Abstract
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.
Highlights
Human aneuploidy, a gain or loss of chromosomes, is associated with both birth defects and cancer (Beach et al, 2017)
We previously constructed hybrid A9 cells containing a copy of HSA21 (Inoue et al, 2001), which was moved into DT40 cells by microcell-mediated chromosome transfer (MMCT) (Tomizuka et al, 1997; Kazuki et al, 2011)
A loxP site was introduced into the NC_000021.9 locus of HSA21 to create the ‘HSA21-loxP’ chromosome, which was transferred by MMCT into Chinese hamster ovary (CHO) cells containing the MAC1 vector (Figure 1A)
Summary
A gain or loss of chromosomes, is associated with both birth defects and cancer (Beach et al, 2017). Down syndrome (DS) is caused by trisomy 21 and is the most common survivable aneuploidy, occurring in about 1 in every 800 in live births (Driscoll and Gross, 2009). A population-based study of 6300 infants with DS born from 1993 to 2003 in US shows that 95% had a complete freely segregating third copy of HSA21, 3% had partial trisomy 21 due to duplication of part of the chromosome, and 2% had mosaic DS in which some cells have three copies of HSA21 while others have two copies (Shin et al, 2010). Both translocation DS and mosaic DS are rare and typically have milder phenotypes compared with those who inherit a complete HSA21 (Prasher, 1995; Chandra et al, 2010)
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