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Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) Contiguous Gene Syndromes by Chromosome Engineering in Mice: Phenotypic Consequences of Gene Dosage Imbalance

Walz, Katherina; Caratini-Rivera, Sandra; Bi, Weimin; Fonseca, Patricia; Mansouri, Dena L.; Lynch, Jennifer; Vogel, Hannes; Noebels, Jeffrey L.; Bradley, Allan; Lupski, James R.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2003 EN
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45.89%
Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangements of which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitive genes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome 17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have been described as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomes carrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome 11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/+ animals are underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination of Df(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dosage effects. Our murine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomic interval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).

Screens for piwi suppressors in Drosophila identify dosage-dependent regulators of germline stem cell division.

Smulders-Srinivasan, Tora K; Lin, Haifan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/2003 EN
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36.14%
The Drosophila piwi gene is the founding member of the only known family of genes whose function in stem cell maintenance is highly conserved in both animal and plant kingdoms. piwi mutants fail to maintain germline stem cells in both male and female gonads. The identification of piwi-interacting genes is essential for understanding how stem cell divisions are regulated by piwi-mediated mechanisms. To search for such genes, we screened the Drosophila third chromosome ( approximately 36% of the euchromatic genome) for suppressor mutations of piwi2 and identified six strong and three weak piwi suppressor genes/sequences. These genes/sequences interact negatively with piwi in a dosage-sensitive manner. Two of the strong suppressors represent known genes--serendipity-delta and similar, both encoding transcription factors. These findings reveal that the genetic regulation of germline stem cell division involves dosage-sensitive mechanisms and that such mechanisms exist at the transcriptional level. In addition, we identified three other types of piwi interactors. The first type consists of deficiencies that dominantly interact with piwi2 to cause male sterility, implying that dosage-sensitive regulation also exists in the male germline. The other two types are deficiencies that cause lethality and female-specific lethality in a piwi2 mutant background...

Natural Gene-Expression Variation in Down Syndrome Modulates the Outcome of Gene-Dosage Imbalance

Prandini, Paola ; Deutsch, Samuel ; Lyle, Robert ; Gagnebin, Maryline ; Vivier, Celine Delucinge ; Delorenzi, Mauro ; Gehrig, Corinne ; Descombes, Patrick ; Sherman, Stephanie ; Bricarelli, Franca Dagna ; Baldo, Chiara ; Novelli, Antonio ; D
Fonte: American Society of Human Genetics Publicador: American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
36.15%
Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels...

Heterozygous Screen in Saccharomyces cerevisiae Identifies Dosage-Sensitive Genes That Affect Chromosome Stability

Strome, Erin D.; Wu, Xiaowei; Kimmel, Marek; Plon, Sharon E.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /03/2008 EN
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66.05%
Current techniques for identifying mutations that convey a small increased cancer risk or those that modify cancer risk in carriers of highly penetrant mutations are limited by the statistical power of epidemiologic studies, which require screening of large populations and candidate genes. To identify dosage-sensitive genes that mediate genomic stability, we performed a genomewide screen in Saccharomyces cerevisiae for heterozygous mutations that increase chromosome instability in a checkpoint-deficient diploid strain. We used two genome stability assays sensitive enough to detect the impact of heterozygous mutations and identified 172 heterozygous gene disruptions that affected chromosome fragment (CF) loss, 45% of which also conferred modest but statistically significant instability of endogenous chromosomes. Analysis of heterozygous deletion of 65 of these genes demonstrated that the majority increased genomic instability in both checkpoint-deficient and wild-type backgrounds. Strains heterozygous for COMA kinetochore complex genes were particularly unstable. Over 50% of the genes identified in this screen have putative human homologs, including CHEK2, ERCC4, and TOPBP1, which are already associated with inherited cancer susceptibility. These findings encourage the incorporation of this orthologous gene list into cancer epidemiology studies and suggest further analysis of heterozygous phenotypes in yeast as models of human disease resulting from haplo-insufficiency.

