gene dosage
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2021 ◽  
Author(s):  
Darcy T. Ahern ◽  
Prakhar Bansal ◽  
Isaac V. Faustino ◽  
Yuvabharath Kondaveeti ◽  
Heather R. Glatt-Deeley ◽  
...  

Mammalian sex chromosomes encode homologous X/Y gene pairs that were retained on the male Y and escape X chromosome inactivation (XCI) in females. Inferred to reflect X/Y-pair dosage sensitivity, monosomy X is a leading cause of miscarriage in humans with near full penetrance. This phenotype is shared with many other mammals but not the mouse, which offers sophisticated genetic tools to generate sex chromosomal aneuploidy but also tolerates its developmental impact. To address this critical gap, we generated X-monosomic human induced pluripotent stem cells (hiPSCs) alongside otherwise isogenic euploid controls from male and female mosaic samples. Phased genomic variants of these hiPSC panels enable systematic investigation of X/Y dosage-sensitive features using in vitro models of human development. Here, we demonstrate the utility of these validated hiPSC lines to test how X/Y-linked gene dosage impacts a widely-used model for the human syncytiotrophoblast. While these isogenic panels trigger a GATA2/3 and TFAP2A/C -driven trophoblast gene circuit irrespective of karyotype, differential expression implicates monosomy X in altered levels of placental genes, and in secretion of placental growth factor (PlGF) and human chorionic gonadotropin (hCG). Remarkably, weighted gene co-expression network modules that significantly reflect these changes are also preserved in first-trimester chorionic villi and term placenta. Our results suggest monosomy X may skew trophoblast cell type composition, and that the pseudoautosomal region likely plays a key role in these changes, which may facilitate prioritization of haploinsufficient drivers of 45,X extra-embryonic phenotypes.


2021 ◽  
Vol 118 (51) ◽  
pp. e2113744118
Author(s):  
Giovanni Bussotti ◽  
Laura Piel ◽  
Pascale Pescher ◽  
Malgorzata A. Domagalska ◽  
K. Shanmugha Rajan ◽  
...  

How genome instability is harnessed for fitness gain despite its potential deleterious effects is largely elusive. An ideal system to address this important open question is provided by the protozoan pathogen Leishmania, which exploits frequent variations in chromosome and gene copy number to regulate expression levels. Using ecological genomics and experimental evolution approaches, we provide evidence that Leishmania adaptation relies on epistatic interactions between functionally associated gene copy number variations in pathways driving fitness gain in a given environment. We further uncover posttranscriptional regulation as a key mechanism that compensates for deleterious gene dosage effects and provides phenotypic robustness to genetically heterogenous parasite populations. Finally, we correlate dynamic variations in small nucleolar RNA (snoRNA) gene dosage with changes in ribosomal RNA 2′-O-methylation and pseudouridylation, suggesting translational control as an additional layer of parasite adaptation. Leishmania genome instability is thus harnessed for fitness gain by genome-dependent variations in gene expression and genome-independent compensatory mechanisms. This allows for polyclonal adaptation and maintenance of genetic heterogeneity despite strong selective pressure. The epistatic adaptation described here needs to be considered in Leishmania epidemiology and biomarker discovery and may be relevant to other fast-evolving eukaryotic cells that exploit genome instability for adaptation, such as fungal pathogens or cancer.


2021 ◽  
Author(s):  
Roberto de la Cerda ◽  
Karsten Hookamp ◽  
Fiona Roche ◽  
Georgia Thompson ◽  
Soukaina Timouma ◽  
...  

