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Deep intronic NIPBL de novo mutations and differential diagnoses revealed by whole genome and RNA sequencing in Cornelia de Lange syndrome patients

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HUMAN MUTATION 2022年第12期43卷 1882-1897页

作者： Coursimault, Juliette Cassinari, Kevin Lecoquierre, Francois Quenez, Olivier Coutant, Sophie Derambure, Celine Vezain, Myriam Drouot, Nathalie Vera, Gabriella Schaefer, Elise Philippe, Anais Doray, Berenice Lambert, Laetitia Ghoumid, Jamal Smol, Thomas Rama, Melanie Legendre, Marine Lacombe, Didier Fergelot, Patricia Olaso, Robert Boland, Anne Deleuze, Jean-Francois Goldenberg, Alice Saugier-Veber, Pascale Nicolas, Gael Normandie Univ UNIROUEN Inserm U1245 F-76000 Rouen France CHU Rouen Dept Genet F-76000 Rouen France Reference Ctr Dev Disorders FHU G4 Genom F-76000 Rouen France Hop Univ Strasbourg Inst Genet Med Alsace IGMA Serv Genet Med Strasbourg France Ctr Hosp Univ Felix Guyon Serv Genet Med Bellepierre St Denis France CHRU Nancy Serv Genet Clin F-54000 Nancy France UMR INSERM U 1256 N GERE F-54000 Nancy France Univ Lille CHU Lille ULR7364 RADEME Clin Genet Guy Fontaine F-59000 Lille France Univ Lille FHU G4 Genom F-59000 Lille France Univ Lille CHU Lille ULR7364 RADEME Inst Genet Med F-59000 Lille France CHU Lille Inst Genet Med Lille France CHU Bordeaux Serv Genet Med Bordeaux France Univ Bordeaux INSERM U1211 Bordeaux France CHU Bordeaux Genet Med Bordeaux France Univ Paris Saclay CEA Ctr Natl Rech Genom Humaine CNRGH F-91057 Evry France

Cornelia de Lange syndrome (CdLS;MIM# 122470) is a rare developmental disorder. Pathogenic variants in 5 genes explain approximately 50% cases, leaving the other 50% unsolved. We performed whole genome sequencing (WGS) +/- RNA sequencing (RNA-seq) in 5 unsolved trios fulfilling the following criteria: (i) clinical diagnosis of classic CdLS, (ii) negative gene panel sequencing from blood and saliva-isolated DNA, (iii) unaffected parents' DNA samples available and (iv) proband's blood-isolated RNA available. A pathogenic de novo mutation (DNM) was observed in a CdLS differential diagnosis gene in 3/5 patients, namely POU3F3, SPEN, and TAF1. In the other two, we identified two distinct deep intronic DNM in NIPBL predicted to create a novel splice site. RT-PCRs and RNA-Seq showed aberrant transcripts leading to the creation of a novel frameshift exon. Our findings suggest the relevance of WGS in unsolved suspected CdLS cases and that deep intronic variants may account for a proportion of them.

关键词： clustered mutations Cornelia de Lange syndrome kataegis neurodevelopmental disorder NIPBL noncoding sequence whole genome sequencing

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Effect of Different Types of sequence Data on Palaeognath Phylogeny

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GENOME BIOLOGY AND EVOLUTION 2023年第6期15卷 evad092页

作者： Takezaki, Naoko Kagawa Univ Fac Med Lab Life Sci Takamatsu Kagawa Japan

Palaeognathae consists of five groups of extant species: flighted tinamous (1) and four flightless groups: kiwi (2), cassowaries and emu (3), rheas (4), and ostriches (5). Molecular studies supported the groupings of extinct moas with tinamous and elephant birds with kiwi as well as ostriches as the group that diverged first among the five groups. However, phylogenetic relationships among the five groups are still controversial. Previous studies showed extensive heterogeneity in estimated gene tree topologies from conserved nonexonic elements, introns, and ultraconserved elements. Using the noncoding loci together with protein-coding loci, this study investigated the factors that affected gene tree estimation error and the relationships among the five groups. Using closely related ostrich rather than distantly related chicken as the outgroup, concatenated and gene tree-based approaches supported rheas as the group that diverged first among groups (1)-(4). Whereas gene tree estimation error increased using loci with low sequence divergence and short length, topological bias in estimated trees occurred using loci with high sequence divergence and/or nucleotide composition bias and heterogeneity, which more occurred in trees estimated from coding loci than noncoding loci. Regarding the relationships of (1)-(4), the site patterns by parsimony criterion appeared less susceptible to the bias than tree construction assuming stationary time-homogeneous model and suggested the clustering of kiwi and cassowaries and emu the most likely with similar to 40% support rather than the clustering of kiwi and rheas and that of kiwi and tinamous with 30% support each.

