Genome Wide-DNA Profiling of Richter’s Syndrome-Diffuse Large B-Cell Lymphoma (RS-DLBCL): Differences with De Novo DLBCL and Possible Mechanisms of Transformation from Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2067-2067
Author(s):  
Francesco Bertoni ◽  
Marta Scandurra ◽  
Michaela Cerri ◽  
Clara Deambrogi ◽  
Paola MV Rancoita ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Dna Profiling ◽  
Lymphocytic Leukemia ◽  
Chromosome 12 ◽  
Chromosome 13 ◽  
Genome Wide ◽  
A Genome ◽  
Igh Rearrangement

Abstract Up to 1/5 of newly diagnosed CLL transform to an aggressive RS-DLBCL. The mechanisms underlying the event are very poorly defined. RS-DLBCL is often clonally related to CLL, as shown by the identity of their IgH rearrangement. Deletion of 13q14.3 is the most common lesion in unselected CLL. Notably, CLL cases showing no chromosome 13q14.3 deletion at diagnosis face a higher risk of transformation, while CLL samples with 13q14.3 deletion do not preserve the 13q deletion in the subclone transformed into RSDLBCL. With the aim of understanding the molecular mechanisms of the transformation from CLL to RS-DLBCL, we have performed a genome wide-DNA profiling. Samples derived from 12 patients were analyzed: 13 samples of RS-DLBCL and 8 matched CLL. In one patient, 2 separate RS-DLBCL sites were analyzed. For comparative purposes, 48 de novo DLBCL cases were also investigated. Tumor samples were analyzed with Affymetrix Human Mapping 250K SNP arrays, starting from frozen biopsies. IgH sequencing and multiple FISH analyzes were also performed. Samples were obtained in the course of routine diagnostics. RS-CLL samples were collected at the time of first diagnosis. The fraction of malignant cells in the pathologic specimen was >70%, as determined by morphologic and immunophenotypic studies. Chromosome 13 gains represented the only recurrent change in 2/8 clonally related CLL and DLBCL samples. RS-DLBCL presented recurrent gains at 1q44, 2p, 3q28, 4q35, 5p15-pter, 7q11-q21, 8q13-qter, 9q22, 13q14-q33, 14q32, 15q21-qter, 18q21-qter, 20q13-q13, 21q22. The whole chromosome 12 was gained in two cases and interstitial gains were observed on both arms of chromosome 7. Recurrent losses affected 1p36, 1q32, 3q28, 4p16, 4q24, 6q25, 7q11, 7q31-qter, 8p23, 8p11, 8q24, 9p21.3, 10q11, 10q11, 10q22, 11q13-q14, 13q14,13q34, 14q11, 15q14-q15, 17p11-pter, 19p13, 20q11. Recurrent regions of copy neutral LOH affected 1p21, 3q26, 6p21, 11q22 and 12q23. At least in one patient, the 1p, the 3q and the 12q regions of copy neutral LOH were already present in the germline DNA, excluding their somatic origin. In CLL, recurrent gains were observed in 2p25, 3q26, 8q21 and 8q22-q24, 9p24, the whole chromosome 12, 14q32 and 15q26. Losses affected 7q32 and 7q36, 8p23, 11q14-q23, 13q14, 14q24-q24, 15q14-q15, and 17p13-pter. Chromosome 13q showed a complex and heterogenous pattern of deletions and gains, including different breakpoints in matched RS-CLL and DLBCL samples, and gains taking place at the deletion breakpoints. Also, a case bearing a deletion in the CLL but not in the RS-phase, presented a heterozygosity of chromosome 13 in the DLBCL, indicating that the two chromosomes were not derived from the normal chromosome still present in the CLL. The comparison between de novo and RS-DLBCL showed differences. RS-DLBCL did not carry 6q deletions and gains of 3p and 19q. In conclusion, RS-DLBCL presented heterogenous genomic lesions, partially different from de novo DLBCL. Despite a common post-GCB/ABC morphology, the genomic profile of RS-DLBCL appeared intermediate between that reported for ABC- and GCB-DLBCL: RS-DLBCL carried only some of the lesions typically reported in ABC-DLBCL, since they lacked 6q (TNFAIP3 locus) deletions but carried 18q (BLC2 locus) gain. Despite being clonally related to the pre-existing CLL, the analyzed matched samples of RS-DLBCL and CLL showed complex lesions suggesting that a direct transformation from CLL to DLBCL might not always be the case.

