Positive natural selection in the human lineage. 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. Overexpression of FT-B1 did not have an effect on spikelet number but accelerated flowering time in warm conditions while deletion of FT-B1 nearly doubled the flowering time and increased spike length and spikelet number24,25. 30, 772–780 (2013). Nagesh • 10. are members of the company TraitGenetics GmbH. Synonymous–non-synonymous mutation rates AAA AAT AAC AAG.. ATA ATC ATG ATT. Internet Explorer). Composite interval mapping and multiple interval mapping: Procedures and guidelines for using Windows QTL cartographer. A nonsynonymous substitution is a nucleotide mutation that alters the amino acid sequence of a protein. Article  1a). Moreover, in some cases, different isoforms of the same gene share the same CDS, which might reduce the bias of this approach (since we only focus on the variations in CDS). Studies have found that CUB and synonymous mutations participate in human diseases like autism [22] and hemophilia B [23]. College of Life Sciences, Beijing Normal University, No. Dixon, L. E. et al. The origin and frequency of a non-synonymous mutation associated with an increased spikelet number was investigated by analyzing a large diversity of land plants and a panel of hexaploid wheat varieties. Higher FT-B1 transcripts levels controlled by the insertion of a retrotransposon in the promoter region (“Hope” allele) accelerated flowering time and transgenic winter wheat transformed with the Hope promoter behaved like spring types. The optimized codon usage in cancer-related genes might contribute to rapid cell growth and could be a potential mechanism related to oncogenesis. Quinlan AR, Hall IM. When occurring in the gene coding regions, SNPs can be synonymous (i.e., not causing a change in the amino acid) or nonsynonymous (when the amino acid is altered). 2013;368(22):2059–74. No consistent QTL were identified for SL. Precision mapping of quantitative trait loci. 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. Kanaya S, Yamada Y, Kinouchi M, Kudo Y, Ikemura T. Codon usage and tRNA genes in eukaryotes: correlation of codon usage diversity with translation efficiency and with CG-dinucleotide usage as assessed by multivariate analysis. PubMed  High-resolution mapping of rachis nodes per rachis, a critical determinant of grain yield components in wheat. As synonymous (silent) mutations are largely invisible to natural selection (but see Akashi 1995 ), while nonsynonymous (amino- acid-replacing) mutations may be under strong selective pressure, comparison of the rates of fixation of those two types of mutations provides a powerful tool for understanding the mechanisms of … comparisons of non synonymous and synonymous changes are not affected by _____ demographic events (like … P-values were calculated using Wilcoxon rank sum tests. 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. & Zeng, Z. “onco” denotes cancer-related genes; “non-onco” denotes other genes. But do not simply treat this codon bias value as the frequency of each codon appearing in the genome. In this study, we retrieved the recent version of human SNP data from NCBI dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) and downloaded the list of human cancer-related genes from cancer gene census website (CGC, https://cancer.sanger.ac.uk/census/). Genetics. Variant VUI 202012/01 has a tyrosine instead of asparagine at position 501 (mutation N501Y). Non-synonymous mutation leading to the loss of epitope allows escaping antibody immunity. & Chan, A. P. PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels. 20, 139. https://doi.org/10.1186/s13059-019-1746-8 (2019). In contrast to Arabidopsis, where FT induces flowering at elevated growth temperature42, the accelerated development pace of domesticated wheat under high temperature is largely independent of FT24,43. P-value was calculated using Fisher’s exact test. 61, 579–590 (2005). Constraint on mutations belonging to different evolutionary categories. Natural selection exists among all living organisms [1]. Selective and mutational patterns associated with gene expression in humans: influences on synonymous composition and intron presence. 6). P-values were calculated using Wilcoxon rank sum tests. 