A pan-cancer analysis of synonymous mutations

Sharma, Yogita; Miladi, Milad; Dukare, Sandeep; Boulay, Karine; Caudron-Herger, Maïwen; Groß, Matthias; Backofen, Rolf; Diederichs, Sven

doi:10.1038/s41467-019-10489-2

Cited by 156 publications

(109 citation statements)

References 70 publications

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“…The impact of allelic variants can be determined by analyzing the position and LD block of the associated SNP within an lncRNA sequence; SNPs not only affect gene expression, but they also influence secondary structure (Castellanos-Rubio and Ghosh, 2019). In addition, a previous study demonstrated that a single SNP could alter RNA conformation (Sharma et al, 2019). A similar behavior has been observed for haplotype blocks, the majority of which influence secondary structures of lncRNA transcripts.…”

Section: Discussionsupporting

confidence: 67%

Detection of Allosteric Effects of lncRNA Secondary Structures Altered by SNPs in Human Diseases

Ding

Bai

et al. 2020

Front. Cell Dev. Biol.

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Recent studies have shown that structuralized long non-coding RNAs (lncRNAs) play important roles in genetic and epigenetic processes. The spatial structures of most lncRNAs can be altered by distinct in vivo and in vitro cellular environments, as well as by DNA structural variations, such as single-nucleotide polymorphisms (SNPs) and variants (SNVs). In the present study, we extended candidate SNPs that had linkage disequilibria with those significantly associated with lung diseases in genome-wide association studies in order to investigate potential disease mechanisms originating from SNP structural changes of host lncRNAs. Following accurate alignments, we recognized 115 ternary-relationship pairs among 41 SNPs, 10 lncRNA transcripts, and 1 type of lung disease (adenocarcinoma of the lung). Then, we evaluated the structural heterogeneity induced by SNP alleles by developing a local-RNA-structure alignment algorithm and employing randomized strategies to determine the significance of structural variation. We identified four ternary-relationship pairs that were significantly associated with SNPinduced lncRNA allosteric effects. Moreover, these conformational changes disrupted the interactive regions and binding affinities of lncRNA-HCG23 and TF-E2F6, suggesting that these may represent regulatory mechanisms in lung diseases. Taken together, our findings support that SNP-induced changes in lncRNA conformations regulate many biological processes, providing novel insight into the role of the lncRNA "structurome" in human diseases.

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Section: Discussionsupporting

confidence: 67%

Detection of Allosteric Effects of lncRNA Secondary Structures Altered by SNPs in Human Diseases

Ding

Bai

et al. 2020

Front. Cell Dev. Biol.

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“…We thus conclude that these NF1 variants classified as synonymous very likely do have downstream transcriptomic effects aligned with those of active NF1 mutations. Although this finding contradicts the intuition that so-called silent mutations should not imbue significant downstream impacts, it is less surprising in light of prior work demonstrating that these mutations can indeed enact non-trivial effects on splicing, transcript folding/stability, translational rates, co-translational folding/stability, and degradation 53,54 . Although NF1 splice mutations are often mistaken for silent mutations by sequencing methods 55,56 , evidence that synonymous mutations of the NF1 gene are selected in cancers such as T-cell acute lymphoblastic leukemia 57 signals a need for more research in this area.…”