scholarly journals Genome-wide identification of endothelial cell–enriched genes in the mouse embryo

Blood ◽  
2012 ◽  
Vol 120 (4) ◽  
pp. 914-923 ◽  
Author(s):  
Haruka Takase ◽  
Ken Matsumoto ◽  
Rie Yamadera ◽  
Yoshiaki Kubota ◽  
Ayaka Otsu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Vascular Development ◽  
Tube Formation ◽  
Vascular Plexus ◽  
Genome Wide ◽  
A Genome ◽  
Human Orthologs ◽  
Rna Knockdown ◽  
Interfering Rna

Abstract The early blood vessels of the embryo and yolk sac in mammals develop by aggregation of de novo–forming angioblasts into a primitive vascular plexus, which then undergoes a complex remodeling process. Angiogenesis is also important for disease progression in the adult. However, the precise molecular mechanism of vascular development remains unclear. It is therefore of great interest to determine which genes are specifically expressed in developing endothelial cells (ECs). Here, we used Flk1-deficient mouse embryos, which lack ECs, to perform a genome-wide survey for genes related to vascular development. We identified 184 genes that are highly enriched in developing ECs. The human orthologs of most of these genes were also expressed in HUVECs, and small interfering RNA knockdown experiments on 22 human orthologs showed that 6 of these genes play a role in tube formation by HUVECs. In addition, we created Arhgef15 knockout and RhoJ knockout mice by a gene-targeting method and found that Arhgef15 and RhoJ were important for neonatal retinal vascularization. Thus, the genes identified in our survey show high expression in ECs; further analysis of these genes should facilitate our understanding of the molecular mechanisms of vascular development in the mouse.

scholarly journals A cross-disorder dosage sensitivity map of the human genome

2021 ◽  
Author(s):  
Ryan L. Collins ◽  
Joseph T. Glessner ◽  
Eleonora Porcu ◽  
Lisa-Marie Niestroj ◽  
Jacob Ulirsch ◽  
...  
Keyword(s):  
Human Genome ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Association Studies ◽  
Disease Genes ◽  
Driver Genes ◽  
Genome Wide ◽  
A Genome ◽  
The Impact ◽  
Dosage Sensitivity

SUMMARYRare deletions and duplications of genomic segments, collectively known as rare copy number variants (rCNVs), contribute to a broad spectrum of human diseases. To date, most disease-association studies of rCNVs have focused on recognized genomic disorders or on the impact of haploinsufficiency caused by deletions. By comparison, our understanding of duplications in disease remains rudimentary as very few individual genes are known to be triplosensitive (i.e., duplication intolerant). In this study, we meta-analyzed rCNVs from 753,994 individuals across 30 primarily neurological disease phenotypes to create a genome-wide catalog of rCNV association statistics across disorders. We discovered 114 rCNV-disease associations at 52 distinct loci surpassing genome-wide significance (P=3.72×10−6), 42% of which involve duplications. Using Bayesian fine-mapping methods, we further prioritized 38 novel triplosensitive disease genes (e.g., GMEB2 in brain abnormalities), including three known haploinsufficient genes that we now reveal as bidirectionally dosage sensitive (e.g., ANKRD11 in growth abnormalities). By integrating our results with prior literature, we found that disease-associated rCNV segments were enriched for genes constrained against damaging coding variation and identified likely dominant driver genes for about one-third (32%) of rCNV segments based on de novo mutations from exome sequencing studies of developmental disorders. However, while the presence of constrained driver genes was a common feature of many pathogenic large rCNVs across disorders, most of the rCNVs showing genome-wide significant association were incompletely penetrant (mean odds ratio=11.6) and we also identified two examples of noncoding disease-associated rCNVs (e.g., intronic CADM2 deletions in behavioral disorders). Finally, we developed a statistical model to predict dosage sensitivity for all genes, which defined 3,006 haploinsufficient and 295 triplosensitive genes where the effect sizes of rCNVs were comparable to deletions of genes constrained against truncating mutations. These dosage sensitivity scores classified disease genes across molecular mechanisms, prioritized pathogenic de novo rCNVs in children with autism, and revealed features that distinguished haploinsufficient and triplosensitive genes, such as insulation from other genes and local cis-regulatory complexity. Collectively, the cross-disorder rCNV maps and metrics derived in this study provide the most comprehensive assessment of dosage sensitive genomic segments and genes in disease to date and set the foundation for future studies of dosage sensitivity throughout the human genome.

