Gene dosage effects of poly(A) track-engineered hypomorphs
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ABSTRACT:
SUBMITTER: Powell G
PROVIDER: S-EPMC8536507 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion < control < duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.
| S-EPMC6705695 | biostudies-literature
Project description:Genomic imprinting results in parent-of-origin-dependent monoallelic gene expression. Early work showed that distal mouse chromosome 2 is imprinted, as maternal and paternal duplications of the region (with corresponding paternal and maternal deficiencies) give rise to different anomalous phenotypes with early postnatal lethalities. Newborns with maternal duplication (MatDp(dist2)) are long, thin and hypoactive whereas those with paternal duplication (PatDp(dist2)) are chunky, oedematous, and hyperactive. Here we focus on PatDp(dist2). Loss of expression of the maternally expressed Gnas transcript at the Gnas cluster has been thought to account for the PatDp(dist2) phenotype. But PatDp(dist2) also have two expressed doses of the paternally expressed Gnasxl transcript. Through the use of targeted mutations, we have generated PatDp(dist2) mice predicted to have 1 or 2 expressed doses of Gnasxl, and 0, 1 or 2 expressed doses of Gnas. We confirm that oedema is due to lack of expression of imprinted Gnas alone. We show that it is the combination of a double dose of Gnasxl, with no dose of imprinted Gnas, that gives rise to the characteristic hyperactive, chunky, oedematous, lethal PatDp(dist2) phenotype, which is also hypoglycaemic. However PatDp(dist2) mice in which the dosage of the Gnasxl and Gnas is balanced (either 2∶2 or 1∶1) are neither dysmorphic nor hyperactive, have normal glucose levels, and are fully viable. But PatDp(dist2) with biallelic expression of both Gnasxl and Gnas show a marked postnatal growth retardation. Our results show that most of the PatDp(dist2) phenotype is due to overexpression of Gnasxl combined with loss of expression of Gnas, and suggest that Gnasxl and Gnas may act antagonistically in a number of tissues and to cause a wide range of phenotypic effects. It can be concluded that monoallelic expression of both Gnasxl and Gnas is a requirement for normal postnatal growth and development.
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Project description: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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Project description:Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual's face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved.
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Project description:The evolutionary process leading to the fixation of newly duplicated genes is not well understood. It was recently proposed that the fixation of duplicate genes is frequently driven by positive selection for increased gene dosage (i.e., the gene dosage hypothesis), because haploinsufficient genes were reported to have more paralogs than haplosufficient genes in the human genome. However, the previous analysis incorrectly assumed that the presence of dominant abnormal alleles of a human gene means that the gene is haploinsufficient, ignoring the fact that many dominant abnormal alleles arise from gain-of-function mutations. Here we show in both humans and yeast that haploinsufficient genes generally do not duplicate more frequently than haplosufficient genes. Yeast haploinsufficient genes do exhibit enhanced retention after whole-genome duplication compared to haplosufficient genes if they encode members of stable protein complexes, but the same phenomenon is absent if the genes do not encode protein complex members, suggesting that the dosage balance effect rather than the dosage effect is the underlying cause of the phenomenon. On the basis of these and other results, we conclude that selection for higher gene dosage does not play a major role in driving the fixation of duplication genes.
