Development 144, 1966–1975 (2017). CAS Plant J. Moreover, in addition to the known effect of synonymous mutations on mRNA splicing [6], we displayed the selection on codon usage bias for synonymous SNPs in cancer-related genes. The Pearson correlation coefficient calculated based on BLUEs indicated a positive and significant (P < 0.001) correlation of TSN with SL, HD and FT, and between HD and FT, while the correlation between SL and the flowering traits was null (Fig. We also illustrated the relative position of the nonsynonymous or synonymous SNPs on the CDSs of these 20 genes (Additional file 3: Figure S2D). P-values were calculated using Fisher’s exact tests. College of Life Sciences, Beijing Normal University, No. Front. Genet. The substrate specificity of the tRNA to the rare codon can affect the timing of translation, and in turn the co-translational folding of the protein. Genetics 136, 1457–1468 (1994). Natl. The nature and locations of epitope losses from the various proteins of SARS-CoV-2 due to non-synonymous mutations are the main focus of the present study. Appl. ref., reference. A non-synonymous mutation may not affect the phenotype (neutral mutation). First we calculated the SNP density (number of SNPs per Kb) in exonic (Additional file 3: Figure S1A) or coding (Additional file 3: Figure S1B) region. Ikemura T. Codon usage and tRNA content in unicellular and multicellular organisms. Nat. Figure S3. Genome Biol Evol. CAS https://doi.org/10.1371/journal.pgen.0020106 (2006). PubMed Central 6). Voss-Fels, K. P. et al. 2c, d). It is the key that opens the door for the entry of the virus into the host cells, and any change in it has potentially important implications for the biology of the virus. The mutation from D to H confers a phenotype similar but weaker than the complete loss of FT-B1 (and 400 other genes) described in Dixon et al.24 and Finnegan et al.25. https://www.R-project.org/. Google Scholar. Genetics. Studies have found that CUB and synonymous mutations participate in human diseases like autism [22] and hemophilia B [23]. CAS Also known as B.1.1.7 strain, its non-synonymous mutations are specified by six mutations and two deletions in the spike glycoprotein (which is a primary vaccine target), two mutations… All phenotyping data analyses, including ANOVAs, Pearson’s correlation coefficient analyses, repeatability among replicates, broad-sense-heritability across years, and statistical tests, were performed using the software R48. Here, with the evidence of purifying selection on synonymous SNPs in cancer-related genes, analyzing these sets of “silent” mutations should be equally crucial in predicting the risk of cancer, and some rare synonymous mutations in cancer-related genes might even be the direct targets in cancer therapy. In brief, each of the 59 sense codons (excluding three stop codons and two codons without synonymous counterparts) has a “codon bias value” between − 1 and 1 (which is actually a correlation coefficient). Question: list out the synonymous, non-synonymous mutations. 2011;12(1):32–42. Note that the conservation level of a site refers to the DNA level conservation pattern across different species (and it has nothing to do with the SNP). STAR: ultrafast universal RNA-seq aligner. PubMed We drew to this conclusion without the requirement of data from cancer tissues or patients. To test the potential interaction between the candidate gene FT-B1 and the vernalization gene VRN-A1, the whole population was genotyped with a Kompetitive Allele Specific PCR (KASP) marker based on the FT-B1 SNP (Supplementary Table S6) and VRN-A1 primers23. Lynch M. Rate, molecular spectrum, and consequences of human mutation. TEOSINTE BRANCHED 1 regulates inflorescence architecture and development in bread wheat (Triticum aestivum). This ratio is used to estimate the selection pressure a given protein or section of DNA experiences. We annotated the SNPs with SnpEff [33] and the canonical transcript of each gene were chosen. & Swain, S. M. New alleles of the wheat domestication gene Q reveal multiple roles in growth and reproductive development. d Correlation between the delta codon bias after the synonymous change and the fraction of cancer-related genes. Thus, digging out some valuable information in cancer-related genes from the commonly available human genome data (or even data in other species) is suitable for most researchers or evolutionary biologists [2]. 2004;22(7):346–53. 60, 1541–1555 (2020). It was previously reported that synonymous mutations might play a role in driving human cancers [6]. 1b). Evol. Sci. To control for the effect of GC content, we chose the top 20% genes with the highest GC content (Additional file 3: Figure S4) and the bottom 20% genes with the lowest GC content (Additional file 3: Figure S5). b Fractions of SNPs that the reference allele is observed in mouse and the alternative allele is observed in monkey. 5c). 