scholarly journals Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Benjamin I. Laufer ◽  
J. Antonio Gomez ◽  
Julia M. Jianu ◽  
Janine M. LaSalle
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Differential Methylation ◽  
Chromosome 21 ◽  
Pairwise Comparisons ◽  
Genome Wide ◽  
A Genome

Abstract Background Down syndrome (DS) is characterized by a genome-wide profile of differential DNA methylation that is skewed towards hypermethylation in most tissues, including brain, and includes pan-tissue differential methylation. The molecular mechanisms involve the overexpression of genes related to DNA methylation on chromosome 21. Here, we stably overexpressed the chromosome 21 gene DNA methyltransferase 3L (DNMT3L) in the human SH-SY5Y neuroblastoma cell line and assayed DNA methylation at over 26 million CpGs by whole genome bisulfite sequencing (WGBS) at three different developmental phases (undifferentiated, differentiating, and differentiated). Results DNMT3L overexpression resulted in global CpG and CpG island hypermethylation as well as thousands of differentially methylated regions (DMRs). The DNMT3L DMRs were skewed towards hypermethylation and mapped to genes involved in neurodevelopment, cellular signaling, and gene regulation. Consensus DNMT3L DMRs showed that cell lines clustered by genotype and then differentiation phase, demonstrating sets of common genes affected across neuronal differentiation. The hypermethylated DNMT3L DMRs from all pairwise comparisons were enriched for regions of bivalent chromatin marked by H3K4me3 as well as differentially methylated sites from previous DS studies of diverse tissues. In contrast, the hypomethylated DNMT3L DMRs from all pairwise comparisons displayed a tissue-specific profile enriched for regions of heterochromatin marked by H3K9me3 during embryonic development. Conclusions Taken together, these results support a mechanism whereby regions of bivalent chromatin that lose H3K4me3 during neuronal differentiation are targeted by excess DNMT3L and become hypermethylated. Overall, these findings demonstrate that DNMT3L overexpression during neurodevelopment recreates a facet of the genome-wide DS DNA methylation signature by targeting known genes and gene clusters that display pan-tissue differential methylation in DS.

scholarly journals A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk

BMC Genetics ◽  
2014 ◽  
Vol 15 (1) ◽  
pp. 24 ◽  
Author(s):  
Samuel G Younkin ◽  
Robert B Scharpf ◽  
Holger Schwender ◽  
Margaret M Parker ◽  
Alan F Scott ◽  
...  
Keyword(s):  
Cleft Lip ◽  
De Novo ◽  
Candidate Locus ◽  
Genome Wide ◽  
A Genome ◽  
Cleft Lip Palate ◽  
Genome Wide Study

Abstract 12192: MBNL1 Directly Regulates the Alternative Splicing of mRNAs That Promote Myofibroblast Differentiation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jennifer Davis ◽  
Michelle Sargent ◽  
Jianjian Shi ◽  
Lei Wei ◽  
Maurice S Swanson ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Ventricular Remodeling ◽  
Cardiac Injury ◽  
Myofibroblast Differentiation ◽  
Genome Wide ◽  
A Genome

