Genetic analysis of triplicated genes affecting sex-specific skeletal deficits in Down syndrome model mice

Down syndrome (DS) is caused by the triplication of human chromosome 21
(Hsa21), resulting in skeletal insufficiency (low bone mineral density)
and altered bone development. DS mouse models recapitulate these deficits,
including sexual dimorphism in long bone alterations. Historically, Ts65Dn
mice provided much of the insight behind DS-related skeletal deficits with
~100 trisomic orthologous genes, but there are concerns about the genetic
fidelity in this model due to the included triplication of genes not
homologous to Hsa21. A new DS model, Ts66Yah, subtracted the non-Hsa21
homologous trisomic genes from Ts65Dn but has not been evaluated for long
bone deficits. Comparing skeletal phenotypes between these models can
determine the contribution of non-Hsa21 homologous trisomic genes and
whether the Ts66Yah mouse is relevant as a model for DS-associated
skeletal deficits. After assessing individual densitometric, morphometric,
and mechanical variables in male and female Ts66Yah femurs at similar ages
to when skeletal deficits were observed in Ts65Dn mice, structural
phenotypes were directly compared to those of Ts65Dn mice using a novel
multivariate principal components analysis method to generate composite
scores. Overall, structural and mechanical bone phenotypes of the femur
appeared milder in Ts66Yah compared to Ts65Dn mice. The appearance of
developmental trabecular microarchitecture deficits, but not other
abnormalities, were evident earlier in Ts65Dn than Ts66Yah mice. Dyrk1a, a
gene triplicated in both models, affected skeletal structure differently
in each model, likely through differing gene interactions. The novel
principal components analysis detected subclinical phenotypes lost in
individual analyses, which could be advantageous when determining overall
skeletal deficits.