| S-EPMC2516101 | biostudies-literature
Project description:Huntington's disease pathogenesis involves a genetic gain-of-function toxicity mechanism triggered by the expanded HTT CAG repeat. Current therapeutic efforts aim to suppress expression of total or mutant huntingtin, though the relationship of huntingtin's normal activities to the gain-of-function mechanism and what the effects of huntingtin-lowering might be are unclear. Here, we have re-investigated a rare family segregating two presumed HTT loss-of-function (LoF) variants associated with the developmental disorder, Lopes-Maciel-Rodan syndrome (LOMARS), using whole-genome sequencing of DNA from cell lines, in conjunction with analysis of mRNA and protein expression. Our findings correct the muddled annotation of these HTT variants, reaffirm they are the genetic cause of the LOMARS phenotype and demonstrate that each variant is a huntingtin hypomorphic mutation. The NM_002111.8: c.4469+1G>A splice donor variant results in aberrant (exon 34) splicing and severely reduced mRNA, whereas, surprisingly, the NM_002111.8: c.8157T>A NP_002102.4: Phe2719Leu missense variant results in abnormally rapid turnover of the Leu2719 huntingtin protein. Thus, although rare and subject to an as yet unknown LoF intolerance at the population level, bona fide HTT LoF variants can be transmitted by normal individuals leading to severe consequences in compound heterozygotes due to huntingtin deficiency.
| S-EPMC8248964 | biostudies-literature
Project description:Hybridization and polyploidy are pervasive evolutionary features of flowering plants and frequent among some animal groups, such as fish. These processes always lead to novel genotypes and various phenotypes, including growth heterosis. However, its genetic basis in lower vertebrate is still poorly understood. Here, we conducted transcriptome-level analyses of the allopolyploid complex of Carassius auratus red var. (R) (♀) × Cyprinus carpio L. (C) (♂), including the allodiploid and allotetraploid with symmetric subgenomes, and the two allotriploids with asymmetric subgenomes. The gradual changes of gene silencing and novel gene expression suggested the weakening of the constraint of polymorphic expression in genotypic changes. Then, analyses of the direction and magnitude of homoeolog expression exhibited various asymmetric expression patterns, which supported that R incomplete dominance and dosage compensation were co-regulated in the two triploids. Under these effects, various magnitudes of R-homoeolog expression bias were observed in growth-regulated genes, suggesting that they might contribute to growth heterosis in the two triploids. The determination of R incomplete dominance and dosage compensation, which might be led by asymmetric subgenomes and multiple sets of homologous chromosomes, explained why various expression patterns were shaped and their potential contribution to growth heterosis in the two triploids.
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Project description:BackgroundAltered dosage of the transcription factor PAX6 causes multiple human eye pathophysiologies. PAX6⁺/⁻ heterozygotes suffer from aniridia and aniridia-related keratopathy (ARK), a corneal deterioration that probably involves a limbal epithelial stem cell (LESC) deficiency. Heterozygous Pax6(+/Sey-Neu) (Pax6⁺/⁻) mice recapitulate the human disease and are a good model of ARK. Corneal pathologies also occur in other mouse Pax6 mutants and in PAX77(Tg/-) transgenics, which over-express Pax6 and model human PAX6 duplication.Methodology/principal findingsWe used electron microscopy to investigate ocular defects in Pax6⁺/⁻ heterozygotes (low Pax6 levels) and PAX77(Tg/-) transgenics (high Pax6 levels). As well as the well-documented epithelial defects, aberrant Pax6 dosage had profound effects on the corneal stroma and endothelium in both genotypes, including cellular vacuolation, similar to that reported for human macular corneal dystrophy. We used mosaic expression of an X-linked LacZ transgene in X-inactivation mosaic female (XLacZ(Tg/-)) mice to investigate corneal epithelial maintenance by LESC clones in Pax6⁺/⁻ and PAX77(Tg/-) mosaic mice. PAX77(Tg/-) mosaics, over-expressing Pax6, produced normal corneal epithelial radial striped patterns (despite other corneal defects), suggesting that centripetal cell movement was unaffected. Moderately disrupted patterns in Pax6⁺/⁻ mosaics were corrected by introducing the PAX77 transgene (in Pax6⁺/⁻, PAX77(Tg/-) mosaics). Pax6(Leca4/+), XLacZ(Tg/-) mosaic mice (heterozygous for the Pax6(Leca4) missense mutation) showed more severely disrupted mosaic patterns. Corrected corneal epithelial stripe numbers (an indirect estimate of active LESC clone numbers) declined with age (between 15 and 30 weeks) in wild-type XLacZ(Tg/-) mosaics. In contrast, corrected stripe numbers were already low at 15 weeks in Pax6⁺/⁻ and PAX77(Tg/-) mosaic corneas, suggesting Pax6 under- and over-expression both affect LESC clones.Conclusions/significancePax6⁺/⁻ and PAX77(Tg/-) genotypes have only relatively minor effects on LESC clone numbers but cause more severe corneal endothelial and stromal defects. This should prompt further investigations of the pathophysiology underlying human aniridia and ARK.
