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. 1995;349:241–7. Bin, Y., Wang, X., Zhao, L. et al. Clearly, the distributions of amino acids are different for the three synonymous mutation datasets. 7a), including 7 transmembrane receptor domain (7tm_1, PF00001), cytidine and deoxycytidylate deaminase zinc-binding region domain (dCMP_cyt_deam_1 domain, PF00383), nucleotide-binding domain (cobW domain, PF02492), Hsp70 protein domain (HSP70 domain, PF00012), ion transport protein domain (Ion_trans domain, PF00520), immunoglobulin I-set domain (I-set domain, PF07679), laminin N-terminal domain (Laminin_N domain, PF00055), membrane-bound O-acyltransferase family domain (MBOAT domain, PF03062) and transmembrane protein 67 domain (Meckelin domain, PF09773). PubMed  Manage cookies/Do not sell my data we use in the preference centre. 2016;17:249–62. Tamura K, Nei M. Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. 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. 2012;22:1589–98. Mol Biol Evol. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, et al. Buske OJ, Manickaraj A, Mital S, Ray PN, Brudno M. Identification of deleterious synonymous variants in human genomes. For example, the oncogene BRAF is frequently mutated in melanoma, whereas KRAS is frequently mutated in … Chen R, Davydov EV, Sirota M, Butte AJ. BMC Genomics. 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. Synonymous codons of amino acids with optimal and non-optimal codons for human genome. Griseri P, Bourcier C, Hieblot C, Essafi-Benkhadir K, Chamorey E, Touriol C, Pages G. A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients. Synonymous mutations had highly variable fitness effects, both deleterious and beneficial, resembling those of nonsynonymous mutations in the same gene. synonymous and nonsynonymous mutations in coagu-lation Factor VIII illustrates a general strategy for inves-tigators to score synonymous mutations [28]. The observation could add perspective to understand cancer-related synonymous mutations. Nature. T125 in TP53 is the most prevalently occurred mutation in nine different cancer types. Hearing silence: non-neutral evolution at synonymous sites in mammals. The cancer related synonymous mutations in TCGA were downloaded from COSMIC v79 (Catalogue of Somatic Mutations in Cancer) [25]. 2008;455:1069–75. In 1000G, Ala is the most frequently mutated amino acid due to G → A transition. 2013;10:1081–2. 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. Figure S3. 4b, the most widespread sequence context undergoes hotspots is NC_GCts sequence context, which presents in 14 cancer types. Moreover, the most frequently substituted bases are C and G, and the most frequently mutated to bases are T and A. A pan-cancer catalogue of cancer driver protein interaction interfaces. Genome Res. EMBO Mol Med. Here, we present evidence that these “silent” mutations frequently contribute to human cancer. Because the cancer patient lacked a second healthy copy of the gene, the silent mutation may have resulted in a complete loss of function of BAP1. Cell. 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. 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. Lower panel: Green bar represents the average numbers of variants per sample. Losi L, Baisse B, Bouzourene H, Benhattar J. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. As a complex genetic disease, cancer was affected by a large number of variants. By chance the precision is gone because of mutation 'Simply diseases.' 1988;78:151–5. Mutational processes molding the genomes of 21 breast cancers. 5, the RS scores of hotspot mutations are significantly higher than those of neutral synonymous mutations in 1000G (p-value <2e-16). 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 [1]. 3a). The aim of 1000G is to discover variants with a frequency of occurrence > 1% in multiple human populations worldwide. 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. 2, 3, 4, and 6 codon represent the numbers of synonymous codons, respectively. 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). A map of human genome variation from population scale sequencing. dCMP_cyt_deam_1 domain is the cytidine and deoxycytidylate deaminase zinc-binding region, which is associated with the catalytic activity of cytidine deaminase. The functions of these domains are different from each other. Copyright © 2014 Elsevier Inc. All rights reserved. 2014;26:479–94. 2014;43:D805–D11. 2017;14:1147–53. Junfeng Xia. 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. There were several methods focused on predicting driver mutations, such as E-Driver [17], MuSiC [18] and OncodriveCLUST [19]. 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. PubMed Central  The enrichment of hotspot mutations reflects the genetic heterogeneity of INAD, which has been discussed in previous research [47]. Download : Download high-res image (129KB)Download : Download full-size image. PubMed Central  Article  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. 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]. 