Articoli di riviste: "Dosage-sensitive genes"

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Reiter, Lawrence T., Tatsufumi Murakami, Laura E. Warner e James R. Lupski. "DNA rearrangements affecting dosage sensitive genes". Mental Retardation and Developmental Disabilities Research Reviews 2, n. 3 (1996): 139–46. http://dx.doi.org/10.1002/(sici)1098-2779(1996)2:3<139::aid-mrdd4>3.0.co;2-n.

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Sapienza, Carmen. "Sex-linked dosage-sensitive modifiers as imprinting genes". Development 108, Supplement (1 aprile 1990): 107–13. http://dx.doi.org/10.1242/dev.108.supplement.107.

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It is proposed that differential genome imprinting is the result of dosage-sensitive modifier genes located on the sex chromosomes. Parallels between variegating position-effects in Drosophila, the phenotype elicited by transgenes in the mouse and data from several pediatric tumors indicate that the net result of the activity of such modifier genes is often cellular mosaicism in the expression of affected alleles. The mechanism by which inactivation of affected alleles is achieved is proposed to be through the formation of heterochromatic domains. Because the relevant sex-linked modifying loci are dosage sensitive in their activity, differential imprinting will occur even within homogeneous genetic backgrounds. The presence of allelic variants at these loci in non-inbred populations will give rise to variation in the observed expressivity and mode of inheritance of affected traits.

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Zimmer, Fabian, Peter W. Harrison, Christophe Dessimoz e Judith E. Mank. "Compensation of Dosage-Sensitive Genes on the Chicken Z Chromosome". Genome Biology and Evolution 8, n. 4 (aprile 2016): 1233–42. http://dx.doi.org/10.1093/gbe/evw075.

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Chang, Andrew Ying-Fei, e Ben-Yang Liao. "Reduced Translational Efficiency of Eukaryotic Genes after Duplication Events". Molecular Biology and Evolution 37, n. 5 (6 gennaio 2020): 1452–61. http://dx.doi.org/10.1093/molbev/msz309.

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Abstract Control of gene expression has been found to be predominantly determined at the level of protein translation. However, to date, reduced expression from duplicated genes in eukaryotes for dosage maintenance has only been linked to transcriptional control involving epigenetic mechanisms. Here, we hypothesize that dosage maintenance following gene duplication also involves regulation at the protein level. To test this hypothesis, we compared transcriptome and proteome data of yeast models, Saccharomyces cerevisiae and Schizosaccharomyces pombe, and worm models, Caenorhabditis elegans and Caenorhabditis briggsae, to investigate lineage-specifically duplicated genes. Duplicated genes in both eukaryotic models exhibited a reduced protein-to-mRNA abundance ratio. Moreover, dosage sensitive genes, represented by genes encoding protein complex subunits, reduced their protein-to-mRNA abundance ratios more significantly than the other genes after duplication events. An analysis of ribosome profiling (Ribo-Seq) data further showed that reduced translational efficiency was more prominent for dosage sensitive genes than for the other genes. Meanwhile, no difference in protein degradation rate was associated with duplication events. Translationally repressed duplicated genes were also more likely to be inhibited at the level of transcription. Taken together, these results suggest that translation-mediated dosage control is partially contributed by natural selection and it enhances transcriptional control in maintaining gene dosage after gene duplication events during eukaryotic genome evolution.

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Plenefisch, J. D., L. DeLong e B. J. Meyer. "Genes that implement the hermaphrodite mode of dosage compensation in Caenorhabditis elegans." Genetics 121, n. 1 (1 gennaio 1989): 57–76. http://dx.doi.org/10.1093/genetics/121.1.57.

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Abstract We report a genetic characterization of several essential components of the dosage compensation process in Caenorhabditis elegans. Mutations in the genes dpy-26, dpy-27, dpy-28, and the newly identified gene dpy-29 disrupt dosage compensation, resulting in elevated X-linked gene expression in XX animals and an incompletely penetrant maternal-effect XX-specific lethality. These dpy mutations appear to cause XX animals to express each set of X-linked genes at a level appropriate for XO animals. XO dpy animals are essentially wild type. Both the viability and the level of X-linked gene expression in XX animals carrying mutations in two or more dpy genes are the same as in animals carrying only a single mutation, consistent with the view that these genes act together in a single process (dosage compensation). To define a potential time of action for the gene dpd-28 we performed reciprocal temperature-shift experiments with a heat sensitive allele. The temperature-sensitive period for lethality begins 5 hr after fertilization at the 300-cell stage and extends to about 9 hr, a point well beyond the end of cell proliferation. This temperature-sensitive period suggests that dosage compensation is functioning in XX animals by mid-embryogenesis, when many zygotically transcribed genes are active. While mutations in the dpy genes have no effect on the sexual phenotype of otherwise wild-type XX or XO animals, they do have a slight feminizing effect on animals whose sex-determination process is already genetically perturbed. The opposite directions of the feminizing effects on sex determination and the masculinizing effects on dosage compensation caused by the dpy mutations are inconsistent with the wild-type dpy genes acting to coordinately control both processes. Instead, the feminizing effects are most likely an indirect consequence of disruptions in dosage compensation caused by the dpy mutations. Based on the cumulative evidence, the likely mechanism of dosage compensation in C. elegans involves reducing X-linked gene expression in XX animals to equal that in XO animals via the action of the dpy genes.

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Thompson, Ammon, Harold H. Zakon e Mark Kirkpatrick. "Compensatory Drift and the Evolutionary Dynamics of Dosage-Sensitive Duplicate Genes". Genetics 202, n. 2 (12 dicembre 2015): 765–74. http://dx.doi.org/10.1534/genetics.115.178137.

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Javed, Sehrish, Tharushan Selliah, Yu-Ju Lee e Wei-Hsiang Huang. "Dosage-sensitive genes in autism spectrum disorders: From neurobiology to therapy". Neuroscience & Biobehavioral Reviews 118 (novembre 2020): 538–67. http://dx.doi.org/10.1016/j.neubiorev.2020.08.009.

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Raznahan, Armin, Neelroop N. Parikshak, Vijay Chandran, Jonathan D. Blumenthal, Liv S. Clasen, Aaron F. Alexander-Bloch, Andrew R. Zinn et al. "Sex-chromosome dosage effects on gene expression in humans". Proceedings of the National Academy of Sciences 115, n. 28 (26 giugno 2018): 7398–403. http://dx.doi.org/10.1073/pnas.1802889115.