Rationale: During the cardiac injury response fibroblasts differentiate into myofibroblasts, a cell type that enhances extracellular matrix production and facilitates ventricular remodeling. To better understand the molecular mechanisms whereby myofibroblasts are generated in the heart we performed a genome-wide screen with 18,000 cDNAs, which identified the RNA-binding protein muscleblind-like splicing regulator 1 (MBNL1), suggesting a novel association between mRNA alternative splicing and the regulation of myofibroblast differentiation. Objective: To determine the mechanism whereby MBNL1 regulates myofibroblast differentiation and the cardiac fibrotic response. Methods and Results: Confirming the results from our genome wide screen, adenoviral-mediated overexpression of MBNL1 promoted transformation of rat cardiac fibroblasts and mouse embryonic fibroblasts (MEFs) into myofibroblasts, similar to the level of conversion obtained by the profibrotic agonist transforming growth factor β (TGFβ). Antithetically, Mbnl1 -/- MEFs were refractory to TGFβ-induced myofibroblast differentiation. MBNL1 expression is induced in transforming fibroblasts in response to TGFβ and angiotensin II. These results were extended in vivo by analysis of dermal wound healing, a process dependent on myofibroblast differentiation and their proper activity. By day 6 control mice had achieved 82% skin wound closure compared with only 40% in Mbnl1 -/- mice. Moreover, Mbnl1 -/- mice had reduced survival following myocardial infarction injury due to defective fibrotic scar formation and healing. High throughput RNA sequencing (RNAseq) and RNA immunoprecipitation revealed that MBNL1 directly regulates the alternative splicing of transcripts for myofibroblast signaling factors and cytoskeletal-assembly elements. Functional analysis of these factors as mediators of MBNL1 activity is also described here. Conclusions: Collectively, our data suggest that MBNL1 coordinates myofibroblast transformation by directly mediating the alternative splicing of an array of mRNAs encoding differentiation-specific signaling transcripts, which then alter the fibroblast proteome for myofibroblast structure and function.

scholarly journals Genome assembly of the JD17 soybean provides a new reference genome for Comparative genomics

2021 ◽  
Author(s):  
Xinxin Yi ◽  
Jing Liu ◽  
Shengcai Chen ◽  
Hao Wu ◽  
Min Liu ◽  
...  
Keyword(s):  
Nitrogen Fixation ◽  
Genome Assembly ◽  
Reference Genome ◽  
De Novo ◽  
Genomic Analysis ◽  
Comparative Genomic ◽  
High Quality ◽  
Genome Wide ◽  
A Genome ◽  
Cultivated Soybean

Cultivated soybean (Glycine max) is an important source for protein and oil. Many elite cultivars with different traits have been developed for different conditions. Each soybean strain has its own genetic diversity, and the availability of more high-quality soybean genomes can enhance comparative genomic analysis for identifying genetic underpinnings for its unique traits. In this study, we constructed a high-quality de novo assembly of an elite soybean cultivar Jidou 17 (JD17) with chromsome contiguity and high accuracy. We annotated 52,840 gene models and reconstructed 74,054 high-quality full-length transcripts. We performed a genome-wide comparative analysis based on the reference genome of JD17 with three published soybeans (WM82, ZH13 and W05) , which identified five large inversions and two large translocations specific to JD17, 20,984 - 46,912 PAVs spanning 13.1 - 46.9 Mb in size, and 5 - 53 large PAV clusters larger than 500kb. 1,695,741 - 3,664,629 SNPs and 446,689 - 800,489 Indels were identified and annotated between JD17 and them. Symbiotic nitrogen fixation (SNF) genes were identified and the effects from these variants were further evaluated. It was found that the coding sequences of 9 nitrogen fixation-related genes were greatly affected. The high-quality genome assembly of JD17 can serve as a valuable reference for soybean functional genomics research.

scholarly journals sPepFinder expedites genome-wide identification of small proteins in bacteria

