An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes.
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ABSTRACT:
SUBMITTER: O'Doherty A
PROVIDER: S-EPMC1378183 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Animal models of Down syndrome (DS), trisomic for human chromosome 21 (HSA21) genes or orthologs, provide insights into better understanding and treatment options. The only existing transchromosomic (Tc) mouse DS model, Tc1, carries a HSA21 with over 50 protein coding genes (PCGs) disrupted. Tc1 is mosaic, compromising interpretation of results. Here, we "clone" the 34 MB long arm of HSA21 (HSA21q) as a mouse artificial chromosome (MAC). Through multiple steps of microcell-mediated chromosome transfer, we created a new Tc DS mouse model, Tc(HSA21q;MAC)1Yakaz ("TcMAC21"). TcMAC21 is not mosaic and contains 93% of HSA21q PCGs that are expressed and regulatable. TcMAC21 recapitulates many DS phenotypes including anomalies in heart, craniofacial skeleton and brain, molecular/cellular pathologies, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete genetic mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research.
| S-EPMC7358007 | biostudies-literature
Project description:Down syndrome caused by chromosome 21 trisomy is the most common genetic cause of mental retardation in humans. Disruption of the phenotype is thought to be the result of gene-dosage imbalance. Variations in chromosome 21 gene expression in Down syndrome were analyzed in lymphoblastoid cells derived from patients and control individuals. Of the 359 genes and predictions displayed on a specifically designed high-content chromosome 21 microarray, one-third were expressed in lymphoblastoid cells. We performed a mixed-model analysis of variance to find genes that are differentially expressed in Down syndrome independent of sex and interindividual variations. In addition, we identified genes with variations between Down syndrome and control samples that were significantly different from the gene-dosage effect (1.5). Microarray data were validated by quantitative polymerase chain reaction. We found that 29% of the expressed chromosome 21 transcripts are overexpressed in Down syndrome and correspond to either genes or open reading frames. Among these, 22% are increased proportional to the gene-dosage effect, and 7% are amplified. The other 71% of expressed sequences are either compensated (56%, with a large proportion of predicted genes and antisense transcripts) or highly variable among individuals (15%). Thus, most of the chromosome 21 transcripts are compensated for the gene-dosage effect. Overexpressed genes are likely to be involved in the Down syndrome phenotype, in contrast to the compensated genes. Highly variable genes could account for phenotypic variations observed in patients. Finally, we show that alternative transcripts belonging to the same gene are similarly regulated in Down syndrome but sense and antisense transcripts are not.
| S-EPMC1950826 | biostudies-literature
Project description:The "Down syndrome critical region" (DSCR) is a chromosome 21 segment purported to contain genes responsible for many features of Down syndrome (DS), including craniofacial dysmorphology. We used chromosome engineering to create mice that were trisomic or monosomic for only the mouse chromosome segment orthologous to the DSCR and assessed dysmorphologies of the craniofacial skeleton that show direct parallels with DS in mice with a larger segmental trisomy. The DSCR genes were not sufficient and were largely not necessary to produce the facial phenotype. These results refute specific predictions of the prevailing hypothesis of gene action in DS.
| S-EPMC4019810 | biostudies-literature
Project description:Down syndrome (DS) is caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is the most common genetic cause for developmental cognitive disability. The regions on Hsa21 are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this report, we describe a new mouse model for DS that carries duplications spanning the entire Hsa21 syntenic regions on all three mouse chromosomes. This mouse mutant exhibits DS-related neurological defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation and hydrocephalus. These results suggest that when all the mouse orthologs of the Hsa21 genes are triplicated, an abnormal cognitively relevant phenotype is the final outcome of the elevated expressions of these orthologs as well as all the possible functional interactions among themselves and/or with other mouse genes. Because of its desirable genotype and phenotype, this mutant may have the potential to serve as one of the reference models for further understanding the developmental cognitive disability associated with DS and may also be used for developing novel therapeutic interventions for this clinical manifestation of the disorder.
| S-EPMC2893810 | biostudies-other
Project description:Aneuploidy, which leads to unpaired chromosomal axes during meiosis, is frequently accompanied by infertility. We previously showed, using three mouse models of Down syndrome, that it is an extra chromosome, but not extra gene dose, that is associated with male infertility and virtual absence of post-meiotic gem cells. Here, we test the hypothesis that aneuploid segments are differentially modified and expressed during meiosis, depending on whether they are present as an extra chromosome or not. In all three models examined, the trisomic region lacks a pairing partner, but in one case, spermatocytes have an extra (and unpaired) chromosome, while the two other models involve translocation of the trisomic region rather than an extra chromosome. An extra unpaired chromosome was always modified by phosphorylation of histone H2AX and lacked RNA PolII. But in the case of trisomic regions attached to a paired chromosome, assembly of these protein modifications was affected by the position of a trisomic region relative to a centromere and the physical extent of the unpaired chromatin. Analysis of gene expression in testes revealed that extra copy number alone was not sufficient for meiotic upregulation of genes in the trisomic interval. Additionally and unexpectedly, presence of meiotic gene silencing chromatin modifications was not sufficient for downregulation of genes in unpaired trisomic chromatin. Thus, the meiotic chromatin modifications that are cytologically visible are unlikely to be directly involved in sterility versus fertility of DS models. Finally, the presence of an extra unpaired chromosome, but not the presence of extra (trisomic) genes, caused global deregulation of transcription in spermatocytes. These results reveal mechanisms by which an extra chromosome, but not trisomic gene dose, impact on meiotic progress and infertility.