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A fundamental question in the biology of sex differences has eluded direct study in humans: How does sex-chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex-chromosome aneuploidies (XO, XXX, XXY, XYY, and XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex-chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. These gene coexpression results converge with analysis of transcription factor binding site enrichment and measures of gene expression in murine knockout models to spotlight the dosage-sensitive X-linked transcription factor ZFX as a key mediator of SCD effects on wider genome expression. Our findings characterize the effects of SCD broadly across the genome, with potential implications for human phenotypic variation.

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Smulders-Srinivasan, Tora K., e Haifan Lin. "Screens for piwi Suppressors in Drosophila Identify Dosage-Dependent Regulators of Germline Stem Cell Division". Genetics 165, n. 4 (1 dicembre 2003): 1971–91. http://dx.doi.org/10.1093/genetics/165.4.1971.

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Abstract 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 (∼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-δ 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, revealing the zygotic function of piwi in somatic development.

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Duffy, Joseph B., James Wells e J. Peter Gergen. "Dosage-Sensitive Maternal Modifiers of the Drosophila Segmentation Gene runt". Genetics 142, n. 3 (1 marzo 1996): 839–52. http://dx.doi.org/10.1093/genetics/142.3.839.

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Abstract The protein encoded by the pair-rule gene runt functions as a transcriptional regulator during anterior-posterior patterning of the Drosophila embryo. Results of over-expression experiments as well as parallels drawn from the recent characterization of vertebrate homologues indicate that interactions with other proteins are likely to be central to the function of the Runt protein. To identify factors important for runt activity, we took advantage of an adult visible phenotype observed in animals heterozygous for runt mutations. Using a set of 126 different deficiency chromosomes we screened ~65% of the genome for genes that act as dose-sensitive maternal modifiers of runt. Eighteen deficiencies representing 12 putative loci were identified as maternally acting enhancers of runt haplo-insufficiency. Further characterization of two of these regions led to the identification of the interacting loci. Both of these loci affect the spatial regulation of runt transcription and appear genetically complex. Furthermore, the effects of one of these loci, M(1)1B, is indirect and mediated through effects on the transcriptional regulation of posterior gap genes.

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Zhang, Shuai, Ruixue Wang, Cheng Huang, Ludan Zhang e Lin Sun. "Modulation of Global Gene Expression by Aneuploidy and CNV of Dosage Sensitive Regulatory Genes". Genes 12, n. 10 (12 ottobre 2021): 1606. http://dx.doi.org/10.3390/genes12101606.

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Aneuploidy, which disrupts the genetic balance due to partial genome dosage changes, is usually more detrimental than euploidy variation. To investigate the modulation of gene expression in aneuploidy, we analyzed the transcriptome sequencing data of autosomal and sex chromosome trisomy in Drosophila. The results showed that most genes on the varied chromosome (cis) present dosage compensation, while the remainder of the genome (trans) produce widespread inverse dosage effects. Some altered functions and pathways were identified as the common characteristics of aneuploidy, and several possible regulatory genes were screened for an inverse dosage effect. Furthermore, we demonstrated that dosage changes of inverse regulator Inr-a/pcf11 can produce a genome-wide inverse dosage effect. All these findings suggest that the mechanism of genomic imbalance is related to the changes in the stoichiometric relationships of macromolecular complex members that affect the overall function. These studies may deepen the understanding of gene expression regulatory mechanisms.

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McNamara, Gráinne I., e Anthony R. Isles. "Dosage-sensitivity of imprinted genes expressed in the brain: 15q11–q13 and neuropsychiatric illness". Biochemical Society Transactions 41, n. 3 (23 maggio 2013): 721–26. http://dx.doi.org/10.1042/bst20130008.

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Imprinted genes, those genes subject to parent-of-origin-specific epigenetic marking resulting in monoallelic parent-specific expression, are sensitive to subtle changes in expression dosage. This has been illustrated in a number of experimental models and the fact that both decreased (or complete loss) and increased imprinted gene expression can lead to human diseases. In the present paper, we discuss the consequence of increased dosage of imprinted genes for brain function, focusing on the PWS (Prader–Willi syndrome) locus on human chromosome 15q11–q13 and how predicted increases in dosage of maternally expressed imprinted genes from this interval are associated with a higher risk of developing psychotic illness. The evidence for this comes from individuals with PWS itself and also non-syndromic cases of psychosis in carriers of a maternally derived copy number variant spanning this locus. Of the known imprinted genes in this region, the prime candidate is maternally expressed UBE3A, which encodes E6-AP (E6-associated protein) ubiquitin ligase and has an influence on a number of important neurotransmitter systems. Furthermore, these findings point to the fact that brain function is exquisitely sensitive to both decreases and increases in the expression of imprinted genes.

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Yang, Hua, Xiaowen Shi, Chen Chen, Jie Hou, Tieming Ji, Jianlin Cheng e James A. Birchler. "Predominantly inverse modulation of gene expression in genomically unbalanced disomic haploid maize". Plant Cell 33, n. 4 (2 febbraio 2021): 901–16. http://dx.doi.org/10.1093/plcell/koab029.

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Abstract The phenotypic consequences of the addition or subtraction of part of a chromosome is more severe than changing the dosage of the whole genome. By crossing diploid trisomies to a haploid inducer, we identified 17 distal segmental haploid disomies that cover ∼80% of the maize genome. Disomic haploids provide a level of genomic imbalance that is not ordinarily achievable in multicellular eukaryotes, allowing the impact to be stronger and more easily studied. Transcriptome size estimates revealed that a few disomies inversely modulate most of the transcriptome. Based on RNA sequencing, the expression levels of genes located on the varied chromosome arms (cis) in disomies ranged from being proportional to chromosomal dosage (dosage effect) to showing dosage compensation with no expression change with dosage. For genes not located on the varied chromosome arm (trans), an obvious trans-acting effect can be observed, with the majority showing a decreased modulation (inverse effect). The extent of dosage compensation of varied cis genes correlates with the extent of trans inverse effects across the 17 genomic regions studied. The results also have implications for the role of stoichiometry in gene expression, the control of quantitative traits, and the evolution of dosage-sensitive genes.

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Xu, Luohao, Martin Irestedt e Qi Zhou. "Sequence Transpositions Restore Genes on the Highly Degenerated W Chromosomes of Songbirds". Genes 11, n. 11 (28 ottobre 2020): 1267. http://dx.doi.org/10.3390/genes11111267.