2020 ◽  
Author(s):  
Lei Li ◽  
Yanjie Chao
Keyword(s):  
De Novo ◽  
Bacterial Species ◽  
Computational Prediction ◽  
Ribosome Profiling ◽  
Support Vector ◽  
Initiation Rate ◽  
E Coli ◽  
Small Proteins ◽  
Genome Wide ◽  
A Genome

ABSTRACTSmall proteins shorter than 50 amino acids have been long overlooked. A number of small proteins have been identified in several model bacteria using experimental approaches and assigned important functions in diverse cellular processes. The recent development of ribosome profiling technologies has allowed a genome-wide identification of small proteins and small ORFs (smORFs), but our incomplete understanding of small proteins hinders de novo computational prediction of smORFs in non-model bacterial species. Here, we have identified several sequence features for smORFs by a systematic analysis of all the known small proteins in E. coli, among which the translation initiation rate is the strongest determinant. By integrating these features into a support vector machine learning model, we have developed a novel sPepFinder algorithm that can predict conserved smORFs in bacterial genomes with a high accuracy of 92.8%. De novo prediction in E. coli has revealed several novel smORFs with evidence of translation supported by ribosome profiling. Further application of sPepFinder in 549 bacterial species has led to the identification of > 100,000 novel smORFs, many of which are conserved at the amino acid and nucleotide levels under purifying selection. Overall, we have established sPepFinder as a valuable tool to identify novel smORFs in both model and non-model bacterial organisms, and provided a large resource of small proteins for functional characterizations.

scholarly journals Common genetic risk variants identified in the SPARK cohort implicate DDHD2 as a novel autism risk gene

2020 ◽  
Author(s):  
Nana Matoba ◽  
Dan Liang ◽  
Huaigu Sun ◽  
Nil Aygün ◽  
Jessica C. McAfee ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Association Study ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Risk Variants ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Gene Regulatory

AbstractBackgroundAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD.MethodsWe performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus.ResultsWe identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains.ConclusionsBy integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

scholarly journals Patterns of genome-wide allele-specific expression in hybrid rice and the implications on the genetic basis of heterosis

2019 ◽  
Vol 116 (12) ◽  
pp. 5653-5658 ◽  
Author(s):  
Lin Shao ◽  
Feng Xing ◽  
Conghao Xu ◽  
Qinghua Zhang ◽  
Jian Che ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Sequencing Data ◽  
Specific Expression ◽  
Allele Specific Expression ◽  
Parental Allele ◽  
Genetic Components ◽  
Genome Wide ◽  
A Genome ◽  
Allele Specific

Utilization of heterosis has greatly increased the productivity of many crops worldwide. Although tremendous progress has been made in characterizing the genetic basis of heterosis using genomic technologies, molecular mechanisms underlying the genetic components are much less understood. Allele-specific expression (ASE), or imbalance between the expression levels of two parental alleles in the hybrid, has been suggested as a mechanism of heterosis. Here, we performed a genome-wide analysis of ASE by comparing the read ratios of the parental alleles in RNA-sequencing data of an elite rice hybrid and its parents using three tissues from plants grown under four conditions. The analysis identified a total of 3,270 genes showing ASE (ASEGs) in various ways, which can be classified into two patterns: consistent ASEGs such that the ASE was biased toward one parental allele in all tissues/conditions, and inconsistent ASEGs such that ASE was found in some but not all tissues/conditions, including direction-shifting ASEGs in which the ASE was biased toward one parental allele in some tissues/conditions while toward the other parental allele in other tissues/conditions. The results suggested that these patterns may have distinct implications in the genetic basis of heterosis: The consistent ASEGs may cause partial to full dominance effects on the traits that they regulate, and direction-shifting ASEGs may cause overdominance. We also showed that ASEGs were significantly enriched in genomic regions that were differentially selected during rice breeding. These ASEGs provide an index of the genes for future pursuit of the genetic and molecular mechanism of heterosis.

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