scholarly journals Aneuploidy and gene expression: is there dosage compensation?

Epigenomics ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1827-1837 ◽  
Author(s):  
Shihoko Kojima ◽  
Daniela Cimini
Keyword(s):  
Gene Expression ◽  
Dosage Compensation ◽  
Current Knowledge ◽  
Gene Dosage ◽  
Congenital Defects ◽  
Gene Products ◽  
Epigenetic Changes ◽  
Transcript Levels ◽  
Compensation Mechanisms ◽  
Additional Chromosome

Aneuploidy (i.e., abnormal chromosome number) is the leading cause of miscarriage and congenital defects in humans. Moreover, aneuploidy is ubiquitous in cancer. The deleterious phenotypes associated with aneuploidy are likely a result of the imbalance in the levels of gene products derived from the additional chromosome(s). Here, we summarize the current knowledge on how the presence of extra chromosomes impacts gene expression. We describe studies that have found a strict correlation between gene dosage and transcript levels as wells as studies that have found a less stringent correlation, hinting at the possible existence of dosage compensation mechanisms. We conclude by peering into the epigenetic changes found in aneuploid cells and outlining current knowledge gaps and potential areas of future investigation.

scholarly journals Gene dosage compensation of rRNA transcript levels in Arabidopsis thaliana lines with reduced ribosomal gene copy number

2021 ◽  
Author(s):  
Francesca B Lopez ◽  
Antoine Fort ◽  
Luca Tadini ◽  
Aline V Probst ◽  
Marcus McHale ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Genome Editing ◽  
Dosage Compensation ◽  
Copy Number ◽  
Gene Dosage ◽  
Rrna Genes ◽  
Gene Copy ◽  
Transcript Levels ◽  
Rdna Copy ◽  
Rdna Copy Number

Abstract The 45S rRNA genes (rDNA) are amongst the largest repetitive elements in eukaryotic genomes. rDNA consists of tandem arrays of rRNA genes, many of which are transcriptionally silenced. Silent rDNA repeats may act as ‘back-up’ copies for ribosome biogenesis and have nuclear organization roles. Through Cas9-mediated genome editing in the Arabidopsis thaliana female gametophyte we reduced 45S rDNA copy number to a plateau of ∼10%. Two independent lines had rDNA copy numbers reduced by up to 90% at the T7 generation, named Low Copy Number (LCN) lines. Despite drastic reduction of rDNA copies, rRNA transcriptional rates and steady-state levels remained the same as wild type plants. Gene dosage compensation of rRNA transcript levels was associated with reduction of silencing histone marks at rDNA loci and altered Nucleolar Organiser Region 2 organization. While overall genome integrity of LCN lines appears unaffected, a chromosome segmental duplication occurred in one of the lines. Transcriptome analysis of LCN seedlings identified several shared dysregulated genes and pathways in both independent lines. Cas9 genome editing of rRNA repeats to generate LCN lines provides a powerful technique to elucidate rDNA dosage compensation mechanisms and impacts of low rDNA copy number on genome stability, development, and cellular processes.

scholarly journals A stochastic model of gene expression with polymerase recruitment and pause release

2019 ◽  
Author(s):  
Z. Cao ◽  
T. Filatova ◽  
D. A. Oyarzún ◽  
R. Grima
Keyword(s):  
Gene Expression ◽  
Steady State ◽  
Rna Polymerase ◽  
Dosage Compensation ◽  
Gene Dosage ◽  
Relative Sensitivity ◽  
Recruitment Rate ◽  
Time Dependent ◽  
Steady State Distribution ◽  
State Distribution

