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2021 ◽  
Vol 22 (12) ◽  
pp. 6319
Author(s):  
Sulev Koks ◽  
Abigail L. Pfaff ◽  
Vivien J. Bubb ◽  
John P. Quinn

Transposable elements (TEs) are repetitive elements that belong to a variety of functional classes and have an important role in shaping genome evolution. Around 50% of the human genome contains TEs, and they have been termed the “dark matter” of the genome because relatively little is known about their function. While TEs have been shown to participate in aberrant gene regulation and the pathogenesis of diseases, only a few studies have explored the systemic effect of TEs on gene expression. In the present study, we analysed whole genome sequences and blood whole transcriptome data from 570 individuals within the Parkinson’s Progressive Markers Initiative (PPMI) cohort to identify expression quantitative trait loci (eQTL) regulating genome-wide gene expression associated with TEs. We identified 2132 reference TEs that were polymorphic for their presence or absence in our study cohort. The presence or absence of the TE element could change the expression of the gene or gene clusters from zero to tens of thousands of copies of RNA. The main finding is that many TEs possess very strong regulatory effects, and they have the potential to modulate large genetic networks with hundreds of target genes over the genome. We illustrate the plethora of regulatory mechanisms using examples of their action at the HLA gene cluster and data showing different TEs' convergence to modulate WFS1 gene expression. In conclusion, the presence or absence of polymorphisms of TEs has an eminent genome-wide regulatory function with large effect size at the level of the whole transcriptome. The role of TEs in explaining, in part, the missing heritability for complex traits is convincing and should be considered.


2021 ◽  
Author(s):  
Athanasios Zervas ◽  
Mizuki Takenaka ◽  
James H. Leebens-Mack ◽  
Ole Seberg ◽  
Gitte Petersen

The profound absence of mitochondrial complex I (NADH-ubiquinone oxidoreductase) genes from the mitogenome of Viscum spp. and the rapid rates of molecular evolution characterizing most of their remaining mitochondrial genes raise questions regarding the possible transfer of the entire nad gene set to the nucleus, as well as for the functionality of the remaining highly divergent genes. Using whole transcriptome sequencing in three species of Viscaceae: V. album, V. crassulae, and Phoradendron leucarpum we were able to confirm transcription of all previously identified genes. However, we did not detect any nad gene transcripts, thus, providing further evidence of the complete loss of complex I in Viscaceae. The results from transcriptome sequencing also revealed that levels and patterns of RNA editing were not different from those found in autotrophic plant species. Hence, RNA editing is not a means of restoring conserved domains or folding sites of the proteins coded for by the divergent mitochondrial genes. Since we were able to recover mitochondrial genes transcripts following a sequencing protocol targeted towards polyadenylated mRNA molecules, it is suggested that mitochondrial genes undergo post-transcriptional polyadenylation in Viscaceae.


PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11420
Author(s):  
Haijin Zhang ◽  
Xue Song ◽  
Zongyan Teng ◽  
Sujun Cheng ◽  
Weigang Yu ◽  
...  

Background Osteoporosis (OP) is a systemic disease with bone loss and microstructural deterioration. Numerous noncoding RNAs (ncRNAs) have been proved to participate in various diseases, especially circular RNAs (circRNAs). However, the expression profile and mechanisms underlying circRNAs in male osteoporosis have not yet been explored. Methods The whole transcriptome expression profile and differences in mRNAs, circRNAs, and microRNAs (miRNAs) were investigated in peripheral blood samples of patients with osteoporosis and healthy controls consisting of males ≥ 60-years-old. Results A total of 398 circRNAs, 51 miRNAs, and 642 mRNAs were significantly and differentially expressed in osteoporosis compared to healthy controls. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the host genes of significantly differentially expressed circRNAs were mainly enriched in the regulation of cell cycle process: biological process (BP), organelle part cellular components (CC), protein binding molecular function (MF), Toll-like receptor signaling pathway, tumor necrosis factor (TNF) signaling pathway, and thyroid hormone signaling pathway. circRNA-miRNA-mRNA regulatory network was constructed using the differentially expressed RNAs. Moreover, key circRNAs (hsa_circ_0042409) in osteoporosis were discovered and validated by qPCR. Conclusions The key cicrRNAs plays a major role in the pathogenesis of osteoporosis and could be used as potential biomarkers or targets in the diagnosis and treatment of osteoporosis.


Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 464
Author(s):  
Xiaopeng An ◽  
Yue Zhang ◽  
Fu Li ◽  
Zhanhang Wang ◽  
Shaohua Yang ◽  
...  

Estrous cycle is one of the placental mammal characteristics after sexual maturity, including estrus stage (ES) and diestrus stage (DS). Estrous cycle is important in female physiology and its disorder may lead to diseases, such as polycystic ovary syndrome, ovarian carcinoma, anxiety, and epilepsy. In the latest years, effects of non-coding RNAs and messenger RNA (mRNA) on estrous cycle have started to arouse much concern, however, a whole transcriptome analysis among non-coding RNAs and mRNA has not been reported. Here, we report a whole transcriptome analysis of goat ovary in estrus and diestrus periods. Estrus synchronization was conducted to induce the estrus phase and on day 32, the goats shifted into the diestrus stage. The ovary RNA of estrus and diestrus stages was respectively collected to perform RNA-sequencing. Then, the circular RNA (circRNA), microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA databases of goat ovary were acquired, and the differential expressions between estrus and diestrus stages were screened to construct circRNA-miRNA-mRNA/lncRNA and lncRNA-miRNA/mRNA networks, thus providing potential pathways that are involved in the regulation of estrous cycle. Differentially expressed mRNAs, such as MMP9, TIMP1, 3BHSD, and PTGIS, and differentially expressed miRNAs that play key roles in the regulation of estrous cycle, such as miR-21-3p, miR-202-3p, and miR-223-3p, were extracted from the network. Our data provided the miRNA, circRNA, lncRNA, and mRNA databases of goat ovary and each differentially expressed profile between ES and DS. Networks among differentially expressed miRNAs, circRNAs, lncRNAs, and mRNAs were constructed to provide valuable resources for the study of estrous cycle and related diseases.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 565-565
Author(s):  
Cathy Graham ◽  
Douglas Kanter Marks ◽  
Nina D'Abreo ◽  
Sami Diab ◽  
Vijayakrishna K. Gadi ◽  
...  

565 Background: Recent prospective clinical trials have demonstrated a differential chemotherapy effect based on age (≤ 50 vs. > 50 years) or menopausal status (pre- vs. post-) in a genomic low risk group. Whether this is a direct anti-tumor effect of chemotherapy or a secondary ovarian function suppression effect caused by chemotherapy is unclear. We aimed to compare the biological characteristics of breast cancer tumors from patients aged ≤ 50 years and from patients aged > 50 years using whole transcriptome analysis to provide insights into this differential chemotherapy response. Methods: The FLEX Registry (NCT03053193) enrolls stage I-III breast cancer patients who receive 70-gene signature (MammaPrint/MP) test with or without 80-gene signature (BluePrint/BP) test and consent to clinically annotated transcriptome data collection. 3868 patients with HR+HER2- tumors were evaluated, of whom 808 were aged ≤ 50 years and 3060 were aged > 50 years. Clinical risk was assessed based on the MINDACT algorithm. MP classified tumors as low risk (LR) or high risk (HR). HR was stratified to H1 or H2; H2 exhibits a greater chemotherapy response. BP and MP classified tumors as luminal A-, luminal B-, HER2-, or basal-type. Differences in MP, BP, and clinical features were assessed by chi-squared or t test. For gene expression analysis, older patients were randomly selected to obtain an equal sample size as younger patients. Differentially expressed genes (DEGs) were detected using limma and considered significant with FDR <0.05 and fold change ≥ 2. Results: Approximately 70% of patients aged ≤ 50 were pre or peri-menopausal, whereas 90% of patients aged > 50 were post-menopausal. A higher proportion of patients aged ≤ 50 had tumors of high clinical risk (54%) compared to patients aged > 50 (39%) (p < 0.001). Approximately 53% of patients aged ≤ 50 had a HR tumor, of whom 25% classified as H2, while patients aged > 50 had a lower frequency (44%) of HR tumors (p<0.001). Additionally, younger patients had more tumors that classified as BP Luminal B and Basal-type than older patients (p<0.001). Principal component analysis of the top 500 genes with the highest variance revealed no distinct clustering by age group. Accordingly, only 5 DEGs were detected in tumors from patients aged ≤ 50 compared to patients aged > 50, and even fewer DEGs were detected when adjusting for MP risk and BP subtype group. Conclusions: Whole transcriptome analysis identified no substantial differences in gene expression between tumors, including Low Risk Luminal-type tumors, from women aged ≤ 50 (mostly pre or peri-menopausal) and women aged > 50 (mostly post-menopausal). These data support the likely explanation that the observed age-dependent difference in chemotherapy benefit in women ≤ 50 or >50 years of age is not due to intrinsic biological differences in breast cancers due to age, but rather to differences in the effect of chemotherapy on the host. Clinical trial information: NCT03053193.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6083-6083
Author(s):  
Lori J. Wirth ◽  
Mimi I-Nan Hu ◽  
Steven G. Waguespack ◽  
Chrysoula Dosiou ◽  
Paul Ladenson ◽  
...  