Haploinsufficiency of DNA Damage Response Genes and their Potential Influence in Human Genomic Disorders

O’Driscoll, Mark
Fonte: Bentham Science Publishers Ltd. Publicador: Bentham Science Publishers Ltd.
Tipo: Artigo de Revista Científica
Publicado em /05/2008 EN
Relevância na Pesquisa
45.81%
Genomic disorders are a clinically diverse group of conditions caused by gain, loss or re-orientation of a genomic region containing dosage-sensitive genes. One class of genomic disorder is caused by hemizygous deletions resulting in haploinsufficiency of a single or, more usually, several genes. For example, the heterozygous contiguous gene deletion on chromosome 22q11.2 causing DiGeorge syndrome involves at least 20-30 genes. Determining how the copy number variation (CNV) affects human variation and contributes to the aetiology and progression of various genomic disorders represents important questions for the future. Here, I will discuss the functional significance of one form of CNV, haploinsufficiency (i.e. loss of a gene copy), of DNA damage response components and its association with certain genomic disorders. There is increasing evidence that haploinsufficiency for certain genes encoding key players in the cells response to DNA damage, particularly those of the Ataxia Telangiectasia and Rad3-related (ATR)-pathway, has a functional impact. I will review this evidence and present examples of some well known clinically similar genomic disorders that have recently been shown to be defective in the ATR-dependent DNA damage response. Finally...

Dosage Sensitivity Shapes the Evolution of Copy-Number Varied Regions

Schuster-Böckler, Benjamin; Conrad, Donald; Bateman, Alex
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 10/03/2010 EN
Relevância na Pesquisa
46.24%
Dosage sensitivity is an important evolutionary force which impacts on gene dispensability and duplicability. The newly available data on human copy-number variation (CNV) allow an analysis of the most recent and ongoing evolution. Provided that heterozygous gene deletions and duplications actually change gene dosage, we expect to observe negative selection against CNVs encompassing dosage sensitive genes. In this study, we make use of several sources of population genetic data to identify selection on structural variations of dosage sensitive genes. We show that CNVs can directly affect expression levels of contained genes. We find that genes encoding members of protein complexes exhibit limited expression variation and overlap significantly with a manually derived set of dosage sensitive genes. We show that complexes and other dosage sensitive genes are underrepresented in CNV regions, with a particular bias against frequent variations and duplications. These results suggest that dosage sensitivity is a significant force of negative selection on regions of copy-number variation.

Dosage-Sensitive Function of RETINOBLASTOMA RELATED and Convergent Epigenetic Control Are Required during the Arabidopsis Life Cycle

Johnston, Amal J.; Kirioukhova, Olga; Barrell, Philippa J.; Rutten, Twan; Moore, James M.; Baskar, Ramamurthy; Grossniklaus, Ueli; Gruissem, Wilhelm
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.02%
The plant life cycle alternates between two distinct multi-cellular generations, the reduced gametophytes and the dominant sporophyte. Little is known about how generation-specific cell fate, differentiation, and development are controlled by the core regulators of the cell cycle. In Arabidopsis, RETINOBLASTOMA RELATED (RBR), an evolutionarily ancient cell cycle regulator, controls cell proliferation, differentiation, and regulation of a subset of Polycomb Repressive Complex 2 (PRC2) genes and METHYLTRANSFERASE 1 (MET1) in the male and female gametophytes, as well as cell fate establishment in the male gametophyte. Here we demonstrate that RBR is also essential for cell fate determination in the female gametophyte, as revealed by loss of cell-specific marker expression in all the gametophytic cells that lack RBR. Maintenance of genome integrity also requires RBR, because diploid plants heterozygous for rbr (rbr/RBR) produce an abnormal portion of triploid offspring, likely due to gametic genome duplication. While the sporophyte of the diploid mutant plants phenocopied wild type due to the haplosufficiency of RBR, genetic analysis of tetraploid plants triplex for rbr (rbr/rbr/rbr/RBR) revealed that RBR has a dosage-dependent pleiotropic effect on sporophytic development...

Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior

Carmona-Mora, Paulina; Walz, Katherina
Fonte: Bentham Science Publishers Ltd Publicador: Bentham Science Publishers Ltd
Tipo: Artigo de Revista Científica
Publicado em /12/2010 EN
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56.17%
Genomic structural changes, such as gene Copy Number Variations (CNVs) are extremely abundant in the human genome. An enormous effort is currently ongoing to recognize and catalogue human CNVs and their associations with abnormal phenotypic outcomes. Recently, several reports related neuropsychiatric diseases (i.e. autism spectrum disorders, schizophrenia, mental retardation, behavioral problems, epilepsy) with specific CNV. Moreover, for some conditions, both the deletion and duplication of the same genomic segment are related to the phenotype. Syndromes associated with CNVs (microdeletion and microduplication) have long been known to display specific neurobehavioral traits. It is important to note that not every gene is susceptible to gene dosage changes and there are only a few dosage sensitive genes. Smith-Magenis (SMS) and Potocki-Lupski (PTLS) syndromes are associated with a reciprocal microdeletion and microduplication within chromosome 17p11.2. in humans. The dosage sensitive gene responsible for most phenotypes in SMS has been identified: the Retinoic Acid Induced 1 (RAI1). Studies on mouse models and humans suggest that RAI1 is likely the dosage sensitive gene responsible for clinical features in PTLS. In addition, the human RAI1 gene has been implicated in several neurobehavioral traits as spinocerebellar ataxia (SCA2)...

Down syndrome: searching for the genetic culprits

Lana-Elola, Eva; Watson-Scales, Sheona D.; Fisher, Elizabeth M. C.; Tybulewicz, Victor L. J.
Fonte: The Company of Biologists Limited Publicador: The Company of Biologists Limited
Tipo: Artigo de Revista Científica
Publicado em /09/2011 EN
Relevância na Pesquisa
36.15%
Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and results in a large number of phenotypes, including learning difficulties, cardiac defects, distinguishing facial features and leukaemia. These are likely to result from an increased dosage of one or more of the ∼310 genes present on Hsa21. The identification of these dosage-sensitive genes has become a major focus in DS research because it is essential for a full understanding of the molecular mechanisms underlying pathology, and might eventually lead to more effective therapy. The search for these dosage-sensitive genes is being carried out using both human and mouse genetics. Studies of humans with partial trisomy of Hsa21 have identified regions of this chromosome that contribute to different phenotypes. In addition, novel engineered mouse models are being used to map the location of dosage-sensitive genes, which, in a few cases, has led to the identification of individual genes that are causative for certain phenotypes. These studies have revealed a complex genetic interplay, showing that the diverse DS phenotypes are likely to be caused by increased copies of many genes, with individual genes contributing in different proportions to the variance in different aspects of the pathology.

Copy-Number Variation: The Balance between Gene Dosage and Expression in Drosophila melanogaster

Zhou, Jun; Lemos, Bernardo; Dopman, Erik B.; Hartl, Daniel L.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
36.17%
Copy-number variants (CNVs) reshape gene structure, modulate gene expression, and contribute to significant phenotypic variation. Previous studies have revealed CNV patterns in natural populations of Drosophila melanogaster and suggested that selection and mutational bias shape genomic patterns of CNV. Although previous CNV studies focused on heterogeneous strains, here, we established a number of second-chromosome substitution lines to uncover CNV characteristics when homozygous. The percentage of genes harboring CNVs is higher than found in previous studies. More CNVs are detected in homozygous than heterozygous substitution strains, suggesting the comparative genomic hybridization arrays underestimate CNV owing to heterozygous masking. We incorporated previous gene expression data collected from some of the same substitution lines to investigate relationships between CNV gene dosage and expression. Most genes present in CNVs show no evidence of increased or diminished transcription, and the fraction of such dosage-insensitive CNVs is greater in heterozygotes. More than 70% of the dosage-sensitive CNVs are recessive with undetectable effects on transcription in heterozygotes. A deficiency of singletons in recessive dosage-sensitive CNVs supports the hypothesis that most CNVs are subject to negative selection. On the other hand...