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The female-specific W chromosomes of most Neognathae birds are highly degenerated and gene-poor. Previous studies have demonstrated that the gene repertoires of the Neognathae bird W chromosomes, despite being in small numbers, are conserved across bird species, likely due to purifying selection maintaining the regulatory and dosage-sensitive genes. Here we report the discovery of DNA-based sequence duplications from the Z to the W chromosome in birds-of-paradise (Paradisaeidae, Passeriformes), through sequence transposition. The original transposition involved nine genes, but only two of them (ANXA1 and ALDH1A1) survived on the W chromosomes. Both ANXA1 and ALDH1A1 are predicted to be dosage-sensitive, and the expression of ANXA1 is restricted to ovaries in all the investigated birds. These analyses suggest the newly transposed gene onto the W chromosomes can be favored for their role in restoring dosage imbalance or through female-specific selection. After examining seven additional songbird genomes, we further identified five other transposed genes on the W chromosomes of Darwin’s finches and one in the great tit, expanding the observation of the Z-to-W transpositions to a larger range of bird species, but not all transposed genes exhibit dosage-sensitivity or ovary-biased expression We demonstrate a new mechanism by which the highly degenerated W chromosomes of songbirds can acquire genes from the homologous Z chromosomes, but further functional investigations are needed to validate the evolutionary forces underlying the transpositions.

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Sood, Sabina, Christopher M. Weber, H. Courtney Hodges, Andrey Krokhotin, Aryaman Shalizi e Gerald R. Crabtree. "CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation". Proceedings of the National Academy of Sciences 117, n. 36 (24 agosto 2020): 22331–40. http://dx.doi.org/10.1073/pnas.1921963117.

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The chromatin remodelerCHD8is among the most frequently mutated genes in autism spectrum disorder (ASD). CHD8 has a dosage-sensitive role in ASD, but when and how it becomes critical to human social function is unclear. Here, we conducted genomic analyses of heterozygous and homozygousChd8mouse embryonic stem cells and differentiated neural progenitors. We identify dosage-sensitive CHD8 transcriptional targets, sites of regulated accessibility, and an unexpected cooperation with SOX transcription factors. Collectively, our findings reveal that CHD8 negatively regulates expression of neuronal genes to maintain pluripotency and also during differentiation. Thus, CHD8 is essential for both the maintenance of pluripotency and neural differentiation, providing mechanistic insight into its function with potential implications for ASD.

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Pessia, E., T. Makino, M. Bailly-Bechet, A. McLysaght e G. A. B. Marais. "Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome". Proceedings of the National Academy of Sciences 109, n. 14 (5 marzo 2012): 5346–51. http://dx.doi.org/10.1073/pnas.1116763109.

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Arthur, Robert K., Ningfei An, Saira Kahn e Megan E. McNerney. "Enhancer-Promoter Looping Deciphers Dosage of the Haploinsufficient Transcription Factor, CUX1". Blood 128, n. 22 (2 dicembre 2016): 2700. http://dx.doi.org/10.1182/blood.v128.22.2700.2700.

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Abstract One third of tumor suppressor genes encode haploinsufficient transcriptional regulators, including transcription factors and chromatin remodelers. This presents a major barrier in oncology, as tumor suppressor genes and transcription factors are inherently difficult to target therapeutically. It remains unknown how a 50% reduction of a transcriptional regulator translates at the cis-regulatory level into a malignant transcriptional program. It is imperative to address this question, in order to predict and target aberrant downstream pathways. CUX1 encodes a quintessential haploinsufficient transcription factor that is recurrently mutated or deleted, monoallelically, in high-risk myeloid neoplasms and across solid tumor types. We hypothesized that the transcriptional response to changes in CUX1 level is encoded within the cis-regulatory architecture of dosage-sensitive CUX1 target genes. In this study, we determined that CUX1 primarily binds distal enhancers, in a tissue-specific manner. CUX1 binding sites are significantly enriched for co-binding with transcriptional activators and cohesin components. Haploinsufficiency of CUX1 in K562 myeloid leukemia cells led to altered expression of mitotic and apoptotic genes with concomitant increased cellular proliferation. Surprisingly, ChIP-seq of CUX1 in the haploinsufficient state revealed a unimodal decrease in CUX1 occupancy genome-wide, with no relevance to differential gene expression. Thus we used a machine-learning algorithm to identify characteristics of CUX1 binding sites at dosage-sensitive target genes and revealed a relationship with distance to the transcription start site, chromatin accessibility, and enhancer activity. Finally, we demonstrate that CUX1 binding sites at dosage-sensitive genes loop to the promoter, and those genes with an intermediate number of Hi-C loops are most responsive to changes in CUX1 abundance. Overall, these data point to a novel mechanism of transcription factor dose-responsiveness mediated by enhancer-promoter looping. Disclosures No relevant conflicts of interest to declare.

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Strome, Erin D., Xiaowei Wu, Marek Kimmel e Sharon E. Plon. "Heterozygous Screen in Saccharomyces cerevisiae Identifies Dosage-Sensitive Genes That Affect Chromosome Stability". Genetics 178, n. 3 (1 febbraio 2008): 1193–207. http://dx.doi.org/10.1534/genetics.107.084103.

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Chang, Zhiqiang, Xinxin Liu, Wenyuan Zhao e Yan Xu. "Identification and Characterization of the Copy Number Dosage-Sensitive Genes in Colorectal Cancer". Molecular Therapy - Methods & Clinical Development 18 (settembre 2020): 501–10. http://dx.doi.org/10.1016/j.omtm.2020.06.020.

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Hiebert, J. C., e J. A. Birchler. "Effects of the maleless mutation on X and autosomal gene expression in Drosophila melanogaster." Genetics 136, n. 3 (1 marzo 1994): 913–26. http://dx.doi.org/10.1093/genetics/136.3.913.

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Abstract The mutational effect of the maleless (mle) gene in Drosophila has been reexamined. Earlier work had suggested that mle along with other male-lethal genes was responsible for hypertranscription of the X chromosome in males to bring about dosage compensation. Prompted by studies on dosage sensitive regulatory genes, we tested for effects of mlets on the phenotypes of 16 X or autosomal mutations in adult escapers of lethality. In third instar larvae, prior to the major lethal phase of mle, we examined activities of 6 X or autosomally encoded enzymes, steady state mRNA levels of 15 X-linked or autosomal genes and transcripts from two large genomic segments derived from either the X or from chromosome 2 and present in yeast artificial chromosomes. In contrast to the previously hypothesized role, we detected pronounced effects of mle on the expression of both X-linked and autosomal loci such that a large proportion of the tested genes were increased in expression, while only two X-linked loci were reduced. The most prevalent consequence was an increase of autosomal gene expression, which can explain previously observed reduced X:autosome transcription ratios. These observations suggest that if mle plays a role in the discrimination of the X and the autosomes, it may do so by modification of the effects of dosage sensitive regulatory genes.

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Drobek, Michaela. "Paralogous Genes Involved in Embryonic Development: Lessons from the Eye and Other Tissues". Genes 13, n. 11 (9 novembre 2022): 2082. http://dx.doi.org/10.3390/genes13112082.