Section: Subgroupings Outperform Mutation Subsets Chosen Using Varianmentioning

confidence: 55%

Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

Grzadkowski

Manning

Somers

et al. 2020

Preprint

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6Genes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor 7 cohorts within which they are frequently mutated. We sought to identify the downstream expres-8 sion effects of these perturbations and to find whether or not this heterogeneity at the genomic 9 level is reflected in a corresponding heterogeneity at the transcriptomic level. Applying a novel 10 hierarchical framework for organizing the mutations present in a cohort along with machine learn-11 ing pipelines trained on sample expression profiles we systematically interrogated the signatures 12 associated with combinations of perturbations recurrent in cancer. This allowed us to catalogue 13 the mutations with discernible downstream expression effects across a number of tumor cohorts 14 as well as to uncover and characterize a multitude of cases where subsets of a genes mutations are 15 clearly divergent in their function from the remaining mutations of the gene. 16 Each tumor faces a common set of obstacles arising from internal dynamics and external de-18 fense mechanisms 1 . Tumor cohorts, however, are replete with diverse yet recurrent tactics for 19 overcoming these shared obstacles. Tumorigenesis can thus be perceived as a landscape within 20 which each tumor navigates a unique, multidimensional path, weaving between segments trodden 21 by other tumors. A number of the early breakthroughs in cancer treatment directly resulted from 22 coarse demarcations of these paths into distinct subtypes based on "landmarks"-usually defined 23 by mutations and/or markers derived from proteomic or transcriptomic data-that were then used 24 to engineer subtype-specific treatments [2][3][4] . 25 Although these biomarker-based treatment matching criteria have proven effective in some 26 precision medicine applications, there is a sizable subset of patients whose tumors harbor no dis-27 cernible drug targets, thus diminishing their likelihood of successful treatment and survival [5][6][7][8] . 28 Developing a more thorough understanding of the downstream effects of landmark events could 29 therefore improve tailored treatment design outcomes. In particular, we envision a tactic which de-30 tects whether two genomic alterations (or combinations thereof) have a shared downstream effect, 31 and can therefore be grouped together when weighing treatment options. This type of approach 32 should also be able to detect whether two such alterations or groupings result in divergent tran-33 scriptional programs and can therefore be considered distinct. Despite recent efforts to profile the 34 downstream effects of mutations recurrent in cancer, for most mutations we still know little about 35 the programs they trigger. As a result, most clinical guidelines depend on only a limited sub-36 set of specific perturbations within a gene or on other coarse biomarker-based demarcations 9,10 . 37A clearer discernment of the convergences and divergences between the downstream programs 38 present within cancer genes is thus a crucial prerequisi...

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“…The g.727C > T mutation of the LHβ gene identified in this study is also a synonymous mutation. Nonetheless, recent studies suggest synonymous mutations can change protein levels or protein conformation by altering regulatory splice sites, mRNA stability, miRNA binding sites, or translation efficiency [29]. To further investigate the effect of this synonymous mutation on sheep phenotype, we analyzed the potential association between genotype and litter size.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization and Expression Profiles of the Ovine LHβ Gene and Its Association with Litter Size in Chinese Indigenous Small-Tailed Han Sheep

Wang

et al. 2020

Animals

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The luteinizing hormone beta polypeptide (LHβ) is a glycoprotein hormone secreted by basophilic granular cells of the adenohypophysis, and plays an important role in mammalian follicular development. In this study, we cloned and analyzed the cDNA sequence of the ovine LHβ gene. RT-qPCR analysis showed that ovine LHβ was widely expressed in tissues, with significantly higher expression in the hypophysis than that in other tissues (heart, liver, spleen, lung, kidney, rumen, duodenum, muscle, fat, hypothalamus, and sex glands) (p < 0.01). Hypophyseal expression of LHβ mRNA in lamb increased with age and reached a peak at 70 days, although a slight decrease was observed at 84 days of age. In addition, the synonymous mutation g.727C > T detected in the LHβ gene was confirmed to be significantly associated with the litter size (p < 0.01). Ewes carrying the TT genotype produced more lambs than those carrying the TC and CC genotypes (0.42 and 0.39 per delivery, respectively; p < 0.05). Our results confirm the association of ovine LHβ with litter size in Small-Tailed Han Sheep and implicate LHβ as a candidate for improving reproductive traits in agricultural sheep breeding programs.

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A pan-cancer analysis of synonymous mutations

Cited by 156 publications

References 70 publications

Detection of Allosteric Effects of lncRNA Secondary Structures Altered by SNPs in Human Diseases

Detection of Allosteric Effects of lncRNA Secondary Structures Altered by SNPs in Human Diseases

Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

Molecular Characterization and Expression Profiles of the Ovine LHβ Gene and Its Association with Litter Size in Chinese Indigenous Small-Tailed Han Sheep

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