6083 Background: Receptor tyrosine kinase (RTK) fusions may be targeted by small molecule inhibitors to treat various advanced tumors, including thyroid cancer. Clinical trials have studied selective inhibitors of ALK, BRAF, NTRK and RET, leading to several FDA-approved therapies. The Afirma Genomic Sequencing Classifier (GSC) classifies cytologically indeterminate thyroid nodules as molecularly benign or suspicious. The Xpression Atlas reports 905 genomic variants and 235 fusion pairs on GSC Suspicious, Suspicious for Malignancy (SFM), and Malignant FNA samples at the time of diagnosis. Here we report the prevalence of these fusion genes in real-world clinical practice. Methods: We analyzed anonymized data from 50,644 consecutive Bethesda III-VI nodule FNA samples submitted to the Veracyte CLIA laboratory for molecular testing using whole transcriptome RNA sequencing (RNA-Seq). Gene pairs are listed alphabetically. Results: 32,080 Bethesda III/IV nodules were classified as GSC Benign and 278 were Parathyroid Classifier positive. No ALK, BRAF, NTRK1/3, or RET fusions were identified among these samples. Among 16,594 Bethesda III/IV GSC Suspicious FNAs, 3% (n = 529) were positive for ALK, BRAF, NTRK1/3 or RET fusions. Among the 1,692 Bethesda V/VI FNAs, the proportion of positive nodules was 8% (n = 135). Among these combined cohorts of Bethesda III/IV GSC Suspicious and Bethesda V/VI, the most common gene fusions observed for each of the 5 studied RTK genes was: ETV6/NTRK3 (n = 164, 72% of NTRK3 fusions), CCDC6/RET (n = 104, 55% of RET), BRAF/SND1 (n = 32, 20% of BRAF), ALK/STRN (n = 20, 37% of ALK), and NTRK1/TPM3 (n = 14, 50% of NTRK1). BRAF showed the highest diversity of fusions, with 80 gene partners. Different gene partners with RET, ALK, NTRK1, and NTRK3 numbered 25, 11, 9, and 5 , respectively . Conclusions: Whole-transcriptome RNA-seq on small sample thyroid FNA specimens can identify clinically relevant ALK, BRAF, NTRK, and RET fusions across Bethesda categories. The prevalence ranges from 3% in Bethesda III/IV Afirma GSC Suspicious specimens to 8% among Bethesda V/VI specimens. Future studies need to determine if detection of precision medicine candidates by pre-operative FNA can optimize initial treatment, predict response to treatment, and prioritize selective targeted therapy should systemic treatment be needed.[Table: see text]


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