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During evolution, gene duplications lead to a naturally increased gene dosage. Duplicated genes can be further retained or eliminated over time by purifying selection pressure. The retention probability is increased by functional diversification and by the acquisition of novel functions. Interestingly, functionally diverged paralogous genes can maintain a certain level of functional redundancy and at least a partial ability to replace each other. In such cases, diversification probably occurred at the level of transcriptional regulation. Nevertheless, some duplicated genes can maintain functional redundancy after duplication and the ability to functionally compensate for the loss of each other. Many of them are involved in proper embryonic development. The development of particular tissues/organs and developmental processes can be more or less sensitive to the overall gene dosage. Alterations in the gene dosage or a decrease below a threshold level may have dramatic phenotypic consequences or even lead to embryonic lethality. The number of functional alleles of particular paralogous genes and their mutual cooperation and interactions influence the gene dosage, and therefore, these factors play a crucial role in development. This review will discuss individual interactions between paralogous genes and gene dosage sensitivity during development. The eye was used as a model system, but other tissues are also included.

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Chiang, Pei-Wen, e David M. Kurnit. "Study of Dosage Compensation in Drosophila". Genetics 165, n. 3 (1 novembre 2003): 1167–81. http://dx.doi.org/10.1093/genetics/165.3.1167.

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Abstract Using a sensitive RT-QPCR assay, we analyzed the regulatory effects of sex and different dosage compensation mutations in Drosophila. To validate the assay, we showed that regulation for several genes indeed varied with the number of functional copies of that gene. We then confirmed that dosage compensation occurred for most genes we examined in male and female flies. Finally, we examined the effects on regulation of several genes in the MSL pathway, presumed to be involved in sex-dependent determination of regulation. Rather than seeing global alterations of either X chromosomal or autosomal genes, regulation of genes on either the X chromosome or the autosomes could be elevated, depressed, or unaltered between sexes in unpredictable ways for the various MSL mutations. Relative dosage for a given gene between the sexes could vary at different developmental times. Autosomal genes often showed deranged regulatory levels, indicating they were in pathways perturbed by X chromosomal changes. As exemplified by the BR-C locus and its dependent Sgs genes, multiple genes in a given pathway could exhibit coordinate regulatory modulation. The variegated pattern shown for expression of both X chromosomal and autosomal loci underscores the complexity of gene expression so that the phenotype of MSL mutations does not reflect only simple perturbations of genes on the X chromosome.

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Zhang, Shuai, Ruixue Wang, Ludan Zhang, James A. Birchler e Lin Sun. "Inverse and Proportional Trans Modulation of Gene Expression in Human Aneuploidies". Genes 15, n. 5 (17 maggio 2024): 637. http://dx.doi.org/10.3390/genes15050637.

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Genomic imbalance in aneuploidy is often detrimental to organisms. To gain insight into the molecular basis of aneuploidies in humans, we analyzed transcriptome data from several autosomal and sex chromosome aneuploidies. The results showed that in human aneuploid cells, genes located on unvaried chromosomes are inversely or proportionally trans-modulated, while a subset of genes on the varied chromosomes are compensated. Less genome-wide modulation is found for sex chromosome aneuploidy compared with autosomal aneuploidy due to X inactivation and the retention of dosage sensitive regulators on both sex chromosomes to limit the effective dosage change. We also found that lncRNA and mRNA can have different responses to aneuploidy. Furthermore, we analyzed the relationship between dosage-sensitive transcription factors and their targets, which illustrated the modulations and indicates genomic imbalance is related to stoichiometric changes in components of gene regulatory complexes.In summary, this study demonstrates the existence of trans-acting effects and compensation mechanisms in human aneuploidies and contributes to our understanding of gene expression regulation in unbalanced genomes and disease states.

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White, Michael A., Jun Kitano e Catherine L. Peichel. "Purifying Selection Maintains Dosage-Sensitive Genes during Degeneration of the Threespine Stickleback Y Chromosome". Molecular Biology and Evolution 32, n. 8 (26 marzo 2015): 1981–95. http://dx.doi.org/10.1093/molbev/msv078.

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Brady, P. D., P. DeKoninck, J. P. Fryns, K. Devriendt, J. A. Deprest e J. R. Vermeesch. "Identification of dosage-sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia". Prenatal Diagnosis 33, n. 13 (14 novembre 2013): 1283–92. http://dx.doi.org/10.1002/pd.4244.

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Liu, Xinyu, Ran Yan, Haosheng Liu, Shuai Zhang, Ruixue Wang, Bowen Zhang e Lin Sun. "Genome-Wide Expression Analysis of Long Noncoding RNAs and Their Target Genes in Metafemale Drosophila". International Journal of Molecular Sciences 24, n. 9 (6 maggio 2023): 8381. http://dx.doi.org/10.3390/ijms24098381.

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Abstract (sommario):

Aneuploidy is usually more detrimental than altered ploidy of the entire set of chromosomes. To explore the regulatory mechanism of gene expression in aneuploidy, we analyzed the transcriptome sequencing data of metafemale Drosophila. The results showed that most genes on the X chromosome undergo dosage compensation, while the genes on the autosomal chromosomes mainly present inverse dosage effects. Furthermore, long noncoding RNAs (lncRNAs) have been identified as key regulators of gene expression, and they are more sensitive to dosage changes than mRNAs. We analyzed differentially expressed mRNAs (DEGs) and differentially expressed lncRNAs (DELs) in metafemale Drosophila and performed functional enrichment analyses of DEGs and the target genes of DELs, and we found that they are involved in several important biological processes. By constructing lncRNA-mRNA interaction networks and calculating the maximal clique centrality (MCC) value of each node in the network, we also identified two key candidate lncRNAs (CR43940 and CR42765), and two of their target genes, Sin3A and MED1, were identified as inverse dosage modulators. These results suggest that lncRNAs play an important role in the regulation of genomic imbalances. This study may deepen the understanding of the gene expression regulatory mechanisms in aneuploidy from the perspective of lncRNAs.

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Last, Robert L., Janine R. Maddock e John L. Woolford. "Evidence for Related Functions of the RNA Genes of Saccharomyces cerevisiae". Genetics 117, n. 4 (1 dicembre 1987): 619–31. http://dx.doi.org/10.1093/genetics/117.4.619.