AbstractTranscriptional bursting is a major source of noise in gene expression. The telegraph model of gene expression, whereby transcription switches between “on” and “off” states, is the dominant model for bursting. Recently it was shown that the telegraph model cannot explain a number of experimental observations from perturbation data. Here we study an alternative model that is consistent with the data and which explicitly describes RNA polymerase recruitment and polymerase pause release, two steps necessary for mRNA production. We derive the exact steady-state distribution of mRNA numbers and an approximate steady-state distribution of protein numbers which are given by generalized hypergeometric functions. The theory is used to calculate the relative sensitivity of the coefficient of variation of mRNA fluctuations for thousands of genes in mouse fibroblasts. This indicates that the size of fluctuations is mostly sensitive to the rate of burst initiation and the mRNA degradation rate. Furthermore we show that (i) the time-dependent distribution of mRNA numbers is accurately approximated by a modified telegraph model with a Michaelis-Menten like dependence of the effective transcription rate on RNA polymerase abundance. (ii) the model predicts that if the polymerase recruitment rate is comparable or less than the pause release rate, then upon gene replication the mean number of RNA per cell remains approximately constant. This gene dosage compensation property has been experimentally observed and cannot be explained by the telegraph model with constant rates.Statement of SignificanceThe random nature of gene expression is well established experimentally. Mathematical modelling provides a means of understanding the factors leading to the observed stochasticity. There is evidence that the classical two-state model of stochastic mRNA dynamics (the telegraph model) cannot describe perturbation experiments and a new model that includes polymerase dynamics has been proposed. In this paper, we present the first detailed study of this model, deriving an exact solution for the mRNA distribution in steady-state conditions, an approximate time-dependent solution and showing the model can explain gene dosage compensation. As well, we use the theory together with transcriptomic data, to deduce which parameters when perturbed lead to a maximal change in the size of mRNA fluctuations.

scholarly journals Diverse developmental strategies of X chromosome dosage compensation in eutherian mammals

2019 ◽  
Vol 63 (3-4-5) ◽  
pp. 223-233 ◽  
Author(s):  
Alexander I. Shevchenko ◽  
Elena V. Dementyeva ◽  
Irina S. Zakharova ◽  
Suren M. Zakian
Keyword(s):  
Gene Expression ◽  
X Chromosome ◽  
Dosage Compensation ◽  
Mammalian Species ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Autosomal Gene ◽  
Mammalian Development ◽  
Compensation Mechanisms ◽  
Early Mammalian Development

In eutherian mammals, dosage compensation arose to balance X-linked gene expression between sexes and relatively to autosomal gene expression in the evolution of sex chromosomes. Dosage compensation occurs in early mammalian development and comprises X chromosome upregulation and inactivation that are tightly coordinated epigenetic processes. Despite a uniform principle of dosage compensation, mechanisms of X chromosome inactivation and upregulation demonstrate a significant variability depending on sex, developmental stage, cell type, individual, and mammalian species. The review focuses on relationships between X chromosome inactivation and upregulation in mammalian early development.

scholarly journals Mechanisms of sex determination and X-chromosome dosage compensation

Genetics ◽  
2022 ◽  
Author(s):  
Barbara J Meyer
Keyword(s):  
Gene Expression ◽  
Chromosome Number ◽  
X Chromosome ◽  
Dosage Compensation ◽  
Molecular Mechanisms ◽  
Chromosome Counting ◽  
Developmental Defects ◽  
Chromosome Gene ◽  
Compensation Mechanisms ◽  
The Difference

Abstract Abnormalities in chromosome number have the potential to disrupt the balance of gene expression and thereby decrease organismal fitness and viability. Such abnormalities occur in most solid tumors and also cause severe developmental defects and spontaneous abortions. In contrast to the imbalances in chromosome dose that cause pathologies, the difference in X-chromosome dose used to determine sexual fate across diverse species is well tolerated. Dosage compensation mechanisms have evolved in such species to balance X-chromosome gene expression between the sexes, allowing them to tolerate the difference in X-chromosome dose. This review analyzes the chromosome counting mechanism that tallies X-chromosome number to determine sex (XO male and XX hermaphrodite) in the nematode Caenorhabditis elegans and the associated dosage compensation mechanism that balances X-chromosome gene expression between the sexes. Dissecting the molecular mechanisms underlying X-chromosome counting has revealed how small quantitative differences in intracellular signals can be translated into dramatically different fates. Dissecting the process of X-chromosome dosage compensation has revealed the interplay between chromatin modification and chromosome structure in regulating gene expression over vast chromosomal territories.