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). Ikemura T. Codon usage and tRNA content in unicellular and multicellular organisms. Science 361, eaar7191. c Conservation level (phyloP score) of nonsynonymous and synonymous SNPs in cancer-related genes and other genes. New Phytol. Dixon et al.24 reported that flowering time, in contrast to spikelet number, was not responsive to changes in ambient temperature in a ft-b1 NIL, suggesting that the promotion of inflorescence development between the double ridge and terminal spikelet stages is regulated by FT-independent thermally responsive factors. Individuals carrying the dominant Vrn-A1a allele (A) flowered on average 3 days earlier than individuals with the recessive vrn-A1 allele (B), while the difference in flowering time caused by the respective FT-B1 allele was only 1 day. New Phytol. Interestingly, these nonsense mutations could be caused by either a single mutation or double (nonsynonymous) mutations within the same codon. The mutation was observed with a frequency of ca. 30, 3059–3066 (2002). Phenotypic distribution of the best linear unbiased estimations (BLUEs) of the investigated traits. All the traits were analyzed with a two-way factorial ANOVA and allele-wise phenotypic distribution was illustrated by plotting the boxplots. PubMed Google Scholar. Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, et al. c the fractions of different types of mutations. P-value was calculated using Fisher’s exact test. 1c). (XLSX 18 kb), Table S2. Natl. The genotyping for VRN-A1 was done according to Zhang et al.23 and alleles were coded according to the rest of the data with TRI-10703 as parent A and TRI-5310 as parent B. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. It may also have been selected for winter hardiness as the histidine mutation was found to be associated with an increased frost tolerance47. Our work should be interesting to the cancer research community and the field of evolutionary biology. d The annotations and proportions of genomic SNPs (left) and exonic SNPs (right) after the above filtering steps. Conservation level of genomic positions is measured by phyloP score (file hg19.100way.phyloP100way.bw, downloaded from UCSC Genome Browser, genome.ucsc.edu). To address these problems, we first decided to take into account the gene expression level. Pleiotropic QTL influencing spikelet number and heading date in common wheat (Triticum aestivum L.). 70, 193–204 (2019). Koppolu, R. & Schnurbusch, T. Developmental pathways for shaping spike inflorescence architecture in barley and wheat. https://doi.org/10.1242/dev.175398 (2019). Article  Among those, we identified a non-synonymous substitution in exon1 of FT-B1 in our parental lines changing the aspartic acid (D) into a histidine (H). Mol Cell. It is reasonably to ask that whether the nsy/syn ratio of genes and the changing direction of codon preference are correlated. https://doi.org/10.1016/j.semcdb.2020.05.007 (2020). The spike traits (TSN and SL) were recorded from ten spikes per plot as the total number of spikelets and spike length in centimeters (cm) from basal spikelet to the top of a spike but excluding the awns. Oncogene. Bioinformatics. Nucleic Acids Res. 13, 219. https://doi.org/10.1186/1471-2105-13-219 (2012). A few genes influencing TSN are known; among them are (1) the Q gene involved in wheat domestication10,11, (2) a putative ortholog to rice MOC112, and (3) a wheat ortholog (TaAPO-A1 or WAPO-A1) to rice ABERRANT PANICLE ORGANIZATION (APO1)13,14,15. Genome Biol. 5d), probably due to their deleterious effect similar to that of nonsynonymous mutations. Correspondence to Genes were divided into ten bins with increasing nsy/syn ratio. Appl. Total spikelet number per spike (TSN) is a major component of spike architecture in wheat (Triticum aestivum L.). Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C. N (6)-methyladenosine modulates messenger RNA translation efficiency. CAS  A Non-Synonymous Mutation in the Canine Pkd1Gene Is Associated with Autosomal Dominant Polycystic Kidney Disease in Bull Terriers Puya Gharahkhani1, Caroline A. O’Leary2*, Myat Kyaw-Tanner1, Richard A. Sturm3, David L. Duffy4 1School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia, 2Centre for Companion Animal Health, The University of Queensland, In wheat FT-B1 acts downstream of PHOTOPERIOD-1 (PPD-1) gene to influence spikelet number, with loss of FT-B1 resulting in increased spikelet number in a thermally responsive manner2,24,25. Soleimani, B. et al. We found that for both the nonsynonymous and synonymous sites in cancer-related genes have higher conservation level than