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ABSTRACT The yeast genes RNA2-RNA11 are necessary for splicing of nuclear intron-containing pre-mRNAs. We investigated the relationships among these genes by asking whether increased expression of one RNA gene leads to suppression of the temperature-sensitive lethality of a mutation in any other RNA gene. The presence of extra plasmid-borne copies of the RNA3 gene relieves the lethality of temperature-sensitive rna4 mutations. A region of the yeast genome (SRN2) is described that suppresses temperature-sensitive rna2 mutations when it is present on either medium or high-copy number plasmids. Neither suppression occurs via a bypass of RNA gene function since null alleles of rna2 and rna4 are not suppressed by elevated dosage of SRN2 and RNA3, respectively. These results suggest that the SRN2 and RNA2 gene products have related functions, as do the RNA3 and RNA4 gene products.

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Makanae, K., R. Kintaka, T. Makino, H. Kitano e H. Moriya. "Identification of dosage-sensitive genes in Saccharomyces cerevisiae using the genetic tug-of-war method". Genome Research 23, n. 2 (28 dicembre 2012): 300–311. http://dx.doi.org/10.1101/gr.146662.112.

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Birchler, J. A., U. Bhadra, L. Rabinow, R. Linsk e A. T. Nguyen-Huynh. "Weakener of white (Wow), a gene that modifies the expression of the white eye color locus and that suppresses position effect variegation in Drosophila melanogaster." Genetics 137, n. 4 (1 agosto 1994): 1057–70. http://dx.doi.org/10.1093/genetics/137.4.1057.

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Abstract A locus is described in Drosophila melanogaster that modifies the expression of the white eye color gene. This trans-acting modifier reduces the expression of the white gene in the eye, but elevates the expression in other adult tissues. Because of the eye phenotype in which the expression of white is lessened but not eliminated, the newly described locus is called the Weakener of white (Wow). Northern analysis reveals that Wow can exert an inverse or direct modifying effect depending upon the developmental stage. Two related genes, brown and scarlet, that are coordinately expressed with white, are also affected by Wow. In addition, Wow modulates the steady state RNA level of the retrotransposon, copia. When tested with a white promoter-Alcohol dehydrogenase reporter. Wow confers the modifying effect to the reporter, suggesting a requirement of the white regulatory sequences for mediating the response. In addition to being a dosage sensitive regulator of white, brown, scarlet and copia, Wow acts as a suppressor of position effect variegation. There are many dosage sensitive suppressors of position effect variegation and many dosage-sensitive modifiers of gene expression. The Wow mutations provide evidence for an overlap between the two types of modifiers.

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Mitsuzawa, H., I. Uno, T. Oshima e T. Ishikawa. "Isolation and characterization of temperature-sensitive mutations in the RAS2 and CYR1 genes of Saccharomyces cerevisiae." Genetics 123, n. 4 (1 dicembre 1989): 739–48. http://dx.doi.org/10.1093/genetics/123.4.739.

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Abstract The yeast Saccharomyces cerevisiae contains two ras homologues, RAS1 and RAS2, whose products have been shown to modulate the activity of adenylate cyclase encoded by the CYR1 gene. To isolate temperature-sensitive mutations in the RAS2 gene, we constructed a plasmid carrying a RAS2 gene whose expression is under the control of the galactose-inducible GAL1 promoter. A ras1 strain transformed with this plasmid was subjected to ethyl methanesulfonate mutagenesis and nystatin enrichment. Screening of approximately 13,000 mutagenized colonies for galactose-dependent growth at a high temperature (37 degrees) yielded six temperature-sensitive ras2 (ras2ts) mutations and one temperature-sensitive cyr1 (cyr1ts) mutation that can be suppressed by overexpression or increased dosage of RAS2. Some ras2ts mutations were shown to be suppressed by an extra copy of CYR1. Therefore increased dosage of either RAS2 or CYR1 can suppress the temperature sensitivity caused by a mutation in the other. ras1 ras2ts and ras1 cyr1ts mutants arrested in the G1 phase of the cell cycle at the restrictive temperature, and showed pleiotropic phenotypes to varying degrees even at a temperature permissive for growth (25 degrees), including slow growth, sporulation on rich media, increased accumulation of glycogen, impaired growth on nonfermentable carbon sources, heat-shock resistance, impaired growth on low concentrations of glucose, and lithium sensitivity. Of these, impaired growth on low concentrations of glucose and sensitivity to lithium are new phenotypes, which have not been reported for mutants defective in the cAMP pathway.

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Kasyan, Armen G., e Kurt Benirschke. "Genetic Haploinsufficiency as a Phenotypic Determinant of a Deletion 13q Syndrome". Pediatric and Developmental Pathology 8, n. 6 (novembre 2005): 658–65. http://dx.doi.org/10.1007/s10024-005-0066-z.

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Two cases of newborns with deletion 13q syndrome were identified and studied using electron microscopy and histologic, immunohistochemical, and special stained sections. We reviewed the published literature on genes that are haploinsufficient in the deletion 13q syndrome. The complexity of the deletion 13q syndrome phenotype is due at least in part to the haploinsufficiency of dosage-sensitive genes. Future studies need to be performed to identify their precise role in the cellular function and the development of the deletion 13q syndrome phenotype.

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32

Kechavarzi, Bobak D., Huanmei Wu e Thompson N. Doman. "Bottom-up, integrated -omics analysis identifies broadly dosage-sensitive genes in breast cancer samples from TCGA". PLOS ONE 14, n. 1 (17 gennaio 2019): e0210910. http://dx.doi.org/10.1371/journal.pone.0210910.

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33

Wright, A. E., e J. E. Mank. "Battle of the sexes: Conflict over dosage-sensitive genes and the origin of X chromosome inactivation". Proceedings of the National Academy of Sciences 109, n. 14 (21 marzo 2012): 5144–45. http://dx.doi.org/10.1073/pnas.1202905109.

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34

Aleksiūnienė, Beata, Egle Preiksaitiene, Aušra Morkūnienė, Laima Ambrozaitytė e Algirdas Utkus. "A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect". Cytogenetic and Genome Research 154, n. 1 (2018): 6–11. http://dx.doi.org/10.1159/000486947.

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Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4-5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23.1 region, arr[GRCh37] 1q22q23.1(155630752_157193893)×1. Real-time PCR analysis confirmed its de novo origin. The deleted region encompasses 50 protein-coding genes, including the morbid genes APOA1BP, ARHGEF2, LAMTOR2, LMNA, NTRK1, PRCC, RIT1, SEMA4A, and YY1AP1. Although the unique phenotype observed in our patient can arise from the haploinsufficiency of the dosage-sensitive LMNA gene, the dosage imbalance of other genes implicated in the rearrangement could also contribute to the phenotype. Further studies are required for the delineation of the phenotype associated with this rare chromosomal alteration and elucidation of the critical genes for manifestation of the specific clinical features.