关键词： coding sequence noncoding sequence outgroup nucleotide composition RY-coding gene tree

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Mechanisms suppressing noncoding translation

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Trends in Cell Biology 2024年

作者： Kesner, Jordan S. Wu, Xuebing Department of Medicine Columbia University Irving Medical Center New York 10032 NY United States Department of Systems Biology Columbia University Irving Medical Center New York 10032 NY United States

The majority of the DNA sequence in our genome is noncoding and not intended for synthesizing proteins. Nonetheless, genome-wide mapping of ribosome footprints has revealed widespread translation in annotated noncoding sequences, including long noncoding RNAs (lncRNAs), untranslated regions (UTRs), and introns of mRNAs. How cells suppress the translation of potentially toxic proteins from various noncoding sequences remains poorly understood. This review summarizes mechanisms for the mitigation of noncoding translation, including the BCL2-associated athanogene 6 (BAG6)-mediated proteasomal degradation pathway, which has emerged as a unifying mechanism to suppress the translation of diverse noncoding sequences in metazoan cells. © 2024 Elsevier Ltd

关键词： BAG6 noncoding sequence noncoding translation protein quality control ribosome

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Mapping inherited and somatic variation in regulatory DNA: new roadmap for common disease clinical discoveries

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EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 2013年第6期13卷 519-522页

作者： Roukos, Dimitrios H. Baltogiannis, Giannis G. Baltogiannis, George Univ Ioannina Ctr Biosyst & Genom Network Med GR-45110 Ioannina Greece Univ Ioannina Dept Cardiol GR-45110 Ioannina Greece Univ Ioannina Dept Surg GR-45110 Ioannina Greece

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关键词： common disease disease genetic variation genetics genome mapping networks genomics noncoding sequence regulatory DBA somatic mutations transcription factors

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noncoding sequences Near Duplicated Genes Evolve Rapidly

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GENOME BIOLOGY AND EVOLUTION 2010年第0期2卷 518-533页

作者： Kostka, Dennis Hahn, Matthew W. Pollard, Katherine S. Univ Calif San Francisco Gladstone Inst Gladstone Inst Cardiovasc Dis San Francisco CA 94143 USA Indiana Univ Dept Biol Bloomington IN 47405 USA Indiana Univ Sch Informat & Comp Bloomington IN 47405 USA Univ Calif San Francisco Inst Human Genet San Francisco CA 94143 USA Univ Calif San Francisco Div Biostat San Francisco CA 94143 USA

Gene expression divergence and chromosomal rearrangements have been put forward as major contributors to phenotypic differences between closely related species. It has also been established that duplicated genes show enhanced rates of positive selection in their amino acid sequences. If functional divergence is largely due to changes in gene expression, it follows that regulatory sequences in duplicated loci should also evolve rapidly. To investigate this hypothesis, we performed likelihood ratio tests (LRTs) on all noncoding loci within 5 kb of every transcript in the human genome and identified sequences with increased substitution rates in the human lineage since divergence from Old World Monkeys. The fraction of rapidly evolving loci is significantly higher nearby genes that duplicated in the common ancestor of humans and chimps compared with nonduplicated genes. We also conducted a genome-wide scan for nucleotide substitutions predicted to affect transcription factor binding. Rates of binding site divergence are elevated in noncoding sequences of duplicated loci with accelerated substitution rates. Many of the genes associated with these fast-evolving genomic elements belong to functional categories identified in previous studies of positive selection on amino acid sequences. In addition, we find enrichment for accelerated evolution nearby genes involved in establishment and maintenance of pregnancy, processes that differ significantly between humans and monkeys. Our findings support the hypothesis that adaptive evolution of the regulation of duplicated genes has played a significant role in human evolution.

关键词： accelerated substitution noncoding sequence gene duplication

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ReAlignerV: Web-based genomic alignment tool with high specificity and robustness estimated by species-specific insertion sequences

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BMC BIOINFORMATICS 2008年第1期9卷 112-112页

作者： Iwana, Hisakazu Hori, Yukio Matsumoto, Kensuke Murao, Koji Ishida, Toshihiko Kagawa Univ Life Sci Res Ctr Kagawa 7610793 Japan Kagawa Univ Fac Med Kagawa 7610793 Japan Kagawa Univ Ctr Informat Technol Saiwai Cho Branch Off Takamatsu Kagawa 7608521 Japan Kagawa Univ Fac Med Dept Internal Med Div Endocrinol & Metab Kagawa 7610793 Japan