The lager yeasts, Saccharomyces pastorianus, are hybrids of Saccharomyces cerevisiae and Saccharomyces eubayanus and are divided into two broad groups, Group I and II. The two groups evolved from at least one common hybridisation event but have subsequently diverged with Group I strains losing many S. cerevisiae chromosomes while the Group II strains retain both sub-genomes. The complex genomes, containing orthologous alleles from the parental chromosomes, pose interesting questions regarding gene regulation and its impact on the fermentation properties of the strains. Superimposed on the presence of orthologous alleles are complexities of gene dosage due to the aneuploid nature of the genomes. We examined the contribution of the S. cerevisiae and S. eubayanus alleles to the gene expression patterns of Group I and II strains during fermentation. We show that the relative expression of S. cerevisiae and S. eubayanus orthologues is positively correlated with gene copy number. Despite the reduced S. cerevisiae content in the Group I strain, S. cerevisiae orthologues contribute to biochemical pathways upregulated during fermentation which may explain the retention of specific chromosomes in the strain. Conversely, S. eubayanus genes are significantly overrepresented in the upregulated gene pool in the Group II strain. Comparison of the transcription profiles of Group I and II strains during fermentation identified both common and unique gene expression patterns, with gene copy number being a dominant contributory factor. Thus, the aneuploid genomes create complex patterns of gene expression during fermentation with gene dosage playing a crucial role both within and between strains.


PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009906
Author(s):  
M. Felicia Basilicata ◽  
Claudia Isabelle Keller Valsecchi

Diploid organisms contain a maternal and a paternal genome complement that is thought to provide robustness and allow developmental progression despite genetic perturbations that occur in heterozygosity. However, changes affecting gene dosage from the chromosome down to the individual gene level possess a significant pathological potential and can lead to developmental disorders (DDs). This indicates that expression from a balanced gene complement is highly relevant for proper cellular and organismal function in eukaryotes. Paradoxically, gene and whole chromosome duplications are a principal driver of evolution, while heteromorphic sex chromosomes (XY and ZW) are naturally occurring aneuploidies important for sex determination. Here, we provide an overview of the biology of gene dosage at the crossroads between evolutionary benefit and pathogenicity during disease. We describe the buffering mechanisms and cellular responses to alterations, which could provide a common ground for the understanding of DDs caused by copy number alterations.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3416
Author(s):  
Reem Makki ◽  
Victoria H. Meller

Organisms with highly differentiated sex chromosomes face an imbalance in X-linked gene dosage. Male Drosophila solve this problem by increasing expression from virtually every gene on their single X chromosome, a process known as dosage compensation. This involves a ribonucleoprotein complex that is recruited to active, X-linked genes to remodel chromatin and increase expression. Interestingly, the male X chromosome is also enriched for several proteins associated with heterochromatin. Furthermore, the polytenized male X is selectively disrupted by the loss of factors involved in repression, silencing, heterochromatin formation or chromatin remodeling. Mutations in many of these factors preferentially reduce male survival or enhance the lethality of mutations that prevent normal recognition of the X chromosome. The involvement of primarily repressive factors in a process that elevates expression has long been puzzling. Interestingly, recent work suggests that the siRNA pathway, often associated with heterochromatin formation and repression, also helps the dosage compensation machinery identify the X chromosome. In light of this finding, we revisit the evidence that links nuclear organization and heterochromatin to regulation of the male X chromosome.


2021 ◽  
Author(s):  
Beatrice Vione ◽  
Chiara Locatelli ◽  
Giacomo Zavaroni ◽  
Angela Piano ◽  
Giorgia La Rocca ◽  
...  

AbstractDown syndrome (DS) is the most common chromosomal disorder, and it is caused by trisomy of chromosome 21 (Hsa21). Subjects with DS can show a large heterogeneity of phenotypes and congenital defects and the most constant clinical features present are typical facies and intellectual disability (ID). Jérôme Lejeune was the first who hypothesized that DS could be a metabolic disease and he noted an alteration of the folate pathway (part of the one-carbon cycle) in trisomic cell lines and subjects with DS. Comparing DS with other metabolic diseases characterized by ID and altered folate pathway he hypothesized a possible correlation among them. Recently, a nuclear magnetic resonance (NMR) analysis of the detectable metabolic part in plasma and urine samples was performed, comparing a group of subjects with DS and a group of control subjects. The data showed a clear difference in the concentration of some metabolites (all involved in central metabolic processes) for the DS group, which was sometimes in agreement with gene dosage expected proportions (3:2). The aim of this work is to underline metabolic differences between subjects with DS and control subjects in order to better understand the dysregulation of the folate pathway in DS. For the first time, we performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 4 different intermediates of the one-carbon cycle, namely tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF and S-adenosyl-homocysteine (SAH) in plasma samples obtained from 153 subjects with DS and 54 euploid subjects. Results highlight specific alterations of some folate pathway related metabolites. The relevance of these results for the biology of intelligence and its impairment in trisomy 21 is discussed leading to the proposal of 5-methyl-THF as the best candidate for a clinical trial aimed at restoring the dysregulation of folate pathway in trisomy 21 and improving cognitive skills of subjects with DS.


