Physical and Comparative Mapping of Distal Mouse Chromosome 16 (original) (raw)
Related papers
Genomics, 2001
Distal mouse chromosome 16 (MMU16) shares conserved linkage with human chromosome 21 (HSA21), trisomy for which causes Down syndrome (DS). A 4.5-Mb physical map extending from Cbr1 to Tmprss2 on MMU16 provides a minimal tiling path of P1 artificial chromosomes (PACs) for comparative mapping and genomic sequencing. Thirty-four expressed sequences were positioned on the mouse map, including 19 that were not physically mapped previously. This region of the mouse:human comparative map shows a high degree of evolutionary conservation of gene order and content, which differs only by insertion of one gene (in mouse) and a small inversion involving two adjacent genes. "Low-pass" (2.2؋) mouse sequence from a portion of the contig was ordered and oriented along 510 kb of finished HSA21 sequence. In combination with 68 kb of unique PAC end sequence, the comparison provided confirmation of genes predicted by comparative mapping, indicated gene predictions that are likely to be incorrect, and identified three candidate genes in mouse and human that were not observed in the initial HSA21 sequence annotation. This comparative map and sequence derived from it are powerful tools for identifying genes and regulatory regions, information that will in turn provide insights into the genetic mechanisms by which trisomy 21 results in DS.
2013
Since the genetic basis for Down syndrome (DS) was described, understanding the causative relationship between genes at dosage imbalance and phenotypes associated with DS has been a principal goal of researchers studying trisomy 21 (Ts21). Though inferences to the genephenotype relationship in humans have been made, evidence linking a specific gene or region to a particular congenital phenotype has been limited. To further understand the genetic basis for DS phenotypes, mouse models with three copies of human chromosome 21 (Hsa21) orthologs have been developed. Mouse models offer access to every tissue at each stage of development, opportunity to manipulate genetic content, and ability to precisely quantify phenotypes. Numerous approaches to recreate trisomic composition and analyze phenotypes similar to DS have resulted in diverse trisomic mouse models. A murine intraspecies comparative analysis of different genetic models of Ts21 and specific DS phenotypes reveals the complexity of trisomy and important considerations to understand the etiology of and strategies for amelioration or prevention of trisomic phenotypes. By analyzing individual phenotypes in different mouse models throughout development, such as neurologic, craniofacial, and cardiovascular abnormalities, greater insight into the genephenotype relationship has been demonstrated. In this review we discuss how phenotype-based comparisons between DS mouse models have been useful in analyzing the relationship of trisomy and DS phenotypes.
Gene Expression From the Aneuploid Chromosome in a Trisomy Mouse Model of Down Syndrome
Genome Research, 2004
Trisomy 21 is the prototype of human aneuploidies. Since its discovery in 1959, the hypothesis has been that overexpression of the ∼230 human chromosome 21 (Hsa21) genes result in the complex phenotype. However, the level of overexpression of Hsa21 genes in trisomic individuals is presently unknown. We have used Taqman real-time quantitative PCR to accurately measure expression of the mouse orthologs of Hsa21 in the partial trisomy mouse model Ts65Dn. The transcript levels of 78 protein-coding genes present in three copies in Ts65Dn and 21 control genes were compared between Ts65Dn and normal mouse littermates. The mean overexpression of the aneuploid genes is very close to the expected 1.5-fold in all six tissues studied. However, only approximately a third of the genes (37%) are expressed at the theoretical value of 1.5-fold. On average, 45% of the genes are expressed at significantly lower than 1.5-fold, and 9% are not significantly different from 1.0. Interestingly, 18% of the aneuploid genes were expressed at levels significantly greater than 1.5-fold. These data provide candidate genes that might be involved in the phenotypes of Down syndrome, and reveal a complex regulation of gene expression that is not only related to gene copy number.
Segmental trisomy of mouse chromosome 17: Introducing an alternative model of Down's syndrome
Comparative and Functional Genomics, 2003
All of the mouse models of human trisomy 21 syndrome that have been studied so far are based on segmental trisomies, encompassing, to a varying extent, distal chromosome 16. Their comparison with one or more unrelated and non-overlapping segmental trisomies may help to distinguish the effects of specific triplicated genes from the phenotypes caused by less specific developmental instability mechanisms. In this paper, the Ts43H segmental trisomy of mouse chromosome 17 is presented as such an alternative model. The trisomy stretches over 32.5 Mb of proximal chromosome 17 and includes 486 genes. The triplicated interval carries seven blocks of synteny with five human chromosomes. The block syntenic to human chromosome 21 contains 20 genes.
