Dissection of a Down syndrome-associated trisomy to separate the gene dosage-dependent and -independent effects of an extra chromosome

Abstract

As an aneuploidy, trisomy is associated with mammalian embryonic and postnatal abnormalities. Understanding the underlying mechanisms involved in mutant phenotypes is broadly important and may lead to new strategies to treat clinical manifestations in individuals with trisomies, such as trisomy 21 (Down syndrome). While increased gene dosage effects due to a trisomy may account for the mutant phenotypes, there is also the possibility that phenotypic consequences of a trisomy can arise because of the presence of a freely segregating extra chromosome with its own centromere, i.e. a ‘free trisomy’ independent of gene dosage effects. Presently, there are no reports of attempts to functionally separate these two types of effects in mammals. To fill this gap, here we describe a strategy that employed two new mouse models of Down syndrome, Ts65Dn;Df(17)2Yey/+ and Dp(16)1Yey/Df(16)8Yey. Both models carry triplications of the same 103 human chromosome 21 gene orthologs; however, only Ts65Dn;Df(17)2Yey/+ mice carry a free trisomy. Comparison of these models revealed the gene dosage-independent impacts of an extra chromosome at the phenotypic and molecular levels for the first time. They are reflected by impairments of Ts65Dn;Df(17)2Yey/+ males in T-maze tests when compared with Dp(16)1Yey/Df(16)8Yey males. Results from the transcriptomic analysis suggest the extra chromosome plays a major role in trisomy-associated expression alterations of disomic genes beyond gene dosage effects. This model system can now be used to deepen our mechanistic understanding of this common human aneuploidy and obtain new insights into the effects of free trisomies in other human diseases such as cancers.

Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model

“…To date, these data are the only reports of sex-specific DYRK1A expression in DS mouse models, emphasizing the limited analysis of effects sex has on protein or transcript quantities in trisomy and the importance of the demonstrated sex differences in DYRK1A expression in the developing brain in the current study. Sex differences in DYRK1A protein expression in Ts65Dn pups may result from the general, genome-wide transcriptional dysregulation in triplicated and non-triplicated genes caused by abnormal gene dosage of Hsa21 genes combined with differences in sex chromosome complement ( Saran et al, 2003 ; Xing et al, 2023 ). The observed sex differences in DYRK1A expression in the developing Ts65Dn brain occur against the backdrop of the developmental cascades of sex differentiation of the typical brain.…”

“…Limitations of the Ts65Dn model have been identified, the most notable being that the trisomic mice also contain ~35 protein coding genes found on mouse chromosome 17 that are not homologous to Hsa21 ( Duchon et al, 2011 ; Reinholdt et al, 2011 ). With the development of the Ts66Yah and other DS mouse models, the contributions of these non-Hsa21 genes are becoming understood ( Duchon et al, 2022 ; Xing et al, 2023 ). These newer models may have more accurate face validity but may still lack many Hsa21 homologous genes.…”