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Hsu, D. R., e B. J. Meyer. "The dpy-30 gene encodes an essential component of the Caenorhabditis elegans dosage compensation machinery." Genetics 137, n. 4 (1 agosto 1994): 999–1018. http://dx.doi.org/10.1093/genetics/137.4.999.

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Abstract The need to regulate X chromosome expression in Caenorhabditis elegans arises as a consequence of the primary sex-determining signal, the X/A ratio (the ratio of X chromosomes to sets of autosomes), which directs 1X@A animals to develop as males and 2X/2A animals to develop as hermaphrodites. C. elegans possesses a dosage compensation mechanism that equalizes X chromosome expression between the two sexes despite their disparity in X chromosome dosage. Previous genetic analysis led to the identification of four autosomal genes, dpy-21, dpy-26, dpy-27 and dpy-28, whose products are essential in XX animals for proper dosage compensation, but not for sex determination. We report the identification and characterization of dpy-30, an essential component of the dosage compensation machinery. Putative null mutations in dpy-30 disrupt dosage compensation and cause a severe maternal-effect, XX-specific lethality. Rare survivors of the dpy-30 lethality are dumpy and express their X-linked genes at higher than wild-type levels. These dpy-30 mutant phenotypes superficially resemble those caused by mutations in dpy-26, dpy-27 and dpy-28; however, detailed phenotypic analysis reveals important differences that distinguish dpy-30 from these genes. In contrast to the XX-specific lethality caused by mutations in the other dpy genes, the XX-specific lethality caused by dpy-30 mutations is completely penetrant and temperature sensitive. In addition, unlike the other genes, dpy-30 is required for the normal development of XO animals. Although dpy-30 mutations do not significantly affect the viability of XO animals, they do cause them to be developmentally delayed and to possess numerous morphological and behavioral abnormalities. Finally, dpy-30 mutations can dramatically influence the choice of sexual fate in animals with an ambiguous sexual identity, despite having no apparent effect on the sexual phenotype of otherwise wild-type animals. Paradoxically, depending on the genetic background, dpy-30 mutations cause either masculinization or feminization, thus revealing the complex regulatory relationship between the sex determination and dosage compensation processes. The novel phenotypes caused by dpy-30 mutations suggest that in addition to acting in the dosage compensation process, dpy-30 may play a more general role in the development of both XX and XO animals.

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Haller, Meade, Qianxing Mo, Akira Imamoto e Dolores J. Lamb. "Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development". Proceedings of the National Academy of Sciences 114, n. 19 (24 aprile 2017): 4981–86. http://dx.doi.org/10.1073/pnas.1619523114.

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Abstract (sommario):

The spectrum of congenital anomalies affecting either the upper tract (kidneys and ureters) or lower tract (reproductive organs) of the genitourinary (GU) system are fundamentally linked by the developmental origin of multiple GU tissues, including the kidneys, gonads, and reproductive ductal systems: the intermediate mesoderm. Although ∼31% of DiGeorge/del22q11.2 syndrome patients exhibit GU defects, little focus has been placed on the molecular etiology of GU defects in this syndrome. Among del22q11.2 patients exhibiting GU anomalies, we have mapped the smallest relevant region to only five genes, including CRKL. CRKL encodes a src-homology adaptor protein implicated in mediating tyrosine kinase signaling, and is expressed in the developing GU-tract in mice and humans. Here we show that Crkl mutant embryos exhibit gene dosage-dependent growth restriction, and homozygous mutants exhibit upper GU defects at a microdissection-detectable rate of 23%. RNA-sequencing revealed that 52 genes are differentially regulated in response to uncoupling Crkl from its signaling pathways in the developing kidney, including a fivefold up-regulation of Foxd1, a known regulator of nephron progenitor differentiation. Additionally, Crkl heterozygous adult males exhibit cryptorchidism, lower testis weight, lower sperm count, and subfertility. Together, these data indicate that CRKL is intimately involved in normal development of both the upper and lower GU tracts, and disruption of CRKL contributes to the high incidence of GU defects associated with deletion at 22q11.2.

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Guo, Mei, e James A. Birchler. "Dosage regulation of Zea mays homeobox (ZmHox) genes and their relationship with the dosage-sensitive regulatory factors of Shrunken 1 (Sh1) in maize". Developmental Genetics 20, n. 1 (1997): 67–73. http://dx.doi.org/10.1002/(sici)1520-6408(1997)20:1<67::aid-dvg8>3.0.co;2-7.

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38

Bowers, Robert R., Tyler J. Slonecki, Bode A. Olukolu, G. Craig Yencho e Phillip A. Wadl. "Genome-Wide Association Study of Sweet Potato Storage Root Traits Using GWASpoly, a Gene Dosage-Sensitive Model". International Journal of Molecular Sciences 25, n. 21 (31 ottobre 2024): 11727. http://dx.doi.org/10.3390/ijms252111727.

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Abstract (sommario):

Sweet potato (Ipomoea batatas) is an important food crop that plays a pivotal role in preserving worldwide food security. Due to its polyploid genome, high heterogeneity, and phenotypic plasticity, sweet potato genetic characterization and breeding is challenging. Genome-wide association studies (GWASs) can provide important resources for breeders to improve breeding efficiency and effectiveness. GWASpoly was used to identify 28 single nucleotide polymorphisms (SNPs), comprising 21 unique genetic loci, associated with sweet potato storage root traits including dry matter (4 loci), subjective flesh color (5 loci), flesh hue angle (3 loci), and subjective skin color and skin hue angle (9 loci), in 384 accessions from the USDA sweet potato germplasm collection. The I. batatas ‘Beauregard’ and I. trifida reference genomes were utilized to identify candidate genes located within 100 kb from the SNPs that may affect the storage traits of dry matter, flesh color, and skin color. These candidate genes include transcription factors (especially Myb, bHLH, and WRKY family members), metabolite transporters, and metabolic enzymes and associated proteins involved in starch, carotenoid, and anthocyanin synthesis. A greater understanding of the genetic loci underlying sweet potato storage root traits will enable marker-assisted breeding of new varieties with desired traits. This study not only reinforces previous research findings on genes associated with dry matter and β-carotene content but also introduces novel genetic loci linked to these traits as well as other root characteristics.

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39

Baldini, Antonio. "The 22q11.2 Deletion Syndrome: A Gene Dosage Perspective". Scientific World JOURNAL 6 (2006): 1881–87. http://dx.doi.org/10.1100/tsw.2006.317.