19, 409. https://doi.org/10.1186/s12864-018-4795-6 (2018). In this gene expression calculation, the canonical transcript of each gene was chosen, and all the reads overlapped with exon regions were counted. Qian WF, Yang JR, Pearson NM, Maclean C, Zhang JZ. 2014;156(6):1324–35. P-value was calculated using Wilcoxon rank sum test. Finnegan, E. J. et al. Polymorphisms between both parental lines were annotated in the MSAs. Genes were divided into ten bins with increasing delta codon bias. Varenne S, Buc J, Lloubes R, Lazdunski C. Translation is a non-uniform process. Next, part of the SNPs has more than one mutation types and might cause conflict in functional annotation. Front. Faure, S., Higgins, J., Turner, A. 4a). https://doi.org/10.1126/science.aar7191 (2018). CAS Chen, Z. et al. This is not paradoxical because the nonsynonymous mutations contribute to cancer by changing the amino acid and the protein function, while synonymous mutations putatively contribute to cancer by affecting codon usage and the mRNA translation rate. Only those SNPs with genomic sequences identical to at least one species in monkey or mouse were considered as ancestral SNPs (Fig. Variant VUI 202012/01 has a tyrosine instead of asparagine at position 501 (mutation N501Y). 31770213). Nonsynonymous substitutions differ from synonymous substitutions, which do not alter amino acid sequences and are (sometimes) silent mutations. Specifically, best linear unbiased estimations (BLUEs) were calculated per year for the spike traits and across years for all traits by assuming fixed effects for the intercept and the genotype and all others as random. R Foundation for Statistical Computing, Vienna, Austria (2020). In gene X, let us suppose: EAAA = (OAAA + OAAG) × 0.59, the expected number of AAA codons (within family “K”). Intriguingly, in the field of CUB, studies have shown that an obvious advantage of optimized codon usage is that it facilitates the cellular translation elongation process and is especially beneficial upon rapid cell growth [24, 25]. Babben, S. et al. Broad sense heritability values calculated over 4 years ranged between 0.71 for SL and 0.88 for FT and HD (Table 1). These QTL most probably correspond to the vernalization gene VRN-A1 (TraesCS5A02G391700). Cartegni L, Chew SL, Krainer AR. 2014;42(14):9171–81. The analyses that take gene expression level into count are conducted using these 439 cancer-related genes versus 8418 other genes. Hd3a promotes lateral branching in rice. Confidence interval for the significant QTL were defined as a continuous genomic region comprised within a 1.5-LOD from the marker with the highest LOD per chromosome passing the threshold54. Phylogenetic analyses identified MFT—the only member of the PEBP family in mosses—as the ancestral gene, and its duplication in FT/TFL1-like genes and their divergence coincided with the evolution of vascular plants28,29. Carcass traits are quantitative traits and modified by numerous genes. Biol. Privacy http://hgdownload.soe.ucsc.edu/goldenPath/hg19/liftOver/, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, https://doi.org/10.1186/s12885-019-5572-x. Take Lys (K) codon AAG for instance, family “K” has two codons AAG and AAA. List of 719 human cancer-related genes. Each spikelet contains 8–12 florets and produces usually 3–5 grains per spikelet1. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Allelic variation at the vernalization genes Vrn-A1, Vrn-B1, Vrn-D1, and Vrn-B3 in Chinese wheat cultivars and their association with growth habit. PubMed b Correlation between codon bias and codon frequency appearing in human genome. J. Exp. Appl. A non-synonymous mutation in this gene has been shown to affect carcass weight (Eberlein et al., 2009; Setoguchi et al., 2009). PubMed A very smart measurement is the phyloP score (downloaded from UCSC Genome Browser, genome.ucsc.edu) calculated from the multiple sequence alignment of a large set of species. Google Scholar. 54, 502–510 (2016). A.) A TaqMan® SNP Genotyping Assay was designed and demonstrated the heterozygous detection of the mutation in 47 Bull Terriers with BTPKD, but not in 102 Bull Terriers over one year of age and without BTPKD. 2010;26(8):345–52. Total spikelet number per spike (TSN) is a major component of spike architecture in wheat (Triticum aestivum L.). Composite interval mapping identified a total of 56 individual QTL at 28 loci for all years, all traits and their resulting BLUEs (Table 2, Supplementary Table S1). Biol. The FLOWERING LOCUS T-like gene family in barley (Hordeum vulgare). This might not be new to us since we did not separate nonsynonymous and synonymous sites. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. However, FT-B1 affected spikelet formation without a major effect on the flowering time. d The annotations and proportions of genomic SNPs (left) and exonic SNPs (right) after the above filtering steps. We searched for the public database and chose an NGS dataset conducted in human HeLa cells (GES63591) [36]. FT-B1 is a member of an evolutionarily well-conserved gene family [phosphatidylethanolamine-binding protein (PEBP)] that is present in all taxa including bacteria, animals, and plants27. A system for detecting high impact-low frequency mutations in primary tumors and metastases. The impact of synonymous mutations is more profound than people used to think. Leu (L), Arg (R) and Ser (S) have six codons so that a single mutation sometimes could not switch one codon to another (for example, AGT and TCT both encode Ser but a single mutation could not change one to another). The three possible stop codons in … Kobayashi, Y., Kaya, H., Goto, K., Iwabuchi, M. & Araki, T. A pair of related genes with antagonistic roles in mediating flowering signals. N