The power of comparative and developmental studies for mouse models of Down syndrome
Mammalian Genome, 2007
Since the genetic basis for Down syndrome (DS) was described, understanding the causative relationship between genes at dosage imbalance and phenotypes associated with DS has been a principal goal of researchers studying trisomy 21 (Ts21). Though inferences to the genephenotype relationship in humans have been made, evidence linking a specific gene or region to a particular congenital phenotype has been limited. To further understand the genetic basis for DS phenotypes, mouse models with three copies of human chromosome 21 (Hsa21) orthologs have been developed. Mouse models offer access to every tissue at each stage of development, opportunity to manipulate genetic content, and ability to precisely quantify phenotypes. Numerous approaches to recreate trisomic composition and analyze phenotypes similar to DS have resulted in diverse trisomic mouse models. A murine intraspecies comparative analysis of different genetic models of Ts21 and specific DS phenotypes reveals the complexity of trisomy and important considerations to understand the etiology of and strategies for amelioration or prevention of trisomic phenotypes. By analyzing individual phenotypes in different mouse models throughout development, such as neurologic, craniofacial, and cardiovascular abnormalities, greater insight into the genephenotype relationship has been demonstrated. In this review we discuss how phenotype-based comparisons between DS mouse models have been useful in analyzing the relationship of trisomy and DS phenotypes.
Mouse-based genetic modeling and analysis of Down syndrome
British medical bulletin, 2016
Down syndrome (DS), caused by human trisomy 21 (Ts21), can be considered as a prototypical model for understanding the effects of chromosomal aneuploidies in other diseases. Human chromosome 21 (Hsa21) is syntenically conserved with three regions in the mouse genome. A review of recent advances in genetic modeling and analysis of DS. Using Cre/loxP-mediated chromosome engineering, a substantial number of new mouse models of DS have recently been generated, which facilitates better understanding of disease mechanisms in DS. Based on evolutionary conservation, Ts21 can be modeled by engineered triplication of Hsa21 syntenic regions in mice. The validity of the models is supported by the exhibition of DS-related phenotypes. Although substantial progress has been made, it remains a challenge to unravel the relative importance of specific candidate genes and molecular mechanisms underlying the various clinical phenotypes. Further understanding of mechanisms based on data from mouse model...
Down syndrome (DS) is a complex human condition, and animal models trisomic for human chromosome 21 (HSA21) genes or orthologs provide insights into better understanding and treating DS. However, HSA21 orthologs are distributed into three mouse chromosomes, preventing us from generating mouse models trisomy of a complete set of HSA21 orthologs. The only existing humanized mouse DS model, Tc1, carries a HSA21 with over 20% of protein coding genes (PCGs) disrupted. More importantly, due to the human centromere, Tc1 is mosaic (a mix of euploid and trisomic cells), which makes every mouse unique and compromises interpretation of results. Here, we used mouse artificial chromosome (MAC) technology to “clone” the 34 MB long arm of HSA21 (HSA21q). Through multiple steps of microcell-mediated chromosome transfer we created a new humanized DS mouse model, Tc(HSA21q;MAC)1Yakaz (“TcMAC21”). Constitutive EGFP expression from the transchromosome and fluorescent in situ hybridization validate that...
Polymerase chain reaction method to identify Down syndrome model segmentally trisomic mice
Analytical Biochemistry, 2005
The Ts65Dn segmentally trisomic mouse possesses an extra copy of a segment of chromosome 16 translocated to chromosome 17. This segment includes the mouse homolog of the Down syndrome critical region of human chromosome 21. The Ts65Dn mouse serves as a useful model to study the developmental regulation of the Down syndrome phenotype. To identify mice bearing the extra chromosome 16 segment, we developed a polymerase chain reaction (PCR) method as an alternative to karyotyping. Conditions under which segments of genes on chromosome 16 (App and Dyrk1a) could be coampliWed with a control gene on chromosome 8 (Acta1) so that the yield of each PCR product was proportional to the amount of its template were determined. The ampliWcation products were resolved and quantiWed by two methods. In the Wrst method, the DNA segments were separated by agarose gel electrophoresis and stained with ethidium bromide. The Xuorescence yields were quantiWed by photodensitometry. In the second method, the fragments were resolved and quantiWed by the high-performance DNA analysis system, a high-throughput, multichannel, microcapillary electrophoresis instrument. The results of both methods were within 10% of the expected ratio of 1.5. Application of these methods has allowed the maintenance of a Ts65Dn breeding colony through six generations and should permit the precise and eYcient identiWcation of trisomic and disomic animals at any developmental stage with minimally invasive procedures.