scholarly journals Evolution of gene dosage on the Z-chromosome of schistosome parasites

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Marion A L Picard ◽  
Celine Cosseau ◽  
Sabrina Ferré ◽  
Thomas Quack ◽  
Christoph G Grevelding ◽  
...  
Keyword(s):  
Gene Expression ◽  
Comparative Genomics ◽  
Schistosoma Mansoni ◽  
Dosage Compensation ◽  
Quantitative Proteomics ◽  
Gene Dosage ◽  
Z Chromosome ◽  
Sex Linkage ◽  
Expression Evolution ◽  
Gene Expression Evolution

XY systems usually show chromosome-wide compensation of X-linked genes, while in many ZW systems, compensation is restricted to a minority of dosage-sensitive genes. Why such differences arose is still unclear. Here, we combine comparative genomics, transcriptomics and proteomics to obtain a complete overview of the evolution of gene dosage on the Z-chromosome of Schistosoma parasites. We compare the Z-chromosome gene content of African (Schistosoma mansoni and S. haematobium) and Asian (S. japonicum) schistosomes and describe lineage-specific evolutionary strata. We use these to assess gene expression evolution following sex-linkage. The resulting patterns suggest a reduction in expression of Z-linked genes in females, combined with upregulation of the Z in both sexes, in line with the first step of Ohno's classic model of dosage compensation evolution. Quantitative proteomics suggest that post-transcriptional mechanisms do not play a major role in balancing the expression of Z-linked genes.

scholarly journals Rapid evolution of complete dosage compensation in Poecilia

2021 ◽  
Author(s):  
David C.H. Metzger ◽  
Benjamin A. Sandkam ◽  
Iulia Darolti ◽  
Judith E. Mank
Keyword(s):  
Gene Expression ◽  
Dosage Compensation ◽  
Sex Chromosomes ◽  
Evolutionary Dynamics ◽  
Common Ancestor ◽  
Sex Chromosome ◽  
Close Relative ◽  
Y Chromosomes ◽  
Compensation Mechanisms ◽  
The Common

ABSTRACTDosage compensation balances gene expression between the sexes in systems with diverged heterogametic sex chromosomes. Theory predicts that dosage compensation should rapidly evolve in parallel with the divergence of sex chromosomes to prevent the deleterious effects of dosage imbalances that occur as a result of sex chromosome divergence. Examples of complete dosage compensation, where gene expression of the entire sex chromosome is compensated, are rare and have only been found in relatively ancient sex chromosome systems. Consequently, very little is known about the evolutionary dynamics of complete dosage compensation systems. We recently found the first example of complete dosage compensation in a fish, Poecilia picta. We also found that the Y chromosome degraded substantially in the common ancestor of P. picta and their close relative Poecilia parae. In this study we find that P. parae also have complete dosage compensation, thus complete dosage compensation likely evolved in the short (∼3.7 my) interval after the split of the ancestor of these two species from P. reticulata, but before they diverged from each other. These data suggest that novel dosage compensation mechanisms can evolve rapidly, thus supporting the longstanding theoretical prediction that such mechanisms arise in parallel with rapidly diverging sex chromosomes.SIGNIFICANCE STATEMENTIn species with XY sex chromosomes, females (XX) have as many copies of X-linked genes compared to males (XY), leading to unbalanced expression between the sexes. Theory predicts that dosage compensation mechanisms should evolve rapidly as X and Y chromosomes diverge, but examples of complete dosage compensation in recently diverged sex chromosomes are scarce, making this theory difficult to test. Across Poeciliid species the X and Y chromosomes have recently diversified. Here we find complete dosage compensation evolved rapidly as the X and Y diverged in the common ancestor of Poecilia parae and P. picta, supporting that novel dosage compensation mechanisms can evolve rapidly in tandem with diverging sex chromosomes. These data confirm longstanding theoretical predictions of sex chromosome evolution.