Engl J Med. When we only consider the 9903 highly expressed genes in HeLa cells, 8857 overlapped with the 17,940 genes with SNPs, and 439 of them belongs to cancer-related genes and 8418 are other genes. The study has fully discussed the effect of synonymous mutations on splicing events, and proposed some awesome ideas like the mutations silent to the protein sequence are not always silent to the function [6]. Sakuma, S. & Schnurbusch, T. Of floral fortune: Tinkering with the grain yield potential of cereal crops. Our study demonstrated the evolutionary constraint on mutations in CDS of cancer-related genes. Genes with at least one common SNP in CDS are given in Additional file 2: Table S2. Plant Sci. Among those 70 PEBP genes, including FT-B1 and its homoeologues on chromosomes 7A and 7D (TraesCS7A02G115400 and TraesCS7D02G111600), the majority possessed an aspartic acid (D) but none had a histidine (Fig. We retrieved the highly expressed genes (NGS read count > 100, see Methods for details) in human HeLa cells. Genetic pathways controlling inflorescence architecture and development in wheat and barley. Among the synonymous SNPs, the codons after mutation in cancer-related genes tend to be preferred and have higher frequency in the genome compared to those in other genes. Dana A, Tuller T. The effect of tRNA levels on decoding times of mRNA codons. mouse). Therefore, if any selection is detected for the nonsynonymous or synonymous sites, it might not be imposed by the selection on splicing events. J. Integr. The best linear unbiased estimations (BLUEs) showed a wide variation within and across years for all traits, with TSN and SL being normally distributed (Shapiro–Wilk test: P = 0.82 for TSN, P = 0.06 for SL, P = 0.001 for HD, and P = 0.003 for FT). 2011;39(Database issue):D945–50. Among the “common” and “all” SNPs that are labeled distinctly in the website, we first chose the common SNPs for analysis due to its higher occurrence and reliability, since the total number of all SNPs already came up to one tenth of the human genome. Analyzing FT-like genes in maize and rice, Zheng et al.34 have shown that those genes had been under positive selection during domestication allowing the plants to adapt to different environments during the range expansion of by modulating their flowering time. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Nonsense mutations are less frequent and located closer to stop codons in cancer-related genes than in other genes, which putatively minimize their deleterious effects. Yan, L. et al. We reveal extra constraint on synonymous mutations in cancer-related genes which is related to codon usage bias and is in addition to the splicing effect. FLOWERING LOCUS T 2 regulates spike development and fertility in temperate cereals. The nonsynonymous to synonymous ratio is significantly lower in cancer-related genes compared to that in other genes, suggesting that the nonsynonymous substitutions in cancer-related genes are suppressed. The bread wheat epigenomic map reveals distinct chromatin architectural and evolutionary features of functional genetic elements. Arrows indicate the phenotypes of the parental lines with parent A corresponding to TRI-10703 and parent B to TRI-5310. 30, 3059–3066 (2002). Article Scientific Reports 2001;53(4–5):290–8. 5c), and the combined effect can even lead to a nonsense mutation. To address these problems, we first decided to take into account the gene expression level. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. conceived, designed, and performed the experiments. Oncogene. Google Scholar. 2a). Individuals carrying the FT-B1 allele with amino acid histidine had, on average, a higher number of spikelets (15.1) than individuals with the aspartic acid allele (14.3) independent of their VRN-A1 allele. Boden, S. A. et al. Science 361, eaar7191. Theor. This gene—an ortholog of Arabidopsis FT and rice RFT1—has three predicted exons encoding a phosphatidylethanolamine-binding protein (PEBP). PubMed The physical interval defined for QTsn.ipk-7B was retrieved from the assemblies of the parental lines sequenced at 10 × coverage with Illumina paired-end sequencing (HiseqXTEN PE150) and assembled as described in Muqaddasi et al.35. and Q.H.M. The list of 719 human cancer-related genes (Additional file 1: Table S1) was downloaded from the latest version of cancer gene census website (CGC, https://cancer.sanger.ac.uk/census/). For QTsn.ipk-7B—located at 0–33.46 cM—the phenotypic variance amounted to 13.1–20.5%. A nonsynonymous substitution is a nucleotide mutation that alters the amino acid sequence of a protein. Nonsynonymous or amino acid-altering mutations are further classified into missense, nonsense, and sense mutations. Nature. c Correlation between the delta codon bias after the synonymous change and the fraction of cancer-related genes. c Conservation level (phyloP score) of nonsynonymous and synonymous SNPs in cancer-related genes and other genes. Therefore, each of these amino acids has to be divided into two synonymous codon families [21]. 2004;32(17):5036–44. Guo, Z. et al. 82, 256–266 (2015). 4c) or delta codon frequency (Fig. Positive natural selection in the human lineage. 2010;26(6):841–2. Thank you for visiting nature.com. PubMed Google Scholar.
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