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A novel mouse model for Down syndrome that harbor a single copy of human artificial chromosome (HAC) carrying a limited number of genes from human chromosome 21

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Abstract

Down syndrome (DS), also known as Trisomy 21, is the most common chromosome aneuploidy in live-born children and displays a complicated symptom. To date, several kinds of mouse models have been generated to understand the molecular pathology of DS, yet the gene dosage effects and gene(s)-phenotype(s) correlation are not well understood. In this study, we established a novel method to generate a partial trisomy mice using the mouse ES cells that harbor a single copy of human artificial chromosome (HAC), into which a small human DNA segment containing human chromosome 21 genes cloned in a bacterial artificial chromosome (BAC) was recombined. The produced mice were found to maintain the HAC carrying human genes as a mini-chromosome, hence termed as a Trans-Mini-Chromosomal (TMC) mouse, and HAC was transmitted for more than twenty generations independent from endogenous mouse chromosomes. The three human transgenes including cystathionine β-synthase, U2 auxiliary factor and crystalline alpha A were expressed in several mouse tissues with various expression levels relative to mouse endogenous genes. The novel system is applicable to any of human and/or mouse BAC clones. Thus, the TMC mouse carrying a HAC with a limited number of genes would provide a novel tool for studying gene dosage effects involved in the DS molecular pathogenesis and the gene(s)-phenotype(s) correlation.

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Abbreviations

DS:

Down syndrome

HAC:

Human artificial chromosome

BAC:

Bacterial artificial chromosome

TMC mouse:

Trans-mini-chromosomal mouse

CBS:

Cystathionine β-synthase

U2AF1:

U2 auxiliary factor

CRYAA:

Crystalline alpha A

FISH:

Fluorescence in situ hybridization

ES cell:

Embryonic stem cell

qPCR:

Quantitative polymerase chain reaction

RT-PCR:

Reverse transcription polymerase chain reaction

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Acknowledgments

We thank Mr. Masahiko Maekawa (GSP laboratory Inc., Kawasaki, Japan) for the technical support of FISH. This work was supported by Grants-in-Aid for Scientific Research (B) (Grant Number 16390307), (A) (Grant Number 19209038), Young Scientists (B) (Grant Number 23791194) and Global COE program for Education and Research Centre for Human Metabolomic Systems Biology from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

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Authors and Affiliations

  1. Laboratory of Gene Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Kenichi Miyamoto, Kosuke Sakai, Jun Kudoh & Masashi Ikeno

  2. Chromo Research Inc., 1212 Shihongi, Midori-ku, Nagoya, Aichi, 458-0039, Japan

    Nobutaka Suzuki, Tsuneko Okazaki & Masashi Ikeno

  3. Laboratory of Aquatic Molecular Biology and Biotechnology, Graduate School of Agricultural and Life Science, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan

    Shuichi Asakawa

  4. Advanced Research Center for Genome Super Power, Keio University, 2 Okubo, Tsukuba, Ibaraki, 300-2611, Japan

    Nobuyoshi Shimizu

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  1. Kenichi Miyamoto
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  2. Nobutaka Suzuki
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  3. Kosuke Sakai
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  4. Shuichi Asakawa
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  5. Tsuneko Okazaki
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  8. Nobuyoshi Shimizu
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Correspondence to Nobuyoshi Shimizu.

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Miyamoto, K., Suzuki, N., Sakai, K. et al. A novel mouse model for Down syndrome that harbor a single copy of human artificial chromosome (HAC) carrying a limited number of genes from human chromosome 21. Transgenic Res 23, 317–329 (2014). https://doi.org/10.1007/s11248-013-9772-x

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