Abstract
Mammalian artificial chromosomes derived from native chromosomes have been applied to biomedical research and development by generating cell sources and transchromosomic (Tc) animals. Human artificial chromosome (HAC) is a precedent chromosomal vector which achieved generation of valuable humanized animal models for fully human antibody production and human pharmacokinetics. While humanized Tc animals created by HAC vector have attained significant contributions, there was a potential issue to be addressed regarding stability in mouse tissues, especially highly proliferating hematopoietic cells. Mouse artificial chromosome (MAC) vectors derived from native mouse chromosome 11 demonstrated improved stability, and they were utilized for humanized Tc mouse production as a standard vector. In mouse, however, stability of MAC vector derived from native mouse chromosome other than mouse chromosome 11 remains to be evaluated. To clarify the potential of mouse centromeres in the additional chromosomes, we constructed a new MAC vector from native mouse chromosome 10 to evaluate the stability in Tc mice. The new MAC vector was transmitted through germline and stably maintained in the mouse tissues without any apparent abnormalities. Through this study, the potential of additional mouse centromere was demonstrated for Tc mouse production, and new MAC is expected to be used for various applications.
Highlights
Mammalian artificial chromosomes derived from native chromosomes have been applied to biomedical research and development by generating cell sources and transchromosomic (Tc) animals
A strategy to design a stable mouse artificial chromosome (MAC) vector was conceived through construction of a Mouse artificial chromosome (MAC) vector from native mouse chromosome 11 based on the hypothesis
The 10MAC1 was transmitted through germline in mice and there was no apparent abnormality in Tc mice carrying 10MAC1 through generations
Summary
Mammalian artificial chromosomes derived from native chromosomes have been applied to biomedical research and development by generating cell sources and transchromosomic (Tc) animals. Human artificial chromosome (HAC) vectors derived from native human chromosomes, independently and stably maintained without disrupting host chromosomes, have capacities to carry desired copy number of genes via recombination sites, and transfer a large quantity of Mb-sized g enes[1] Taking these advantages over conventional vectors, transchromosomic (Tc) mice into which arbitrary genes were introduced via the HAC vectors, have been generated[2,3]. In an attempt to create a mouse model, the HAC vectors have demonstrated a variable retention rate in tissues of mouse individuals, and that stability is low in hematopoietic cells with high proliferation[4] To address this issue, we established a chromosome transfer- and recombinase-mediated genomic transfer (CT-RMGT) method that maintains an arbitrary human chromosomal region at the chromosome end of the mouse host via chromosome engineering technologies[5].
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