| S-EPMC2848991 | biostudies-literature
Project description:Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability. The Dp10(1)Yey (Dp10) is a mouse model of DS that is trisomic for orthologs of 25% of the Hsa21 protein-coding genes, the entirety of the Hsa21 syntenic region on mouse chromosome 10. Trisomic genes include several involved in brain development and function, two that modify and regulate the activities of sex hormones, and two that produce sex-specific phenotypes as null mutants. These last four are the only Hsa21 genes with known sexually dimorphic properties. Relatively little is known about the potential contributions to the DS phenotype of segmental trisomy of Mmu10 orthologs. Here, we have tested separate cohorts of female and male Dp10 mice, at 3 and 9 months of age, in an open field elevated zero maze, rotarod, and balance beam, plus the learning and memory tasks, spontaneous alternation, puzzle box, double-H maze, context fear conditioning, and acoustic startle/prepulse inhibition, that depend upon the function of the prefrontal cortex, striatum, hippocampus, and cerebellum. We show that there are age and sex-specific differences in strengths and weaknesses, suggesting that genes within the telomere proximal region of Hsa21 influence the DS phenotype.
| S-EPMC8618694 | biostudies-literature
Project description:Comprehensive knowledge of the gene content of human chromosome 21 (HSA21) is essential for understanding the etiology of Down syndrome (DS). Here we report the largest comparison of finished mouse and human sequence to date for a 1.35-Mb region of mouse chromosome 16 (MMU16) that corresponds to human chromosome 21q22.2. This includes a portion of the commonly described "DS critical region," thought to contain a gene or genes whose dosage imbalance contributes to a number of phenotypes associated with DS. We used comparative sequence analysis to construct a DNA feature map of this region that includes all known genes, plus 144 conserved sequences > or =100 bp long that show > or =80% identity between mouse and human but do not match known exons. Twenty of these have matches to expressed sequence tag and cDNA databases, indicating that they may be transcribed sequences from chromosome 21. Eight putative CpG islands are found at conserved positions. Models for two human genes, DSCR4 and DSCR8, are not supported by conserved sequence, and close examination indicates that low-level transcripts from these loci are unlikely to encode proteins. Gene prediction programs give different results when used to analyze the well-conserved regions between mouse and human sequences. Our findings have implications for evolution and for modeling the genetic basis of DS in mice.
| S-EPMC186650 | biostudies-literature
Project description:Progress in earlier detection and clinical management has increased life expectancy and quality of life in people with Down syndrome (DS). However, no drug has been approved to help individuals with DS live independently and fully. Although rat models could support more robust physiological, behavioral, and toxicology analysis than mouse models during preclinical validation, no DS rat model is available as a result of technical challenges. We developed a transchromosomic rat model of DS, TcHSA21rat, which contains a freely segregating, EGFP-inserted, human chromosome 21 (HSA21) with >93% of its protein-coding genes. RNA-seq of neonatal forebrains demonstrates that TcHSA21rat expresses HSA21 genes and has an imbalance in global gene expression. Using EGFP as a marker for trisomic cells, flow cytometry analyses of peripheral blood cells from 361 adult TcHSA21rat animals show that 81% of animals retain HSA21 in >80% of cells, the criterion for a "Down syndrome karyotype" in people. TcHSA21rat exhibits learning and memory deficits and shows increased anxiety and hyperactivity. TcHSA21rat recapitulates well-characterized DS brain morphology, including smaller brain volume and reduced cerebellar size. In addition, the rat model shows reduced cerebellar foliation, which is not observed in DS mouse models. Moreover, TcHSA21rat exhibits anomalies in craniofacial morphology, heart development, husbandry, and stature. TcHSA21rat is a robust DS animal model that can facilitate DS basic research and provide a unique tool for preclinical validation to accelerate DS drug development.
| S-EPMC8874226 | biostudies-literature
Project description:The recent completion of the DNA sequence of human chromosome 21 has provided the first look at the 225 genes that are candidates for involvement in Down syndrome (trisomy 21). A broad functional classification of these genes, their expression data and evolutionary conservation, and comparison with the gene content of the major mouse models of Down syndrome, suggest how the chromosome sequence may help in understanding the complex Down syndrome phenotype.
| S-EPMC138845 | biostudies-literature
Project description:Homologous sets of transcription factors direct conserved tissue-specific gene expression, yet transcription factor-binding events diverge rapidly between closely related species. We used hepatocytes from an aneuploid mouse strain carrying human chromosome 21 to determine, on a chromosomal scale, whether interspecies differences in transcriptional regulation are primarily directed by human genetic sequence or mouse nuclear environment. Virtually all transcription factor-binding locations, landmarks of transcription initiation, and the resulting gene expression observed in human hepatocytes were recapitulated across the entire human chromosome 21 in the mouse hepatocyte nucleus. Thus, in homologous tissues, genetic sequence is largely responsible for directing transcriptional programs; interspecies differences in epigenetic machinery, cellular environment, and transcription factors themselves play secondary roles.
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