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Abstract (sommario):

The 22q11.2 deletion/DiGeorge syndrome is a relatively common “genomic” disorder that results from heterozygous deletion of a 3-Mbp segment of chromosome 22. Of the more than 30 genes deleted in this syndrome,TBX1is the only one that has been found to be mutated in some patients with a phenotype that is very similar to that of patients with the full deletion, suggesting thatTBX1haploinsufficiency is a major contributor to the syndromes phenotype. Multi- and single-gene mouse models have provided a considerable amount of information about the consequences of decreased and increased dosage of the genomic region (and in particular of theTbx1gene) on mouse embryonic development. Modified alleles ofTbx1, as well as conditional ablation strategies have been utilized to mapin vivothe tissues and developmental stages most sensitive to gene dosage. These experiments have revealed substantially different sensitivity to gene dosage in different tissues and at different times, underlying the importance of the developmental context within which gene dosage reduction occurs.

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40

Carter, Jennifer, Melinda Zombor, Adrienn Máté, László Sztriha e Jonathan J. Waters. "De Novo Interstitial Microdeletion at 1q32.1 in a 10-Year-Old Boy with Developmental Delay and Dysmorphism". Case Reports in Genetics 2016 (2016): 1–3. http://dx.doi.org/10.1155/2016/2501741.

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Abstract (sommario):

A 10-year-old boy was referred with developmental delay and dysmorphism. Genomewide aCGH microarray analysis detected a de novo 3.7 Mb deletion at 1q32.1: arr 1q32.1(199,985,888-203,690,832)x1 dn [build HG19]. This first report of a deletion in this region implies a critical role for dosage-sensitive genes within 1q32.1 in neurological development. This is consistent with previously reported duplications of this region in patients with a similar phenotype.

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Duffy, Supipi, Hok Khim Fam, Yi Kan Wang, Erin B. Styles, Jung-Hyun Kim, J. Sidney Ang, Tejomayee Singh et al. "Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer". Proceedings of the National Academy of Sciences 113, n. 36 (22 agosto 2016): 9967–76. http://dx.doi.org/10.1073/pnas.1611839113.

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Abstract (sommario):

Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes,TDP1, a tyrosyl-DNA-phosphdiesterase, andTAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown ofTDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylaseRPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.

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42

Yamagishi, J., T. Kojima, Y. Oyamada, K. Fujimoto, H. Hattori, S. Nakamura e M. Inoue. "Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 40, n. 5 (maggio 1996): 1157–63. http://dx.doi.org/10.1128/aac.40.5.1157.

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Abstract (sommario):

A 4.2-kb DNA fragment conferring quinolone resistance was cloned from a quinolone-resistant clinical isolate of Staphylococcus aureus and was shown to possess a part of the grlB gene and a mutated grlA gene. S-80-->F and E-84-->K mutations in the grlA gene product were responsible for the quinolone resistance. The mutated grlA genes responsible for quinolone resistance were dominant over the wild-type allele, irrespective of gene dosage in a transformation experiment with the grlA gene alone. However, dominance by mutated grlA genes depended on gene dosage when bacteria were transformed with the grlA and grlB genes in combination. Quinolone-resistant gyrA mutants were easily isolated from a strain, S. aureus RN4220, carrying a plasmid with the mutated grlA gene, though this was not the case for other S. aureus strains lacking the plasmid. The elimination of this plasmid from such quinolone-resistant gyrA mutants resulted in marked increases in quinolone susceptibility. These results suggest that both DNA gyrase and DNA topoisomerase IV may be targets of quinolones and that the quinolone susceptibility of organisms may be determined by which of these enzymes is most quinolone sensitive.

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Phillips, M. D., e A. Shearn. "Mutations in polycombeotic, a Drosophila polycomb-group gene, cause a wide range of maternal and zygotic phenotypes." Genetics 125, n. 1 (1 maggio 1990): 91–101. http://dx.doi.org/10.1093/genetics/125.1.91.

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Abstract (sommario):

Abstract The polycomb-group genes, a set of genes characterized by mutations that cause similar phenotypes and dosage-dependent interactions, are required for the normal expression of segment-specific homeotic loci. Here we report that polycombeotic (formerly 1(3)1902), originally identified by a lethal mutation that causes a small-disc phenotype, is also a member of this group of essential genes. Adults homozygous for temperature-sensitive pco alleles that were exposed to the restrictive temperature during larval life display the second and third leg to first leg transformation characteristic of polycomb-group mutants. Adult females homozygous for temperature-sensitive alleles exposed to the restrictive temperature during oogenesis produce embryos that show anterior segments with structures normally unique to the eighth abdominal segment, another transformation characteristic of polycomb-group mutants. Mutations in the polycombeotic gene also cause defects not reported for mutations in other polycomb-group genes. Females homozygous for the most extreme temperature-sensitive allele are sterile, and larvae homozygous for null alleles have small imaginal discs and reduced frequencies of mitotic figures in the brain. Dominant mutations originally identified as enhancers or suppressors of zeste are gain-of-function alleles of polycombeotic. The type and variety of defects displayed by different mutations in this gene indicate that the product might be involved in chromosome structure and/or function.

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Kuzmin, Elena, Jean Monlong, Mathieu Bourgey, Jarry Barber, Tom Lesluyes, Toby Baker, Genevieve Morin et al. "Abstract 44: Evolution of large copy number variants in breast cancer through genetic network rewiring". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 44. http://dx.doi.org/10.1158/1538-7445.am2022-44.

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Abstract (sommario):

Abstract Large chromosomal alterations are common in cancer and often show preferential gain or loss across many cancer types indicating their selective advantage. Triple negative breast cancer (TNBC) exhibits complex mutational spectrum without common oncogenic drivers yet displays consistent loss of large chromosomal regions. Here, we characterize selection pressures that maintain a recurrently deleted region of chromosome 4p in TNBC. We used single cell and bulk WGS phylogenetic analysis of TNCB PT/PDX panel to show that chr4p deletion is an early event in tumor evolution. We used scRNAseq gene expression and inferred copy number analysis to show that chr4p loss is associated with a proliferative state. This finding was confirmed by a combination of RNA in situ hybridization and immunofluorescence. We then tested the dosage sensitivity of genes residing within this region by individual and dual overexpression in TNBC PDX-derived cell lines and control normal cell line by assessing their effect on cell proliferation. The overexpression of genes within chr4p elicited a strong cell proliferation defect in cancer but not normal cell line models. We also characterized an unknown gene within chr4p region as a novel member of the STRIPAK complex. Genome-wide pooled ORFeome library screens identified a global pattern of background-specific dosage sensitive regions. Our study shows that large chromosomal deletions are maintained due to evolutionary early genetic network rewiring rendering multiple genes within such regions to be dosage sensitive. Ultimately, this work enhances our understanding of genetic events that modulate TNBC. Citation Format: Elena Kuzmin, Jean Monlong, Mathieu Bourgey, Jarry Barber, Tom Lesluyes, Toby Baker, Genevieve Morin, Dongmei Zou, Michael Schwartz, Yang Yang, Alain Pacis, Constanza Martinez, Hellen Kuasne, Anne-Marie Fortier, Rui Li, Claudia Kleinman, Sidong Huang, Peter van Loo, Quaid Morris, Jiannis Ragoussis, Guillaume Bourque, Morag Park. Evolution of large copy number variants in breast cancer through genetic network rewiring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 44.

