocarcinoma (LUAD), ovarian carcinoma (OVCA), prostate adenocarcinoma (PRAD), skin cancer (SKCA), stomach adenocarcinoma (STAD), thyroid carcinoma (THCA) and urinary tract carcinoma (UTCA). Google Scholar. Analysis of mutation distribution in protein domains. The result indicated that there were significant differences in conservation, amino acids and domain characterization between hotspots and neutral synonymous mutations. A p-value < 0.05 was considered statistically significant. 2017;14:1147–53. Non-synonymous and synonymous coding SNPs show similar likelihood and effect size of human disease association. 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). Lastly, in this study, to avoid the bias of background number of passenger mutations, we only selected the hotspot mutations that predicted as the pathogenic mutations by Functional Analysis through Hidden Markov Models [25]. Gut. 2006;314:1930–3. However, there are some differences for proportions of mutational nucleotide changes between TCGA and 1000G datasets. Melanoma's high C>T mutation rate: is deamination playing a role? Omid • 570. Moreover, in CEAD and THCA, the hotspots are only enriched in NC_GCts. 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]. Diederichs S, Bartsch L, Berkmann JC, Frose K, Heitmann J, Hoppe C, Iggena D, Jazmati D, Karschnia P, Linsenmeier M, et al. Article  But in this study, we just performed a pan-cancer analyzed of the hotspots. In LICA, OVCA and UTCA, the sequence contexts under which hotspot mutations occur are equal. Synonymous SNPs are the most polymorphic, indicating that most such m… However, relatively little research has specifically delineated the functionality of synonymous mutations in cancer. Mutational processes molding the genomes of 21 breast cancers. Thirty-five different Pfam domains were detected in the proteins under which the hotspot mutations occurred, whereas 29 and 91 protein domains under which neutral synonymous and non-hotspot mutations happened, respectively. Meanwhile, we nominated 97 hotspot mutations in 86 genes in TCGA as potential drivers by considering their mutational rates across different mutational subtypes. PubMed Central  2010;467:1061–73. 1). resolved mechanisms by which synonymous mutations can have an effect on fitness: splice regulation, miRNA binding, mRNA folding and protein folding. 2000;101:425–33. The p53 tumor suppressor (TP53) also has recurrent synonymous mutations, but, in contrast to those in oncogenes, these are adjacent to splice sites and inactivate them. And heterogeneity may affect the progression of INAD from the early to the advanced stages, drive phenotypic variations and present a significant challenge to personalized medicine. The Pfam protein families database: towards a more sustainable future. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. Vast literature is available, if you Google The roughly 10,000 variants in the coding region of every human genome that have no effect on the resulting product protein sequence are termed synonymous SNVs (sSNVs) (Shen et al., 2013). We mapped the hotspot mutations to conserved protein domains obtained from Pfam-A (version 29.0), a database of protein domain families [28], and manually curated data were used in this work. 2010;11:174. Genetic variation drives evolution. 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]. 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. dCMP_cyt_deam_1 domain is the cytidine and deoxycytidylate deaminase zinc-binding region, which is associated with the catalytic activity of cytidine deaminase. In this study, we not only investigated the distribution and mutational nucleotide changes of synonymous mutations across 15 cancer types, but also made the comparison of synonymous mutational signatures between TCGA and 1000G at nucleotide and amino acid levels. Losi L, Baisse B, Bouzourene H, Benhattar J. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Cancer Res. PubMed  It is notable that among the three amino acids with six synonymous codons, Arg (R) shows the fewest number of mutations not only in TCGA but also in 1000G, which may be associated with the synonymous codon usage bias (R has only one optimal codon while Ser and L both have two optimal codons). 2012;22:1589–98. The cancer related synonymous mutations in TCGA were downloaded from COSMIC v79 (Catalogue of Somatic Mutations in Cancer) [25]. By contrast, HLTU has none hotspot and THCA has only one hotspot mutation in ILF3 (N192). 3a). 2016;8:442–57. Pecce V(1), Sponziello M(1), Damante G(2), Rosignolo F(1), Durante C(1), Lamartina L(1), Grani G(1), Russo D(3), di Gioia CR(4), Filetti S(1), Verrienti A(1). The enrichment of hotspot mutations reflects the genetic heterogeneity of INAD, which has been discussed in previous research [47]. Synonymous mutations can affect transcription, splicing, mRNA transport, and translation, any of which could alter phenotype, rendering the synonymous mutation non-silent. Single-tailed unpaired t-test was used to test significantly difference between hotspot mutations, neutral synonymous mutations and non-hotspot mutations. In hotspot mutation dataset, L and Phe (12.37 and 11.34%, respectively) are the most mutated amino acids due to prevalent C → T transition, which is involved the transformation between optimal and non-optimal codons. This article has been published as part of BMC Medical Genetics Volume 20 Supplement 2, 2019: Proceedings of the 2018 International Conference on Intelligent Computing (ICIC 2018) and Intelligent Computing and Biomedical Informatics (ICBI) 2018 conference: medical genetics. © 2021 BioMed Central Ltd unless otherwise stated. The result suggests that the sites which hotspots occur on are more conservative than those of neutral synonymous mutations. Although Silent Variant Analyzer [20] is a tool for the annotation and prediction of pathogenic synonymous mutations, the small datasets for training and validation restrict its applicability. 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]. 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.

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