Modeling Partial Monosomy for Human Chromosome 21q11.2-q21.1 Reveals Haploinsufficient Genes Influencing Behavior and Fat Deposition

Migdalska, Anna M.; van der Weyden, Louise; Ismail, Ozama; White, Jacqueline K.; Project, Sanger Mouse Genetics; Sánchez-Andrade, Gabriela; Logan, Darren W.; Arends, Mark J.; Adams, David J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 20/01/2012 EN
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45.79%
Haploinsufficiency of part of human chromosome 21 results in a rare condition known as Monosomy 21. This disease displays a variety of clinical phenotypes, including intellectual disability, craniofacial dysmorphology, skeletal and cardiac abnormalities, and respiratory complications. To search for dosage-sensitive genes involved in this disorder, we used chromosome engineering to generate a mouse model carrying a deletion of the Lipi–Usp25 interval, syntenic with 21q11.2-q21.1 in humans. Haploinsufficiency for the 6 genes in this interval resulted in no gross morphological defects and behavioral analysis performed using an open field test, a test of anxiety, and tests for social interaction were normal in monosomic mice. Monosomic mice did, however, display impaired memory retention compared to control animals. Moreover, when fed a high-fat diet (HFD) monosomic mice exhibited a significant increase in fat mass/fat percentage estimate compared with controls, severe fatty changes in their livers, and thickened subcutaneous fat. Thus, genes within the Lipi–Usp25 interval may participate in memory retention and in the regulation of fat deposition.

Sex Reversal in C57BL/6J XY Mice Caused by Increased Expression of Ovarian Genes and Insufficient Activation of the Testis Determining Pathway

Correa, Stephanie M.; Washburn, Linda L.; Kahlon, Ravi S.; Musson, Michelle C.; Bouma, Gerrit J.; Eicher, Eva M.; Albrecht, Kenneth H.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
36.17%
Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over-express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XYB6 mice impaired testis differentiation, but no ovarian tissue developed. If, however, a YAKR chromosome replaced the YB6 chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/− B6 XYAKR, Wt1+/− B6 XYAKR, B6 XYPOS, and B6 XYAKR fetuses. We propose that Wt1B6 and Sf1B6 are hypomorphic alleles of testis-determining pathway genes and that Wnt4B6 is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal...

Identification of dosage-sensitive genes in Saccharomyces cerevisiae using the genetic tug-of-war method

Makanae, Koji; Kintaka, Reiko; Makino, Takashi; Kitano, Hiroaki; Moriya, Hisao
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /02/2013 EN
Relevância na Pesquisa
66.14%
Gene overexpression beyond a permissible limit causes defects in cellular functions. However, the permissible limits of most genes are unclear. Previously, we developed a genetic method designated genetic tug-of-war (gTOW) to measure the copy number limit of overexpression of a target gene. In the current study, we applied gTOW to the analysis of all protein-coding genes in the budding yeast Saccharomyces cerevisiae. We showed that the yeast cellular system was robust against an increase in the copy number by up to 100 copies in >80% of the genes. After frameshift and segmentation analyses, we isolated 115 dosage-sensitive genes (DSGs) with copy number limits of 10 or less. DSGs contained a significant number of genes involved in cytoskeletal organization and intracellular transport. DSGs tended to be highly expressed and to encode protein complex members. We demonstrated that the protein burden caused the dosage sensitivity of highly expressed genes using a gTOW experiment in which the open reading frame was replaced with GFP. Dosage sensitivities of some DSGs were rescued by the simultaneous increase in the copy numbers of partner genes, indicating that stoichiometric imbalances among complexes cause dosage sensitivity. The results obtained in this study will provide basic knowledge about the physiology of chromosomal abnormalities and the evolution of chromosomal composition.

Widespread rescue of Y-linked genes by gene movement to autosomes

Malone, John H.
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.74%
A new study provides evidence that gene transposition from sex chromosomes to autosomes is a conserved phenomenon across mammalian species that rescues dosage-sensitive genes.