those in other genes (Fig. https://doi.org/10.1126/science.aar7191 (2018). Cell. Oncogene. The predicted score above the threshold level is the Yellow region showing epitope. (A change in an amino acid resulting from a nonsynonymous mutation is called a replacement.) QTL repeatedly identified in the same interval each year and in their BLUEs were defined as major and consistent. We followed an early study [21] and calculated the parameters needed for codon bias (see Methods for detail). Estimation of synonymous and nonsynonymous substitution rates is important in understanding the dynamics of molecular sequence evolution (Kimura 1983; Gillespie 1991 ; Ohta 1995 ). Biol. Evaluating all non-synonymous mutations affecting the 121 high-confidence genes present in the QTL interval, only eight were considered as potentially deleterious. 75–119 (Humana Press, Totowa, 2012). 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. Polymorphisms between both parental lines were annotated in the MSAs. Gustafsson C, Govindarajan S, Minshull J. Codon bias and heterologous protein expression. We removed the SNPs in splicing regions, which potentially excludes the effect of mutations on splicing patterns. Theor. Genes were divided into ten bins with increasing delta codon bias. PubMed Central  ADS  Ppd-1 is a key regulator of inflorescence architecture and paired spikelet development in wheat. Oncogene. Bot. In the field of cancer research, many attentions have been payed to the detection of mutations in tumor organs/tissues/cells since this is the direct way to search for driver mutations that cause the cancer [28,29,30,31], and little is done in analyzing the SNP or population genomic data from normal/healthy individuals. Our study demonstrated the evolutionary constraint on mutations in CDS of cancer-related genes without the requirement of data from cancer tissues or patients. Higher correlation coefficient suggests stronger bias (preferred) for a codon. The lower nonsynonymous to synonymous ratio observed in cancer-related genes suggests the suppression of amino acid substitutions in these genes. 3b for pooled result). PubMed  3 3 3 3 . In one of the parental lines, FT-B1 carried a non-synonymous substitution on position 19 of the coding sequence. Article  (a) Effect of P4715L mutation in RdRp. P-value was calculated using Wilcoxon rank sum test. Plant Biotechnol. “onco” denotes cancer-related genes; “non-onco” denotes other genes. The synonymous SNPs, after excluding those in splicing regions, exhibit preferred changes in codon usage and higher codon frequencies in cancer-related genes compared to other genes, indicating the constraint exerted on these mutations. Linkage mapping revealed the effects of FT-B1 on total spikelet number in the genetic background of a doubled haploid spring wheat population, while the heading and flowering time was dominated by the effects of a segregating VRN-A1 gene. Brassac, J., Muqaddasi, Q.H., Plieske, J. et al. In a set of 377 homologs retrieved by PROVEAN from the NCBI database across a large diversity of flowering plants as well as a few Gymnosperms, 86.4% had a D, 7.1% possessed an asparagine (N), and 5.5% had a glutamic acid (E). Choi, Y. Nonsynonymous mutations change the protein sequences and are frequently subjected to natural selection. https://doi.org/10.1186/s12885-019-5572-x, DOI: https://doi.org/10.1186/s12885-019-5572-x. Compared to the two other gene families, FT-like genes, evolving via small- and large-scale duplications, are the most numerous among monocots with 13 paralogs identified in rice, five in barley, and nine in wheat based on expressed sequences tags (ESTs) data31,32. An example of synonymous mutiation can be found in amino acid chains, which form many different types of proteins. Article  J Mol Evol. and Q.H.M. Nucleic Acids Res. CAS  The nonsense mutations in cancer-related genes are less frequent and meanwhile located closer to the end of CDSs. Nucleic Acids Res. P-value was calculated using Fisher’s exact test. For each synonymous human SNP, we calculated the change (delta) of codon bias and codon frequency after mutation. 2c), they are significantly avoided in cancer-related genes (Fig. There is a tendency that G/C ending codons are preferred and A/T ending codons are unpreferred. The sequences of the genes present in the interval were mapped to the sequences of the parental lines and then extracted. 