Meta-Analyses of Splicing and Expression Quantitative Trait Loci Identified Susceptibility Genes of Glioma

Patro, C. Pawan K.; Nousome, Darryl; Lai, Rose; Claus, Elizabeth B.; Il’yasova, Dora; Schildkraut, Joellen; Barnholtz‐Sloan, Jill S.; Bernstein, Jonine L.; Johansen, Christoffer; Jenkins, Robert B.; Melin, Beatrice; Wrensch, Margaret; Houlston, Richard S.; Bondy, Melissa L.

doi:10.3389/fgene.2021.609657

Cited by 9 publications

(4 citation statements)

References 79 publications

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“…Here we explore two major heritable mechanisms of transcriptional regulation and modification, expression-quantitative trait loci (eQTLs) and splicing-QTL (sQTLs), to elucidate the molecular basis of ecological speciation. Since transcription has substantial genetic control, eQTL, and sQTL mapping provides information about genetic variants with modular effects on gene expression ( Carroll et al 2005 ; Wittkopp and Kalay 2012 ; Ishikawa et al 2017 ; Verta and Jones 2019 ; Leal-Gutiérrez et al 2020 ; Kerimov et al 2021 ; Patro et al 2021 ), which are useful for understanding the genomic architecture and evolution of complex traits. Both eQTLs and sQTLs can be classified into cis (local) and trans (distant) effects.…”

Section: Introductionmentioning

confidence: 99%

Ecological Speciation Promoted by Divergent Regulation of Functional Genes Within African Cichlid Fishes

Carruthers

Edgley

Saxon

et al. 2022

Molecular Biology and Evolution

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Rapid ecological speciation along depth gradients has taken place repeatedly in freshwater fishes, yet molecular mechanisms facilitating such diversification are typically unclear. In Lake Masoko, an African crater lake, the cichlid Astatotilapia calliptera has diverged into shallow littoral and deep benthic ecomorphs with strikingly different jaw structures within the last 1,000 years. Using genome-wide transcriptome data, we explore two major regulatory transcriptional mechanisms, expression and splicing QTL variants, and examine their contributions to differential gene expression underpinning functional phenotypes. We identified 7,550 genes with significant differential expression between ecomorphs, of which 5.4% were regulated by cis-regulatory expression QTLs, and 9.2% were regulated by cis-regulatory splicing QTLs. We also found strong signals of divergent selection on differentially expressed genes associated with craniofacial development. These results suggest that large-scale transcriptome modification plays an important role during early-stage speciation. We conclude that regulatory-variants are important targets of selection driving ecologically-relevant divergence in gene expression during adaptive diversification.

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Section: Introductionmentioning

confidence: 99%

Ecological Speciation Promoted by Divergent Regulation of Functional Genes Within African Cichlid Fishes

Carruthers

Edgley

Saxon

et al. 2022

Molecular Biology and Evolution

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“…SNPs associated with spliced RNA are mostly found within the binding sites for RNA‐binding proteins (RBPs), which may alter the ability of RBPs to bind and interact with pre‐mRNA and other RBPs within a spliceosome. 91 A functional SNP on the 20q13.33 region in linkage disequilibrium with another SNP mapped to intron 14 of RTEL1 affects the activity of an enhancer on 20q13.33 that leads to modulated expression of multiple genes implicated in glioma risks, including RTEL1 . RTEL1 expression is modulated by this SNP in isocitrate dehydrogenase I wild‐type glioma and during early brain development but not in normal adult brain tissues.…”

Section: Rtel1 Over‐expression/activity Promotes Tumorigen...mentioning

confidence: 99%

“…The 20q13.33 genomic region including RTEL1 may mediate its risk effect in gliomagenesis by regulating the transcriptome through its multiple alternatively spliced transcripts such as exome skipping. SNPs associated with spliced RNA are mostly found within the binding sites for RNA‐binding proteins (RBPs), which may alter the ability of RBPs to bind and interact with pre‐mRNA and other RBPs within a spliceosome 91 . A functional SNP on the 20q13.33 region in linkage disequilibrium with another SNP mapped to intron 14 of RTEL1 affects the activity of an enhancer on 20q13.33 that leads to modulated expression of multiple genes implicated in glioma risks, including RTEL1 .…”