4a), the number of hotspot mutations under NC_GCts sequence context (consists of C:G → T:A transitions) is the largest one compared with the other types, and that under ATtv (consists of A:T → C:G and A↔T transversions) is the least one. And then, we nominated synonymous hotspot mutations as candidate drivers based on the mutational rates across different sequence contexts and investigated the features (such as conservation, distribution of amino acids and protein domains undergo mutations) of hotspots, neutral synonymous mutations and non-hotspots in the hotspot-mutation-containing-genes (HMCGs). The TP53 LSDB paradigm. Schutz FA, Pomerantz MM, Gray KP, Atkins MB, Rosenberg JE, Hirsch MS, McDermott DF, Lampron ME, Lee GS, Signoretti S, et al. Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. In mammals, contrary to what is usually assumed, recent evidence suggests that synonymous mutations may not be selectively neutral. Supek F, Miñana B, Valcárcel J, Gabaldón T, Lehner B. Synonymous mutations frequently act as driver mutations in human cancers. By continuing you agree to the use of cookies. 7tm_1 domain is the highest proportion of hotspot mutations and consists of the group of G protein-coupled receptor, which could promote cancer metastasis [52]. APIS: accurate prediction of hot spots in protein interfaces by combining protrusion index with solvent accessibility. The conservation of nucleotide sequence for each gene was assessed by rejected substitution (RS) score, computed by GERP++ [27]. Cite this article. Moreover, the average numbers of variants per sample across 15 cancer types are different with each other (the lower panel of Fig. Exp Dermatol. For the comprehensiveness of analysis, this study not only highlights the nucleotide level preferences, but also amino acids level, and especially hotspot mutations. 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. Non-synonymous and synonymous coding SNPs show similar likelihood and effect size of human disease association. A p-value < 0.05 is considered to be significant. 2014;23:551–2. We use cookies to help provide and enhance our service and tailor content and ads. Sanchez MI, Grichnik JM. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, Ding M, Bamford S, Cole C, Ward S. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. And it is also the most prevalent sequence context in nine cancer types (CEAD, CNST, ENAD, INAD, KICA, PRAD, SKCA, STAD and THCA). Laminin_N domain is extracellular matrix molecule and MBOAT domain contains various acyltransferase enzymes. Comparison of RS scores between the datasets of hotspots and neutral synonymous mutations, non-hotspots. 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. © 2021 BioMed Central Ltd unless otherwise stated. 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. There are several types of mutations, some of which have no effect while others have a major effect. 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]. 2008;455:1061–8. Question: Synonymous Mutations And Their Effect On Splice Site. Springer Nature. Carcinogenesis. The x-axis represents the cancer types. Then we analyzed the distributions of hotspot, neutral synonymous and non-hotspot mutations under the nine common protein domains. 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]. PubMed  Cancer Cell. 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. 2015;11:e1004518. We reported hotspot mutations in amino acid position with adjusted p-values < 0.05 corrected by false discovery rate. Positive selection implies an excess of nonsynonymous versus synonymous substitutions with change of residue at a given position. Vast literature is available, if you Google Since genes that shared a common domain are more likely to share related functions, the important mutations in certain genes tend to cluster in close proximity within functional domains [18, 29, 30]. 2013;4:312. Our study suggested that synonymous mutations in the MDR1 haplotype produce a subtle but measurable change in substrate binding site conformation. Hum Mol Genet. However, in LUAD, the hotspot mutations are enriched in NC_GCtv sequence context. P Natl Acad Sci Usa. 8.4 years ago by. 2012;149:979–93. We also found that the hotspots were more conserved than neutral mutations of hotspot-mutation-containing-genes and frequently happened at leucine. 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). Nat Methods. Plotkin JB, Kudla G. Synonymous but not the same: the causes and consequences of codon bias. 2011;12:32–42. Cancer Sci. Among transversions, the C → A substitution is the most frequent one (6.18%). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Etcheverry A, Aubry M, de Tayrac M, Vauleon E, Boniface R, Guenot F, Saikali S, Hamlat A, Riffaud L, Menei P, et al. Article  The MDR1 … For the proportion of tumor samples (yellow bar), BRCA is the most and UTCA the fewest. 5 … 2010;467:1061–73. The result indicated that there were significant differences in conservation, amino acids and domain characterization between hotspots and neutral synonymous mutations. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. 