2002;3(4):285–98. Allele-wise phenotypic distribution of the KASP marker designed for FT-B1 of the best linear unbiased estimations (BLUEs) for the investigated traits in dominant (A) or recessive (B) VRN-A1 background. Theor. We selected the cancer-related genes with relatively low nsy/syn ratios (nsy ≤ 2 and syn ≥ 2), and displayed the top 20 genes with the highest delta codon bias (Additional file 3: Figure S2C). The Y-axis is the frequency of AAG among “AAG + AAA” in each gene (each dot represents a gene). Cooke SL, Ng CK, Melnyk N, Garcia MJ, Hardcastle T, Temple J, Langdon S, Huntsman D, Brenton JD. A major and consistent quantitative trait locus (QTL) was discovered for TSN in a doubled haploid spring wheat population grown in the field over 4 years. N Engl J Med. mouse). Significance of the mean differences of the marker alleles obtained from a Wilcoxon rank-sum test. & Laurie, D. A. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Google Scholar. Significance of the correlations is indicated with ***P < 0.001. Carcass weight of the animals with C/T allele (473.9 ± 6.0 kg) was significantly heavier than that of the C/C homozygotes (459.2 ± 2.8 kg). The synonymous mutations that are originally thought neutral are now recognized to impact the codon usage bias and undergo natural selection as well. PubMed  Rep. 9, 13853. https://doi.org/10.1038/s41598-019-50331-9 (2019). d Fractions of conserved orthologous sites in mouse genome. To obtain The density is calculated by the number of CDS SNPs divided by the length (Kb) of the CDS. 12, 787–796 (2014). 5c). Yang JR, Chen X, Zhang J. Codon-by-codon modulation of translational speed and accuracy via mRNA folding. It may, therefore, be concluded that the FT-B1 effects on pre-flowering phases play a major role. We sought for the ancestral variants in human (Homo sapiens) genome according to the orthologous sites in two other mammalian species, rhesus macaque (monkey, Macaca mulatta) and mouse (Mus musculus). The heading and flowering time were in all years governed by a major QTL on chromosome 5A which represented the effect of VRN-A1, while on chromosome 7B representing FT-B1 only minor QTL were observed for HD and FT (Table 2, Supplementary Table S1). Hd3a, a rice ortholog of the Arabidopsis FT gene, promotes transition to flowering downstream of Hd1 under short-day conditions. Science. 105, 666–675 (2014). The homoeologues in the parental lines were identical to each other and to the reference (Fig. However, the selection on synonymous mutations for a long time was thought to be negligible or very weak. PubMed Central  Katoh, K. & Standley, D. M. MAFFT multiple sequence alignment software version 7: Improvements in performance and usability. 2004;32(17):5036–44. c A schematic diagram showing the definition of mutation to mouse. This might not be new to us since we did not separate nonsynonymous and synonymous sites. a Relative position of the nonsense variants in cancer-related genes and other genes. b Comparison between the pooled nsy/syn ratio of cancer-related genes and other genes. 4c) or delta codon frequency (Fig. P-value was calculated using Wilcoxon rank sum test. PubMed  Wang, S., Basten, C. J. GGA GGC GGG GGT. In Quantitative Trait Loci (QTL): Methods and Protocols (ed. The amino acids are color coded according to their side chain polarity with nonpolar (gold), polar (green), basic polar (blue), and acidic polar (red). “chisq.test” is a function in R language (http://www.R-project.org/) for conducting chi square tests. Cite this article. The datasets supporting the conclusions of this article are available in the NCBI website (ftp://ftp.ncbi.nih.gov/)as described in the Methods section. Plant Biotechnol. 41, 1715–1725 (2018). A synonymous mutation is when there is a change in the genetic sequence of DNA, but the change results in the same genetic output. The uniquely mapped reads were kept for downstream analysis. In wheat, the FT-B1 gene on chromosome 7B was originally reported as VRN-B3 that affects the vernalization requirement in wheat and—besides the three VRN-1 genes—that determines the spring or winter growth type of hexaploid wheat22,23. Nonsynonymous and synonymous SNPs were labeled by red and blue asterisks, respectively. Figure S5. 61, 278–295 (2019). PubMed  Wang, S. et al. We defined “mutation to monkey” as the human SNPs with reference allele identical to the mouse genome and the alternative allele identical to the monkey genome (Fig.
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