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Down syndrome: New genetic approaches

A recent review, published in Cell, has examined the lessons learned from model systems and has explored emerging methods for better understanding the genetic basis of Down syndrome.

Down syndrome

Down syndrome is the result of an extra copy of all or, rarely, part of the long arm of human chromosome 21 (Hsa21). It comprises of a range of phenotypic features, with all individuals displaying some level of intellectual disability. Additionally, individuals also present with hypotonia, cerebellar hypoplasia and midface skeletal retrusion. The incidence of Down syndrome worldwide remains at more than 1 in 1000 live births.

The main scientific question researchers have been trying to explore is understanding which subsets of genes on chromosome 21 contribute to specific phenotypic features. Chromosome 21 encodes over 500 genes. Most of these genes, even the encoding proteins, have unknown functions. Overexpression of these genes due to trisomy causes widespread disruption in the transcriptome and proteome. As a result, these impact the development and function of most organs and organ systems.

Model organisms

The use of model organisms has been critical to determine gene functions and create models of trisomy. The mouse model has typically been the model of choice yet has its own limitations and challenges. Other less complex organisms, such as the zebrafish, fruit fly, nematode worm and yeast, have also been exploited. To maximise the potential of these systems, the authors in this review noted that it is important to understand the unique advantages and limitations of each.

It is important to identify reliable orthologous genes within model organisms that meet several criteria, mainly a statistically significant sequence similarity. This identification can be easily done in mammals when a comprehensive transcriptome and/or genomic sequence are available. For example, Ptr21q in chimpanzees is essentially conserved with Hsa21q in humans, with no species-specific genes. For non-mammalian model organisms, identification requires manual examination of significant matches and also functional information.

Researchers frequently perform knockouts and/or knockdowns in model organisms, which are important for uncovering gene function. However, the authors noted that the interpretation of results and claims of relevance to Down syndrome must be done with caution. Results can indicate the role of potential pathways or cellular processes that may require further investigation. 

Despite challenges in experimental design and interpretation, yeast, nematode, fruit fly and zebrafish are cheap and relatively quick to experiment on. Studies on these organisms can provide important insights into the functions of individual genes and their effects on other target genes and pathways. Most importantly, they can support prediction of how their human orthologues may contribute to the phenotypic features of Down syndrome.

Saccharomyces cerevisiae

Researchers have suggested that some trisomy-associated features may result from the presence of an extra chromosome, regardless of the specific genes that it encodes. However, testing this hypothesis in vertebrate models is challenging because nearly all autosomal aneuploidies are nonviable. Simple yeast, Saccharomyces, tolerate some whole-chromosome aneuploidies and are therefore, an ideal system for studying the general effects of aneuploidy.

Caenorhabditis elegans

Caenorhabditis elegans enable inexpensive large-scale chemical and genetic screens. As a result, they can provide a suitable detailed genetic analysis of development and the nervous system. Around 40% of human genes have worm orthologues. However, many Hsa21 genes are dispersed throughout the six pairs of chromosomes of C. elegans. While it is impractical to create aneuploid worms, models of gene overexpression may be useful for identifying drug targets in Down syndrome-associated Alzheimer’s disease.

Drosophila melanogaster

Drosophila are useful as they have an extensive history of genetic manipulation. They are also small in size and produce large numbers of progeny. Like C. elegans, Hsa21 orthologues in fruit flies are dispersed throughout the genome. Thereby, making it impractical to create flies with simultaneous trisomy. Drosophila studies are useful for determining the function of uncharacterised genes, exploring genetic interactions and defining the cellular and molecular mechanisms by which protein overexpression causes phenotypes.


Zebrafish are useful for studying the effects of genes on development. They develop rapidly, their embryos are transparent and researchers have sequenced their genome – which shows substantial conservation with mammals. Danio rerio has a partial genome duplication which can affect interpretation of experimental genome manipulations. The ability to assess early development has been used to study the impact of gene dosage relevant to Down syndrome.


The mouse model has made major contributions to understanding the consequences of gene dosage imbalance in Down syndrome. Muriel Davisson’s Ts65Dn mouse was the first model to assess the effects of gene dosage imbalance on multiple features relevant to Down syndrome. Nevertheless, it is trisomic for only ~60% of Hsa21-orthologous mouse genes. Since its development, more than 20 mouse models have been generated. There are also several emerging opportunities for creating better murine models, including mouse artificial chromosome models, induced pluripotent stem cell models and rat models.

Concluding comments

Animal models are critical for understanding the complex consequences of simultaneous expression of genes seen in Down syndrome. Yeast, nematodes, fruit flies and zebrafish enable high-throughput functional screens of Hsa21 orthologues. Mouse models, and emerging models, provide developed and physiologically functional systems that reflect important aspects of human biology. The authors emphasised that there is no ‘best’ model of Down syndrome, rather multiple appropriate models for a well-defined experimental goal. The application of new technologies, such as CRISPR, will hopefully improve our ability to study consequences of gene dosage alterations. Nonetheless, the authors noted that it is necessary to ensure that experimental systems are designed to reflect the relevant features of the human condition.

Image credit: Image Team –

More on these topics

Down Syndrome / Genetics / Trisomy