Mouse models of aneuploidy to understand chromosome disorders

Abstract

An organism or cell carrying a number of chromosomes that is not a multiple of the haploid count is in a state of aneuploidy. This condition results in significant changes in the level of expression of genes that are gained or lost from the aneuploid chromosome(s) and most cases in humans are not compatible with life. However, a few aneuploidies can lead to live births, typically associated with deleterious phenotypes. We do not understand why phenotypes arise from aneuploid syndromes in humans. Animal models have the potential to provide great insight, but less than a handful of mouse models of aneuploidy have been made, and no ideal system exists in which to study the effects of aneuploidy per se versus those of raised gene dosage. Here, we give an overview of human aneuploid syndromes, the effects on physiology of having an altered number of chromosomes and we present the currently available mouse models of aneuploidy, focusing on models of trisomy 21 (which causes Down syndrome) because this is the most common, and therefore, the most studied autosomal aneuploidy. Finally, we discuss the potential role of carrying an extra chromosome on aneuploid phenotypes, independent of changes in gene dosage, and methods by which this could be investigated further.

Fig. 1

Graph showing the number of known protein coding genes on each human chromosome. Trisomies of chromosomes with bars below the orange line are compatible with life. All gene totals taken from Ensembl genome build GRCh38.p13. Sex chromosomes are shown in grey

Fig. 2

Aneuploid mouse models of DS. A schematic megabasepair ruler is shown at the top. Human chromosome 21 (p and q arms with G-banding) is shown below this. The Tc1 model is shown in blue with deletions and a duplication (double line segment) relative to Hsa21. The transchromosomic TcMAC21 is depicted in green with deletions relative to Hsa21. The Hsa21 trisomic region in TcMAC21 is incorporated into a mouse artificial chromosome with a mouse centromere. The trisomic Hsa21-orthologous region in Ts65Dn mice is shown in orange relative to Hsa21. Numbers of trisomic Hsa21 genes (or mouse orthologues) in each model are shown to the right in parentheses. The Ts65Dn model carries an extra 43 protein coding genes not orthologous to Hsa21

Fig. 3

A proposed animal model system for DS (trisomy 21) consisting of two complementary models. For the gene dosage model, gene targeting is used to insert recombination sites (LoxP) into sequences close to the centromere of Hsa21 and telomere of a mouse chromosome. MMCT is used to move Hsa21 into targeted mouse embryonic stem cells. In vitro Cre expression recombines Hsa21q onto the end of the mouse chromosome. Resulting mice will have 3 copies of Hsa21 orthologues but will have a euploid chromosome count (reciprocal hybrid chromosome not shown and would not be retained). For the aneuploid model, gene targeting is used to insert recombination sites (LoxP) into sequences close to the centromere of Hsa21 and centromere of a mouse chromosome. MMCT is used to move Hsa21 into targeted mouse embryonic stem cells. In vitro Cre expression replaces the endogenous mouse chromosome arm with Hsa21q. After generation of mice and backcrossing, resulting mice will have 3 copies Hsa21 orthologues with an aneuploid chromosome count of 41 (the euploid mouse chromosome karyotype has 40 chromosomes)