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. CAS  In LICA, OVCA and UTCA, the sequence contexts under which hotspot mutations occur are equal. Hotspot represents hotspot mutations; 1000G represents neutral synonymous mutations of HMCGs in 1000G dataset; Non-hotspot represents non-hotspot mutations of HMCGs in TCGA dataset. 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. Illustration of analysis procedure of cancer associated synonymous mutations. Kobe B, Kajava AV. 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. PubMed  1993;10:512–26. DNA methylation in endometrial cancer. 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. 2011;20:4556–68. 3b). But to date, the targets of drugs and treatments associated with cancer are limited on a few genes, therefore, it is difficult to achieve cures for cancer. Hum Mutat. 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]. There is none synonymous mutation under Met and Trp due to the lack of synonymous codons. Blue, salmon and green sections on the bar represent which proportions of the total mutations are hotspot, neutral synonymous and non-hotspot mutations, respectively. Google Scholar. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, et al. As an important amino acid of leucine-rich repeats, L is associated with a versatile structural framework for the formation of protein-protein interactions [49]. Studies have shown that nucleotide substitutions, including synonymous mutations, could be related to carcinogen exposures and DNA repair processes [35,36,37]. 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 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. 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]. An analysis of mutational signatures of synonymous mutations across 15 cancer types. Mutational landscape and significance across 12 major cancer types. This variation in fitness was underlain by changes in transcription linked to the creation of internal promoter sites. YB performed the analysis and drafted the manuscript. Upper panel: blue and yellow bars represent the proportions of synonymous variants and corresponding tumor samples, respectively. 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]. Lancet Oncol. Deng SP, Huang DS. It is now known that synonymous mutations can either reduce or enhance protein synthesis. But there are some limitations in this study. A synonymous RET substitution enhances the oncogenic effect of an in-cis missense mutation by increasing constitutive splicing efficiency. 2014;35:643–53. The authors declare that they have no competing interests. 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. 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. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Galphaq-p63RhoGEF-rho GTPase pathway. JX designed the study, performed the analysis, and drafted the manuscript. Becchetti A, Munaron L, Arcangeli A. California Privacy Statement, Part of 2001;11:725–32. Each bar represents the percentage of mutational types. 1, with regard to synonymous mutation proportion (blue bar), SKCA is the largest and HLTU the smallest. PLoS One. Diederichs S, Bartsch L, Berkmann JC, Frose K, Heitmann J, Hoppe C, Iggena D, Jazmati D, Karschnia P, Linsenmeier M, et al. 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. Genome Res. 2014;156:1324–35. But there is no significant different between hotspot and non-hotspot datasets (p-value = 0.93) for RS score. a miscopied DNA nucleotide that only changes one base pair in the RNA copy of the DNA. SFAPS: an R package for structure/function analysis of protein sequences based on informational spectrum method. From TCGA, we obtained 373,434 synonymous mutations of 5749 tumor samples from 15 types of cancer. https://doi.org/10.1186/s12881-019-0926-4, DOI: https://doi.org/10.1186/s12881-019-0926-4. Their subsequent experiments suggest that the mutation has this effect by disrupting cells’ RNA splicing process, by which freshly transcribed messenger RNA (mRNA) is converted into digestible fragments ready to be translated into protein. We illustrated the preferences of cancer associated synonymous mutations, especially hotspots, and laid the groundwork for understanding the synonymous mutations act as drivers in cancer. Single nucleotide polymorphisms and risk of recurrence of renal-cell carcinoma: a cohort study. More information: Yogita Sharma et al, A pan-cancer analysis of synonymous mutations, Nature Communications (2019).DOI: 10.1038/s41467-019-10489-2 Somatic mutations affect key pathways in lung adenocarcinoma. In addition, our analyses suggest that dosage-sensitive oncogenes have selected mutations in their 3′ UTRs. Google Scholar. 2003;13:838–44. Next, 97 synonymous hotspot mutations in 86 genes were nominated as candidate drivers with potential cancer risk by considering the mutational rates across different sequence contexts. 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, … ‘All’ in this figure represents the average proportions of mutational types across 15 cancer types. This phenomenon is due to the most frequency of C → T and G → A transitions and least frequency of A:T → C:G and A↔T transversions (Fig. 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).