The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity

Petrovski, Slavé; Gussow, Ayal B.; Wang, Quanli; Halvorsen, Matt; Han, Yujun; Weir, William H.; Allen, Andrew S.; Goldstein, David B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 02/09/2015 EN
Relevância na Pesquisa
46.21%
Noncoding sequence contains pathogenic mutations. Yet, compared with mutations in protein-coding sequence, pathogenic regulatory mutations are notoriously difficult to recognize. Most fundamentally, we are not yet adept at recognizing the sequence stretches in the human genome that are most important in regulating the expression of genes. For this reason, it is difficult to apply to the regulatory regions the same kinds of analytical paradigms that are being successfully applied to identify mutations among protein-coding regions that influence risk. To determine whether dosage sensitive genes have distinct patterns among their noncoding sequence, we present two primary approaches that focus solely on a gene’s proximal noncoding regulatory sequence. The first approach is a regulatory sequence analogue of the recently introduced residual variation intolerance score (RVIS), termed noncoding RVIS, or ncRVIS. The ncRVIS compares observed and predicted levels of standing variation in the regulatory sequence of human genes. The second approach, termed ncGERP, reflects the phylogenetic conservation of a gene’s regulatory sequence using GERP++. We assess how well these two approaches correlate with four gene lists that use different ways to identify genes known or likely to cause disease through changes in expression: 1) genes that are known to cause disease through haploinsufficiency...

Quantitative Mass Spectrometry Reveals Partial Translational Regulation for Dosage Compensation in Chicken

Uebbing, Severin; Konzer, Anne; Xu, Luohao; Backström, Niclas; Brunström, Björn; Bergquist, Jonas; Ellegren, Hans
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.05%
There is increasing evidence that dosage compensation is not a ubiquitous feature following sex chromosome evolution, especially not in organisms where females are the heterogametic sex, like in birds. Even when it occurs, compensation can be incomplete and limited to dosage-sensitive genes. However, previous work has mainly studied transcriptional regulation of sex-linked genes, which may not reflect expression at the protein level. Here, we used liquid chromatography–tandem mass spectrometry to detect and quantify expressed levels of more than 2,400 proteins in ten different tissues of male and female chicken embryos. For comparison, transcriptome sequencing was performed in the same individuals, five of each sex. The proteomic analysis revealed that dosage compensation was incomplete, with a mean male-to-female (M:F) expression ratio of Z-linked genes of 1.32 across tissues, similar to that at the RNA level (1.29). The mean Z chromosome-to-autosome expression ratio was close to 1 in males and lower than 1 in females, consistent with partly reduced Z chromosome expression in females. Although our results exclude a general mechanism for chromosome-wide dosage compensation at translation, 30% of all proteins encoded from Z-linked genes showed a significant change in the M:F ratio compared with the corresponding ratio at the RNA level. This resulted in a pattern where some genes showed balanced expression between sexes and some close to 2-fold higher expression in males. This suggests that proteomic analyses will be necessary to reveal a more complete picture of gene regulation and sex chromosome evolution.

The shaping and functional consequences of the dosage effect landscape in multiple myeloma

Samur, Mehmet K; Shah, Parantu K; Wang, Xujun; Minvielle, Stéphane; Magrangeas, Florence; Avet-Loiseau, Hervé; Munshi, Nikhil C; Li, Cheng
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
56.21%
Background: Multiple myeloma (MM) is a malignant proliferation of plasma B cells. Based on recurrent aneuploidy such as copy number alterations (CNAs), myeloma is divided into two subtypes with different CNA patterns and patient survival outcomes. How aneuploidy events arise, and whether they contribute to cancer cell evolution are actively studied. The large amount of transcriptomic changes resultant of CNAs (dosage effect) pose big challenges for identifying functional consequences of CNAs in myeloma in terms of specific driver genes and pathways. In this study, we hypothesize that gene-wise dosage effect varies as a result from complex regulatory networks that translate the impact of CNAs to gene expression, and studying this variation can provide insights into functional effects of CNAs. Results: We propose gene-wise dosage effect score and genome-wide karyotype plot as tools to measure and visualize concordant copy number and expression changes across cancer samples. We find that dosage effect in myeloma is widespread yet variable, and it is correlated with gene expression level and CNA frequencies in different chromosomes. Our analysis suggests that despite the enrichment of differentially expressed genes between hyperdiploid MM and non-hyperdiploid MM in the trisomy chromosomes...