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Kuzmin, Elena, Jean Monlong, Mathieu Bourgey, Tom Lesluyes, Toby Barker, Genevieve Morin, Dongmei Zou et al. "Abstract 1512: Evolution of large copy number variants in breast cancer through genetic network rewiring". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 1512. http://dx.doi.org/10.1158/1538-7445.am2023-1512.

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Abstract (sommario):

Abstract Large chromosomal alterations are common in cancer and often show preferential gain or loss across many cancer types indicating their selective advantage. Triple negative breast cancer (TNBC) exhibits complex mutational spectrum without common oncogenic drivers yet displays consistent loss of large chromosomal regions. Here, we characterize selection pressures that maintain a recurrently deleted region of chromosome 4p in TNBC. We used bulk WGS phylogenetic analysis of TNCB PT/PDX panel to show that chr4p deletion is an early event in tumor evolution. We used scRNAseq gene expression and inferred copy number analysis to show that chr4p loss is associated with a proliferative state. This finding was confirmed by a combination of RNA in situ hybridization and immunofluorescence. We then tested the dosage sensitivity of genes residing within this region by individual and dual overexpression in TNBC PDX-derived cell lines and control normal cell line by assessing their effect on cell proliferation. The overexpression of genes within chr4p elicited a strong cell proliferation defect in cancer but not normal cell line models. We also characterized an unknown gene within chr4p region as a novel member of the STRIPAK complex. Genome-wide pooled ORFeome library screens identified a global pattern of background-specific dosage sensitive regions. Our study shows that large chromosomal deletions are maintained due to evolutionary early genetic network rewiring rendering multiple genes within such regions to be dosage sensitive. Ultimately, this work enhances our understanding of genetic events that modulate TNBC. Citation Format: Elena Kuzmin, Jean Monlong, Mathieu Bourgey, Tom Lesluyes, Toby Barker, Genevieve Morin, Dongmei Zou, Michael Schwartz, Yang Yang, Alain Pacis, Constanza Martinez, Hellen Kuasne, Anne-Marie Fortier, Rui Li, Claudia Kleinman, Sidong Huang, Peter van Loo, Jiannis Ragoussis, Guillaume Bourque, Morag Park. Evolution of large copy number variants in breast cancer through genetic network rewiring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1512.

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Bonney, Megan E., Hisao Moriya e Angelika Amon. "Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage-sensitive genes". Genes & Development 29, n. 9 (1 maggio 2015): 898–903. http://dx.doi.org/10.1101/gad.261743.115.

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47

Lewis, Zoe, Daniel Reich e Denise Quigley. "P541: Updating patient results for genomic CNVs intersecting dosage sensitive genes on the ACMG secondary findings v3.1 list". Genetics in Medicine Open 1, n. 1 (2023): 100588. http://dx.doi.org/10.1016/j.gimo.2023.100588.

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48

Ishihara, Keiichi. "Genes Associated with Disturbed Cerebral Neurogenesis in the Embryonic Brain of Mouse Models of Down Syndrome". Genes 12, n. 10 (11 ottobre 2021): 1598. http://dx.doi.org/10.3390/genes12101598.

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Abstract (sommario):

Down syndrome (DS), also known as trisomy 21, is the most frequent genetic cause of intellectual disability. Although the mechanism remains unknown, delayed brain development is assumed to be involved in DS intellectual disability. Analyses with human with DS and mouse models have shown that defects in embryonic cortical neurogenesis may lead to delayed brain development. Cre-loxP-mediated chromosomal engineering has allowed the generation of a variety of mouse models carrying various partial Mmu16 segments. These mouse models are useful for determining genotype–phenotype correlations and identifying dosage-sensitive genes involved in the impaired neurogenesis. In this review, we summarize several candidate genes and pathways that have been linked to defective cortical neurogenesis in DS.

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Gubb, David, John Roote, Jennifer Trenear, Darin Coulson e Michael Ashburner. "Topological Constraints on Transvection Between white Genes Within the Transposing Element TE35B in Drosophila melanogaster". Genetics 146, n. 3 (1 luglio 1997): 919–37. http://dx.doi.org/10.1093/genetics/146.3.919.

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Abstract (sommario):

The transposable element TE35B carries two copies of the white (w) gene at 35B1.2 on the second chromosome. These w genes are suppressed in a zeste-1 (z1) mutant background in a synapsis-dependent manner. Single-copy derivatives of the original TE35B stock give red eyes when heterozygous, but zeste eyes when homozygous. TE35B derivatives carrying single, double or triple copies of w were crossed to generate flies carrying from two to five ectopic w genes. Within this range, z1-mediated suppression is insensitive to copynumber and does not distinguish between w genes that are in cis or in trans. Suppression does not require the juxtaposition of even numbers of w genes, but is extremely sensitive to chromosomal topology. When arranged in a tight cluster, in triple-copy TE derivatives, w genes are non-suppressible. Breakpoints falling within TE35B and separating two functional w genes act as partial suppressors of z1. Similarly, breakpoints immediately proximal or distal to both w genes give partial suppression. This transvection-dependent downregulation of w genes may result from mis-activation of the X-chromosome dosage compensation mechanism.

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Krasnow, R. E., L. L. Wong e P. N. Adler. "Dishevelled is a component of the frizzled signaling pathway in Drosophila". Development 121, n. 12 (1 dicembre 1995): 4095–102. http://dx.doi.org/10.1242/dev.121.12.4095.

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Abstract (sommario):

The tissue polarity genes in Drosophila are required to coordinate cell polarity within the plane of the epidermis. Evidence to date suggests that these genes may encode components of a novel signal transduction pathway. Three of the genes, frizzled (fz), dishevelled (dsh), and prickle (pk) share a similar tissue polarity phenotype, suggesting that they function together in a single process. dsh is also known to function as a mediator of wingless (wg) signaling in a variety of developmental patterning processes in the fly. In this study, we make use of a fz transgene and a hypomorphic fz allele as genetic tools in an attempt to order these genes in a genetic hierarchy. Our results argue that dsh encodes a dosage sensitive component required for fz function and that it likely acts downstream of fz in the generation of tissue polarity. Our findings suggest that dsh may have a general role in signal transduction, perhaps as a component of a receptor complex.

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