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Abstract
ABSTRACTDown syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.
Highlights
Down syndrome, which arises from trisomy of Hsa21, is a complex condition affecting many tissues with different severity and penetrance (Antonarakis et al, 2020)
The Dp1Tyb mouse model of Down syndrome (DS) has an extra copy of 63% of Hsa21-orthologous mouse genes
In order to establish if this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered
Summary
Down syndrome, which arises from trisomy of Hsa, is a complex condition affecting many tissues with different severity and penetrance (Antonarakis et al, 2020). With a prevalence of ~1 in 800 live births, DS is the most common genetic cause of intellectual disability, AD and heart defects (Antonarakis, 2017; Wiseman et al, 2015). Phenotypes likely result from increased dosage of Hsa genes, which comprise ~230 coding genes, and many more non-coding elements (Antonarakis, 2017). Identification of dosage-sensitive Hsa genes causing DS phenotypes would facilitate studies of underlying pathological mechanisms, and development of new treatments. For most DS phenotypes, causative genes are unknown (Lana-Elola et al, 2011)
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