Molecular basis of gene dosage sensitivity

Chen, Jianping
Fonte: Universidade Rice Publicador: Universidade Rice
ENG
Relevância na Pesquisa
46.2%
Deviation of gene expression from normal levels has been associated with diseases. Both under- and overexpression of genes could lead to deleterious biological consequences. Dosage balance has been proposed to be a key issue of determining gene expression phenotype. Gene deletion or overexpression of any component in a protein complex produces abnormal phenotypes. As a result, interacting partners should be co-expressed to avoid dosage imbalance effects. The strength of transcriptional co-regulation of interacting partners is supposed to reflect gene dosage sensitivity. Although many cases of dosage imbalance effects have been reported, the molecular attributes determining dosage sensitivity remain unknown. This thesis uses a protein structure analysis protocol to explore the molecular basis of gene dosage sensitivity, and studies the post-transcriptional regulation of dosage sensitive genes. Solvent-exposed backbone hydrogen bond (SEBH or called as dehydron) provides a structure marker for protein interaction. Protein structure vulnerability, defined as the ratio of SEBHs to the overall number of backbone hydrogen bonds, quantifies the extent to which protein relies on its binding partners to maintain structure integrity. Genes encoding vulnerable proteins need to be highly co-expressed with their interacting partners. Protein structure vulnerability may hence serves as a structure marker for dosage sensitivity. This hypothesis is examined through the integration of gene expression...

Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome

Pessia, Eugénie; Makino, Takashi; Bailly-Bechet, Marc; McLysaght, Aoife; Marais, Gabriel A. B.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
66.28%
How and why female somatic X-chromosome inactivation (XCI) evolved in mammals remains poorly understood. It has been proposed that XCI is a dosage-compensation mechanism that evolved to equalize expression levels of X-linked genes in females (2X) and males (1X), with a prior twofold increase in expression of X-linked genes in both sexes (“Ohno's hypothesis”). Whereas the parity of X chromosome expression between the sexes has been clearly demonstrated, tests for the doubling of expression levels globally along the X chromosome have returned contradictory results. However, changes in gene dosage during sex-chromosome evolution are not expected to impact on all genes equally, and should have greater consequences for dosage-sensitive genes. We show that, for genes encoding components of large protein complexes (≥ 7 members)—a class of genes that is expected to be dosage-sensitive—expression of X-linked genes is similar to that of autosomal genes within the complex. These data support Ohno's hypothesis that XCI acts as a dosage-compensation mechanism, and allow us to refine Ohno's model of XCI evolution. We also explore the contribution of dosage-sensitive genes to X aneuploidy phenotypes in humans, such as Turner (X0) and Klinefelter (XXY) syndromes. X aneuploidy in humans is common and is known to have mild effects because most of the supernumerary X genes are inactivated and not affected by aneuploidy. Only genes escaping XCI experience dosage changes in X-aneuploidy patients. We combined data on dosage sensitivity and XCI to compute a list of candidate genes for X-aneuploidy syndromes.

The evolution of X chromosome inactivation in mammals: the demise of Ohno’s hypothesis?

Pessia, Eugénie; Engelstädter, Jan; Marais, Gabriel A. B.
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
Publicado em /04/2014 ENG
Relevância na Pesquisa
66.1%
Ohno's hypothesis states that dosage compensation in mammals evolved in two steps: a twofold hyperactivation of the X chromosome in both sexes to compensate for gene losses on the Y chromosome, and silencing of one X (X-chromosome inactivation, XCI) in females to restore optimal dosage. Recent tests of this hypothesis have returned contradictory results. In this review, we explain this ongoing controversy and argue that a novel view on dosage compensation evolution in mammals is starting to emerge. Ohno's hypothesis may be true for a few, dosage-sensitive genes only. If so few genes are compensated, then why has XCI evolved as a chromosome-wide mechanism? This and several other questions raised by the new data in mammals are discussed, and future research directions are proposed.; Agence Nationale de la Recherche grant number: (ANR-12-BSV7-0002), Instituto Gulbenkian de Ciência.