scholarly journals Multilayered Tuning of Dosage Compensation and Z-Chromosome Masculinization in the Wood White (Leptidea sinapis) Butterfly

2019 ◽  
Vol 11 (9) ◽  
pp. 2633-2652
Author(s):  
Lars Höök ◽  
Luis Leal ◽  
Venkat Talla ◽  
Niclas Backström
Keyword(s):  
Dosage Compensation ◽  
Developmental Stages ◽  
Current Knowledge ◽  
Gene Dosage ◽  
Model Organisms ◽  
Z Chromosome ◽  
Xy Model ◽  
Expression Levels ◽  
Male Specific Lethal ◽  
Male Specific

AbstractIn species with genetic sex determination, dosage compensation can evolve to equal expression levels of sex-linked and autosomal genes. Current knowledge about dosage compensation has mainly been derived from male-heterogametic (XX/XY) model organisms, whereas less is understood about the process in female-heterogametic systems (ZZ/ZW). In moths and butterflies, downregulation of Z-linked expression in males (ZZ) to match the expression level in females (ZW) is often observed. However, little is known about the underlying regulatory mechanisms, or if dosage compensation patterns vary across ontogenetic stages. In this study, we assessed dynamics of Z-linked and autosomal expression levels across developmental stages in the wood white (Leptidea sinapis). We found that although expression of Z-linked genes in general was reduced compared with autosomal genes, dosage compensation was actually complete for some categories of genes, in particular sex-biased genes, but equalization in females was constrained to a narrower gene set. We also observed a noticeable convergence in Z-linked expression between males and females after correcting for sex-biased genes. Sex-biased expression increased successively across developmental stages, and male-biased genes were enriched on the Z-chromosome. Finally, all five core genes associated with the ribonucleoprotein dosage compensation complex male-specific lethal were detected in adult females, in correspondence with a reduction in the expression difference between autosomes and the single Z-chromosome. We show that tuning of gene dosage is multilayered in Lepidoptera and argue that expression balance across chromosomal classes may predominantly be driven by enrichment of male-biased genes on the Z-chromosome and cooption of available dosage regulators.

scholarly journals Evolved Differences in cis and trans Regulation Between the Maternal and Zygotic mRNA Complements in the Drosophila Embryo

Genetics ◽  
2020 ◽  
Vol 216 (3) ◽  
pp. 805-821
Author(s):  
Emily L. Cartwright ◽  
Susan E. Lott
Keyword(s):  
Gene Expression ◽  
Developmental Stages ◽  
Transcript Level ◽  
Drosophila Embryo ◽  
Gene Products ◽  
Regulatory Evolution ◽  
Transcript Levels ◽  
Maternal Transcript ◽  
Zygotic Transcription ◽  
Trans Regulation

How gene expression can evolve depends on the mechanisms driving gene expression. Gene expression is controlled in different ways in different developmental stages; here we ask whether different developmental stages show different patterns of regulatory evolution. To explore the mode of regulatory evolution, we used the early stages of embryonic development controlled by two different genomes, that of the mother and that of the zygote. During embryogenesis in all animals, initial developmental processes are driven entirely by maternally provided gene products deposited into the oocyte. The zygotic genome is activated later, when developmental control is handed off from maternal gene products to the zygote during the maternal-to-zygotic transition. Using hybrid crosses between sister species of Drosophila (D. simulans, D. sechellia, and D. mauritiana) and transcriptomics, we find that the regulation of maternal transcript deposition and zygotic transcription evolve through different mechanisms. We find that patterns of transcript level inheritance in hybrids, relative to parental species, differ between maternal and zygotic transcripts, and maternal transcript levels are more likely to be conserved. Changes in transcript levels occur predominantly through differences in trans regulation for maternal genes, while changes in zygotic transcription occur through a combination of both cis and trans regulatory changes. Differences in the underlying regulatory landscape in the mother and the zygote are likely the primary determinants for how maternal and zygotic transcripts evolve.