2021 ◽  
Vol 118 (49) ◽  
pp. e2111841118
Author(s):  
Kenneth Wu ◽  
Namrita Dhillon ◽  
Kelvin Du ◽  
Rohinton T. Kamakaka

Gene silencing in budding yeast is mediated by Sir protein binding to unacetylated nucleosomes to form a chromatin structure that inhibits transcription. Transcriptional silencing is characterized by the high-fidelity transmission of the silent state. Despite its relative stability, the constituent parts of the silent state are in constant flux, giving rise to a model that silent loci can tolerate such fluctuations without functional consequences. However, the level of tolerance is unknown, and we developed methods to measure the threshold of histone acetylation that causes the silent chromatin state to switch to the active state as well as to measure the levels of the enzymes and structural proteins necessary for silencing. We show that loss of silencing required 50 to 75% acetyl-mimic histones, though the precise levels were influenced by silencer strength and upstream activating sequence (UAS) enhancer/promoter strength. Measurements of repressor protein levels necessary for silencing showed that reducing SIR4 gene dosage two- to threefold significantly weakened silencing, though reducing the gene copy numbers for Sir2 or Sir3 to the same extent did not significantly affect silencing suggesting that Sir4 was a limiting component in gene silencing. Calculations suggest that a mere twofold reduction in the ability of acetyltransferases to acetylate nucleosomes across a large array of nucleosomes may be sufficient to generate a transcriptionally silent domain.


PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009939
Author(s):  
Xiao-Pan Hu ◽  
Martin J. Lercher

The distribution of cellular resources across bacterial proteins has been quantified through phenomenological growth laws. Here, we describe a complementary bacterial growth law for RNA composition, emerging from optimal cellular resource allocation into ribosomes and ternary complexes. The predicted decline of the tRNA/rRNA ratio with growth rate agrees quantitatively with experimental data. Its regulation appears to be implemented in part through chromosomal localization, as rRNA genes are typically closer to the origin of replication than tRNA genes and thus have increasingly higher gene dosage at faster growth. At the highest growth rates in E. coli, the tRNA/rRNA gene dosage ratio based on chromosomal positions is almost identical to the observed and theoretically optimal tRNA/rRNA expression ratio, indicating that the chromosomal arrangement has evolved to favor maximal transcription of both types of genes at this condition.


2021 ◽  
Author(s):  
Kevin A Bird ◽  
J Chris Pires ◽  
Robert VanBuren ◽  
Zhiyong Xiong ◽  
Patrick P. Edger

Allopolyploidy involves the hybridization of two evolutionary diverged species and the doubling of genomic material. Frequently, allopolyploids exhibit genomic rearrangements that recombine, duplicate, or delete homoeologous regions of the newly formed genome. While decades of investigation have focused on how genome duplication leads to systematic differences in the retention and expression of duplicate genes, the impact of genomic rearrangements on genome evolution has received less attention. We used genomic and transcriptomic data for six independently resynthesized, isogenic Brassica napus lines in the first, fifth, and tenth generation to identify genomic rearrangements and assess their impact on gene expression dynamics related to subgenome dominance and gene dosage constraint. We find that dosage constraints on the gene expression response to polyploidy begin to loosen within the first ten generations of evolution and systematically differ between dominant and non-dominant subgenomes. We also show that genomic rearrangements can bias estimation of homoeolog expression bias, but fail to fully obscure which subgenome is dominantly expressed. Finally, we demonstrate that dosage-sensitive genes exhibit the same kind of coordinated response to homoeologous exchange as they do for genome duplication, suggesting constraint on dosage balance also acts on these changes to gene dosage.


Author(s):  
Shubham Goel ◽  
Hye Sun Kuehn ◽  
Javier Chinen ◽  
Julie Niemela ◽  
Jennifer Stoddard ◽  
...  

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