Background: Detecting conserved noncoding sequences (CNSs) across species highlights the functional elements. Alignment procedures combined with computational prediction of transcription factor binding sites (TFBSs) can narrow down key regulatory elements. Repeat masking processes are often performed before alignment to mask insertion sequences such as transposable elements (TEs). However, recently such TEs have been reported to influence the gene regulatory network evolution. Therefore, an alignment approach that is robust to TE insertions is meaningful for finding novel conserved TFBSs in TEs. Results: We constructed a web server 'ReAlignerV' for complex alignment of genomic sequences. ReAlignerV returns ladder-like schematic alignments that integrate predicted TFBSs and the location of TEs. It also provides pair-wise alignments in which the predicted TFBS sites and their names are shown alongside each sequence. Furthermore, we evaluated false positive aligned sites by focusing on the species-specific TEs (SSTEs), and found that ReAlignerV has a higher specificity and robustness to insertions for sequences having more than 20% TE content, compared to LAGAN, AVID, MAVID and BLASTZ. Conclusion: ReAlignerV can be applied successfully to TE-insertion-rich sequences without prior repeat masking, and this increases the chances of finding regulatory sequences hidden in TEs, which are important sources of the regulatory network evolution. ReAlignerV can be accessed through and downloaded from http://***/.

关键词： Translation Start Site noncoding sequence Alignment Procedure Significance Index Short Intersperse Nuclear Element

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Genome-wide identification of coding and non-coding conserved sequence tags in human and mouse genomes

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BMC GENOMICS 2008年第1期9卷 277-277页

作者： Mignone, Flavio Anselmo, Anna Donvito, Giacinto Maggi, Giorgio P. Grillo, Giorgio Pesole, Graziano Univ Milan Dept Struct Chem & Inorgan Stereochem Sch Pharm I-20122 Milan Italy Univ Milan Dept Biomol Sci & Biotechnol I-20122 Milan Italy Natl Inst Nucl Phys Bari Italy CNR Ist Tecnol Biomed Bari Italy Univ Bari Dipartmento Biochim & Biol Mol I-70121 Bari Italy

Background: The accurate detection of genes and the identification of functional regions is still an open issue in the annotation of genomic sequences. This problem affects new genomes but also those of very well studied organisms such as human and mouse where, despite the great efforts, the inventory of genes and regulatory regions is far from complete. Comparative genomics is an effective approach to address this problem. Unfortunately it is limited by the computational requirements needed to perform genome-wide comparisons and by the problem of discriminating between conserved coding and non-coding sequences. This discrimination is often based (thus dependent) on the availability of annotated proteins. Results: In this paper we present the results of a comprehensive comparison of human and mouse genomes performed with a new high throughput grid-based system which allows the rapid detection of conserved sequences and accurate assessment of their coding potential. By detecting clusters of coding conserved sequences the system is also suitable to accurately identify potential gene loci. Following this analysis we created a collection of human-mouse conserved sequence tags and carefully compared our results to reliable annotations in order to benchmark the reliability of our classifications. Strikingly we were able to detect several potential gene loci supported by EST sequences but not corresponding to as yet annotated genes. Conclusion: Here we present a new system which allows comprehensive comparison of genomes to detect conserved coding and non-coding sequences and the identification of potential gene loci. Our system does not require the availability of any annotated sequence thus is suitable for the analysis of new or poorly annotated genomes.

关键词： Mouse Genome noncoding sequence Annotate Protein High Score Segment Pair Unannotated Gene

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RNA expression in a cartilaginous fish cell line reveals ancient 3′ noncoding regions highly conserved in vertebrates

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2007年第4期104卷 1224-1229页

作者： Forest, David Nishikawa, Ryuhei Kobayashi, Hiroshi Parton, Angela Bayne, Christopher J. Barnes, David W. Mt Desert Isl Biol Lab Salsbury Cove ME 04672 USA

We have established a cartilaginous fish cell line [Squalus acanthias embryo cell line (SAE)], a mesenchymal stem cell line derived from the embryo of an elasmobranch, the spiny dogfish shark S. acanthias. Elasmobranchs (sharks and rays) first appeared > 400 million years ago, and existing species provide useful models for comparative vertebrate cell biology, physiology, and genomics. Comparative vertebrate genomics among evolutionarily distant organisms can provide sequence conservation information that facilitates identification of critical coding and noncoding regions. Although these genomic analyses are informative, experimental verification of functions of genomic sequences depends heavily on cell culture approaches. Using ESTs defining mRNAs derived from the SAE cell line, we identified lengthy and highly conserved gene-specific nucleotide sequences in the noncoding 3' UTRs of eight genes involved in the regulation of cell growth and proliferation. Conserved noncoding 3' mRNA regions detected by using the shark nucleotide sequences as a starting point were found in a range of other vertebrate orders, including bony fish, birds, amphibians, and mammals. Nucleotide identity of shark and human in these regions was remarkably well conserved. Our results indicate that highly conserved gene sequences dating from the appearance of jawed vertebrates and representing potential cis-regulatory elements can be identified through the use of cartilaginous fish as a baseline. Because the expression of genes in the SAE cell line was prerequisite for their identification, this cartilaginous fish culture system also provides a physiologically valid tool to test functional hypotheses on the role of these ancient conserved sequences in comparative cell biology.