A novel pathological role of p53 in kidney development revealed by gene-environment interactions

2005 ◽  
Vol 288 (1) ◽  
pp. F98-F107 ◽  
Author(s):  
Hao Fan ◽  
Jessica R. Harrell ◽  
Susana Dipp ◽  
Zubaida Saifudeen ◽  
Samir S. El-Dahr
Keyword(s):  
Gene Expression ◽  
Kidney Development ◽  
Gene Dosage ◽  
Early Death ◽  
P53 Gene ◽  
Congenital Defects ◽  
Γ Irradiation ◽  
Gene Environment ◽  
Exon 1 ◽  
E Cadherin

Gene-environment interactions are implicated in congenital human disorders. Accordingly, there is a pressing need to develop animal models of human disease, which are the product of defined gene-environment interactions. Previously, our laboratory demonstrated that gestational salt stress of bradykinin B2 receptor (B2R)-null mice induces renal dysgenesis and early death of the offspring (El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S. Physiol Genomics 3: 121–131, 2000). In contrast, salt-stressed B2R +/+ or +/− littermates have normal development. The present study investigates the mechanisms underlying the susceptibility of B2R-null mice to renal dysgenesis. Proteomic and conventional Western blot screens identified E-cadherin among the differentially repressed proteins in B2R−/− kidneys, whereas the checkpoint kinase Chk1 and its substrate P-Ser20 p53 were induced. We tested the hypothesis that p53 mediates repression of E-cadherin gene expression and is causally linked to the renal dysgenesis. Genetic crosses between B2R −/− and p53+/− mice revealed that germline reduction of p53 gene dosage rescues B2R−/− mice from renal dysgenesis and restores kidney E-cadherin gene expression. Furthermore, γ-irradiation induces repression of E-cadherin gene expression in p53+/+ but not −/− cells. In transient transfection assays, p53 repressed human E-cadherin promoter-driven reporter activity, whereas a mutant p53, which cannot bind DNA, did not. Functional promoter analysis indicated the presence of a p53-responsive element in exon 1, which partially mediates p53-induced repression. Chromatin immunoprecipitation assays revealed that p53 inhibits histone acetylation of the E-cadherin promoter. Treatment with a histone deacetylase inhibitor reversed both p53-mediated promoter repression and deacetylation. In conclusion, this study demonstrates that gene-environment interactions cooperate to induce congenital defects through p53 activation.

scholarly journals DNA replication timing influences gene expression level

2017 ◽  
Vol 216 (7) ◽  
pp. 1907-1914 ◽  
Author(s):  
Carolin A. Müller ◽  
Conrad A. Nieduszynski
Keyword(s):  
Gene Expression ◽  
Dosage Compensation ◽  
Temporal Order ◽  
Yeast Species ◽  
Replication Timing ◽  
Histone Genes ◽  
Cell Cycle Genes ◽  
Compensation Mechanisms ◽  
Dna Replication Timing ◽  
Eukaryotic Genomes

Eukaryotic genomes are replicated in a reproducible temporal order; however, the physiological significance is poorly understood. We compared replication timing in divergent yeast species and identified genomic features with conserved replication times. Histone genes were among the earliest replicating loci in all species. We specifically delayed the replication of HTA1-HTB1 and discovered that this halved the expression of these histone genes. Finally, we showed that histone and cell cycle genes in general are exempt from Rtt109-dependent dosage compensation, suggesting the existence of pathways excluding specific loci from dosage compensation mechanisms. Thus, we have uncovered one of the first physiological requirements for regulated replication time and demonstrated a direct link between replication timing and gene expression.

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