Section: Rtel1 Over‐expression/activity Promotes Tumorigenesismentioning

confidence: 99%

Regulator of telomere elongation helicase 1 gene and its association with malignancy

2022

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Background With the progression of next‐generation sequencing technologies, researchers have identified numerous variants of the regulator of telomere elongation helicase 1 ( RTEL1 ) gene that are associated with a broad spectrum of phenotypic manifestations, including malignancies. At the molecular level, RTEL1 is involved in the regulation of the repair, replication, and transcription of deoxyribonucleic acid (DNA) and the maintenance of telomere length. RTEL1 can act both as a promotor and inhibitor of tumorigenesis. Here, we review the potential mechanisms implicated in the malignant transformation of tissues under conditions of RTEL1 deficiency or its aberrant overexpression. Recent findings A major hemostatic challenge during RTEL1 dysfunction could arise from its unbalanced activity for unwinding guanine‐rich quadruplex DNA (G4‐DNA) structures. In contrast, RTEL1 deficiency leads to alterations in telomeric and genome‐wide DNA maintenance mechanisms, ribonucleoprotein metabolism, and the creation of an inflammatory and immune‐deficient microenvironment, all promoting malignancy. Additionally, we hypothesize that functionally similar molecules could act to compensate for the deteriorated functions of RTEL1 , thereby facilitating the survival of malignant cells. On the contrary, RTEL1 over‐expression was directed toward G4‐unwinding, by promoting replication fork progression and maintaining intact telomeres, may facilitate malignant transformation and proliferation of various pre‐malignant cellular compartments. Conclusions Therefore, restoring the equilibrium of RTEL1 functions could serve as a therapeutic approach for preventing and treating malignancies.

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“…Traditionally, investigators have used expression quantitative trait loci (eQTL) or alternative splicing quantitative trait loci to explain molecular mechanisms [ 16 – 17 ] . Studies demonstrated that genetic variants correlated with APA were associated with the development of multiple diseases by altering the transcript length in the 3′ UTR of the gene [ 18 ] .…”

Section: Introductionmentioning

confidence: 99%

Alternative polyadenylation-related genetic variants contribute to bladder cancer risk

Liu¹,

Gu²,

Li³

et al. 2023

J Biomed Res

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Aberrant alternative polyadenylation (APA) events play an important role in cancers, but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer. Previous genome-wide association study performed APA quantitative trait loci (apaQTL) analyses in bladder cancer, and identified 17 955 single nucleotide polymorphisms (SNPs). We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-associated SNPs rs34402449 C>A, rs2683524 C>T, and rs11540872 C>G were significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% confidence interval [CI]: 1.159–1.583, P = 1.33 × 10 −4 ; rs2683524: OR = 1.378, 95% CI: 1.164–1.632, P = 2.03 × 10 −4 ; rs11540872: OR = 1.472, 95% CI: 1.193–1.815, P = 3.06 × 10 −4 ). Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer ( P trend = 2.87 × 10 −12 ). We found that PRR13 , being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines, was more highly expressed in bladder cancer tissues than in adjacent normal tissues. Moreover, the rs2683524 T allele was correlated with shorter 3′ untranslated regions of PRR13 and increased PRR13 expression levels. Collectively, our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.

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Meta-Analyses of Splicing and Expression Quantitative Trait Loci Identified Susceptibility Genes of Glioma

Cited by 9 publications

References 79 publications

Ecological Speciation Promoted by Divergent Regulation of Functional Genes Within African Cichlid Fishes

Ecological Speciation Promoted by Divergent Regulation of Functional Genes Within African Cichlid Fishes

Regulator of telomere elongation helicase 1 gene and its association with malignancy

Alternative polyadenylation-related genetic variants contribute to bladder cancer risk

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