Divergence of exonic splicing elements after gene duplication and the impact on gene structures

An analysis of human exonic splicing elements in duplicated genes reveals their important role in the generation of new gene structures

Dosage compensation on the active X chromosome minimizes transcriptional noise of X-linked genes in mammals

Comparison of gene expression variation in autosomal and X-linked genes reveals that high transcriptional noise is not a necessary consequence of haploid expression

Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay

<p>Abstract</p> <p>Background</p> <p>Nonsense-mediated decay is a mechanism that degrades mRNAs with a premature termination codon. That some exons have premature termination codons at fixation is paradoxical: why make a transcript if it is only to be destroyed? One model supposes that splicing is inherently noisy and spurious transcripts are common. The evolution of a premature termination codon in a regularly made unwanted transcript can be a means to prevent costly translation. Alternatively, nonsense-mediated decay can be regulated under certain conditions so the presence of a premature termination codon can be a means to up-regulate transcripts needed when nonsense-mediated decay is suppressed.</p> <p>Results</p> <p>To resolve this issue we examined the properties of putative nonsense-mediated decay targets in humans and mice. We started with a well-annotated set of protein coding genes and found that 2 to 4% of genes are probably subject to nonsense-mediated decay, and that the premature termination codon reflects neither rare mutations nor sequencing artefacts. Several lines of evidence suggested that the noisy splicing model has considerable relevance: 1) exons that are uniquely found in nonsense-mediated decay transcripts (nonsense-mediated decay-specific exons) tend to be newly created; 2) have low-inclusion level; 3) tend not to be a multiple of three long; 4) belong to genes with multiple splice isoforms more often than expected; and 5) these genes are not obviously enriched for any functional class nor conserved as nonsense-mediated decay candidates in other species. However, nonsense-mediated decay-specific exons for which distant orthologous exons can be found tend to have been under purifying selection, consistent with the regulation model.</p> <p>Conclusion</p> <p>We conclude that for recently evolved exons the noisy splicing model is the better explanation of their properties, while for ancient exons the nonsense-mediated decay regulated gene expression is a viable explanation.</p

Evidence for common short natural trans sense-antisense pairing between transcripts from protein coding genes

A computational prediction of human coding RNA trans short sense-antisense pairs suggests that mRNA regulation by other coding transcripts might be a common occurrence

Removal of Hsf4 leads to cataract development in mice through down-regulation of γS-crystallin and Bfsp expression

<p>Abstract</p> <p>Background</p> <p>Heat-shock transcription factor 4 (HSF4) mutations are associated with autosomal dominant lamellar cataract and Marner cataract. Disruptions of the <it>Hsf4 </it>gene cause lens defects in mice, indicating a requirement for HSF4 in fiber cell differentiation during lens development. However, neither the relationship between HSF4 and crystallins nor the detailed mechanism of maintenance of lens transparency by HSF4 is fully understood.</p> <p>Results</p> <p>In an attempt to determine how the underlying biomedical and physiological mechanisms resulting from loss of HSF4 contribute to cataract formation, we generated an <it>Hsf4 </it>knockout mouse model. We showed that the <it>Hsf4 </it>knockout mouse (<it>Hsf4</it>^-/-) partially mimics the human cataract caused by HSF4 mutations. Q-PCR analysis revealed down-regulation of several cataract-relevant genes, including <it>γS-crystallin (Crygs) </it>and lens-specific beaded filament proteins 1 and 2 (<it>Bfsp1 </it>and <it>Bfsp2</it>), in the lens of the <it>Hsf4</it>^-/-mouse. Transcription activity analysis using the dual-luciferase system suggested that these cataract-relevant genes are the direct downstream targets of HSF4. The effect of HSF4 on <it>γS-crystallin </it>is exemplified by the cataractogenesis seen in the <it>Hsf4</it>^-/-,<it>rncat </it>intercross. The 2D electrophoretic analysis of whole-lens lysates revealed a different expression pattern in 8-week-old <it>Hsf4</it>^-/-mice compared with their wild-type counterparts, including the loss of some αA-crystallin modifications and reduced expression of γ-crystallin proteins.</p> <p>Conclusion</p> <p>Our results indicate that HSF4 is sufficiently important to lens development and disruption of the <it>Hsf4 </it>gene leads to cataracts via at least three pathways: 1) down-regulation of <it>γ-crystallin</it>, particularly <it>γS-crystallin</it>; 2) decreased lens beaded filament expression; and 3) loss of post-translational modification of αA-crystallin.</p

Nonsense‐mediated decay targets have multiple sequence‐related features that can inhibit translation

Nonsense-mediated mRNA decay (NMD) is a surveillance system that eliminates transcripts with premature termination codons. In this study, we show that mRNAs targeted by NMD are also suppressed at the translational level. The low translational efficiency (TE) is a consequence of multiple features acting in concert, including low translation initiation rate, mediated by 5′ secondary structure and by use of weak initiation sites, and low translation elongation speed, mediated by low codon usage bias. Despite low elongation rates, NMD transcripts show low ribosome density in the coding sequence, probably owing to low initiation rates, high abortion rates or rapid transit of the ribosome following initiation failure. The low TE is observed in the absence of NMD and is not explained by low transcript abundance. Translational inefficiency is flexible, such that NMD targets have increased TE upon starvation. We propose that the low TE predisposes to NMD and/or that it is part of a mechanism for regulation of NMD transcripts

Alternative Promoters Influence Alternative Splicing at the Genomic Level

Background: More and more experiments have shown that transcription and mRNA processing are not two independent events but are tightly coupled to each other. Both promoter and transcription rate were found to influence alternative splicing. More than half of human genes have alternative promoters, but it is still not clear why there are so many alternative promoters and what their biological roles are. Methodology/Principal Findings: In this study, we explored whether there is a functional correlation between alternative promoters and alternative splicing by a genome-wide analysis of human and mouse genes. We constructed a large data set of genes with alternative promoter and alternative splicing annotations. By analyzing these genes, we showed that genes with alternative promoters tended to demonstrate alternative splicing compare to genes with single promoter, and, genes with more alternative promoters tend to have more alternative splicing variants. Furthermore, transcripts from different alternative promoters tended to splice differently. Conclusions/Significance: Thus at the genomic level, alternative promoters are positively correlated with alternativ

Novel Association Strategy with Copy Number Variation for Identifying New Risk Loci of Human Diseases

Copy number variations (CNV) are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.Here, we developed a novel integrated strategy to test CNV-association in genome-wide case-control studies. We converted the single-nucleotide polymorphism (SNP) signal to copy number states using a well-trained hidden Markov model. We mapped the susceptible CNV-loci through SNP site-specific testing to cope with the physiological complexity of CNVs. We also ensured the credibility of the associated CNVs through further window-based CNV-pattern clustering. Genome-wide data with seven diseases were used to test our strategy and, in total, we identified 36 new susceptible loci that are associated with CNVs for the seven diseases: 5 with bipolar disorder, 4 with coronary artery disease, 1 with Crohn's disease, 7 with hypertension, 9 with rheumatoid arthritis, 7 with type 1 diabetes and 3 with type 2 diabetes. Fifteen of these identified loci were validated through genotype-association and physiological function from previous studies, which provide further confidence for our results. Notably, the genes associated with bipolar disorder converged in the phosphoinositide/calcium signaling, a well-known affected pathway in bipolar disorder, which further supports that CNVs have impact on bipolar disorder.Our results demonstrated the effectiveness and robustness of our CNV-association analysis and provided an alternative avenue for discovering new associated loci of human diseases