关键词： noncoding sequence sequence conservation Squalus acanthias

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A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud

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GENOMICS 2007年第2期89卷 207-214页

作者： Masuya, Hiroshi Sezutsu, Hideki Sakuraba, Yoshiyuki Sagai, Tomoko Hosoya, Masaki Kaneda, Hideki Miura, Ikuo Kobayashi, Kimio Sumiyama, Kenta Shimizu, Aya Nagano, Junko Yokoyama, Haruka Kaneko, Satoko Sakurai, Noriko Okagaki, Yuka Noda, Tetsuo Wakana, Shigeharu Gondo, Yoichi Shiroishi, Toshihiko RIKEN Mouse Funct Genom Res Grp GSC Tsukuba Ibaraki 3050074 Japan RIKEN Populat & Quantitat Genom Team GSC Tsurumi Ku Yokohama Kanagawa 2300045 Japan Natl Inst Genet Mammalian Genet Lab Mishima Shizuoka 4118540 Japan Natl Inst Genet Div Populat Genet Mishima Shizuoka 4118540 Japan

Mammal-fish-conserved-sequence 1 (MFCS1) is a highly conserved sequence that acts as a limb-specific cis-acting regulator of Sonic hedgehog (Shh) expression, residing 1 Mb away from the Shh coding sequence in mouse. Using gene-driven screening of an ENU-mutagenized mouse archive, we obtained mice with three new point mutations in MFCS 1: M101116, M10111 7, and M101192. Phenotype analysis revealed that M101116 mice exhibit preaxial polydactyly and ectopic Shh expression at the anterior margin of the limb buds like a previously identified mutant, M100081. In contrast, M10111 7 and M101192 show no marked abnon-nalities in limb morphology. Furthermore, transgenic analysis revealed that the M101116 and MI00081 sequences drive ectopic reporter gene expression at the anterior margin of the limb bud, in addition to the normal posterior expression. Such ectopic expression was not observed in the embryos carrying a reporter transgeDe driven by M101117. These results suggest that M101116 and M100081 affect the negative regulatory activity of MFCSI, which suppresses anterior Shh expression in developing limb buds. Thus, this study shows that gene-driven screening for ENU-induced mutations is an effective approach for exploring the function of conserved, noncoding sequences and potential cis-regulatory elements. (c) 2006 Elsevier Inc. All rights reserved.

关键词： cis-regulatory element MFCS1 sonic hedgehog noncoding sequence ENU mutagenesis single nucleotide polymorphism limb development axis formation

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Patterns of selective constraints in noncoding DNA of rice

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BMC EVOLUTIONARY BIOLOGY 2007年第1期7卷 208-208页

作者： Guo, Xingyi Wang, Yu Keightley, Peter D. Fan, Longjiang Zhejiang Univ Inst Crop Sci Hangzhou 310029 Peoples R China Zhejiang Univ Inst Bioinformat Hangzhou 310029 Peoples R China Univ Edinburgh Inst Evolut Biol Edinburgh EH9 3JT Midlothian Scotland

Background: Several studies have investigated the relationships between selective constraints in introns and their length, GC content and location within genes. To date, however, no such investigation has been done in plants. Studies of selective constraints in noncoding DNA have generally involved interspecific comparisons, under the assumption of the same selective pressures acting in each lineage. Such comparisons are limited to cases in which the noncoding sequences are not too strongly diverged so that reliable sequence alignments can be obtained. Here, we investigate selective constraints in a recent segmental duplication that includes 605 paralogous intron pairs that occurred about 7 million years ago in rice (O. sativa). Results: Our principal findings are: (1) intronic divergence is negatively correlated with intron length, a pattern that has previously been described in Drosophila and mammals;(2) there is a signature of strong purifying selection at splice control sites;(3) first introns are significantly longer and have a higher GC content than other introns;(4) the divergences of first and non-first introns are not significantly different from one another, a pattern that differs from Drosophila and mammals;and (5) short introns are more diverged than four-fold degenerate sites suggesting that selection reduces divergence at four-fold sites. Conclusion: Our observation of stronger selective constraints in long introns suggests that functional elements subject to purifying selection may be concentrated within long introns. Our results are consistent with the presence of strong purifying selection at splicing control sites. Selective constraints are not significantly stronger in first introns of rice, as they are in other species.

关键词： Selective Constraint Evolutionary Constraint Intron Length noncoding sequence Ordinal Position

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