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Project description:The present study examines whether the Fast Track (FT) intervention, a 10-year randomized controlled trial with children at risk for conduct problems, affects family formation in adulthood, as indexed by partnerships, parenthood, and family structure, and whether the intervention effect differs across participants' gender and race/ethnicity. Participants included 891 children (intervention n = 445; control n = 446; 69% male; 51% Black, 47% White) who were recruited in kindergarten and followed to age 32 or 34 (80% participation of still-living participants), when they reported on their romantic partnerships, parenthood, and family structure. Controlling for numerous covariates that are related to family formation, intervention participants were more likely than those in the control group to be married rather than single and to have a larger number of children; the intervention and control groups did not differ on cohabitation status, age at first marriage, whether they had ever been divorced, their likelihood of being a parent, the age at which they first became a parent, the spacing of births, family structure (partnered or not, with or without children), or in whether they were residentially independent of their parents and grandparents. Intervention effects were not moderated by gender, but race/ethnicity moderated the effect of the intervention on the probability of having any children and the number of children. These findings suggest that several elements of family formation may remain unchanged by an intervention that changes many other behavioral and psychological trajectories of participants. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
| S-EPMC9870928 | biostudies-literature
Project description:Experiment on the effects of ethanol (acute oral) on induction of genes by polyinosinic polycytidylic acid (poly IC). Microarray methodology follows: cDNA for each sample was synthesized from 8.5 µg total RNA using a Superscript cDNA Synthesis Kit (Invitrogen, Carlsbad, CA) in combination with a T7-(dT)24 primer. Following phenol-chloroform extraction of the cDNA, biotinylated cRNA was transcribed in vitro using the BioArray HighYield RNA Transcript Labeling Kit (ENZO Biochem, New York, NY) and purified using the RNeasy Mini Kit (Qiagen, Valencia, CA). Twenty micrograms of purified cRNA was fragmented by incubation in fragmentation buffer (200 mM Tris-acetate, pH 8.1, 500 mM potassium acetate, 150 mM magnesium acetate) at 94°C for 35 minutes and chilled on ice. Fifteen micrograms of fragmented biotin-labeled cRNA was hybridized to the Murine Genome U74Av2 Array (Affymetrix, Santa Clara, CA), interrogating a total of 12,488 murine gene cDNA probes, for 16 hr at 45°C with constant rotation (60 rpm). The arrays were washed and then stained for 10 min at 25°C with 10 µg/mL streptavidin-R phycoerythrin (Vector Laboratories, Burlingame, CA) followed by 3 µg/mL biotinylated goat anti-streptavidin antibody (Vector Laboratories) for 10 minutes at 25°C. Arrays were then stained once again with streptavidin-R phycoerythrin for 10 min at 25°C. After washing and staining, the arrays were scanned using an Agilent GeneArray Scanner (Agilent Technologies) at 570 nm. Pixel intensities were measured, expression signals were analyzed and features extracted using a commercial software package (Microarray Suite ver 5.0, Affymetrix). Data mining and statistical analyses were performed with Data Mining Tool ver 3.0 (Affymetrix) algorithms. Arrays were globally scaled to a target intensity value of 2,500 in order to compare individual experiments. The absolute call (present, marginal, absent) of 12,488 gene expressions in each sample, as well as the direction of change, and fold change of gene expressions between samples were identified using the above-mentioned software. Keywords: other
2004-04-15 | GSE1308 | GEO