Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). Approximately 0.45% of human conceptions are trisomic for Hsa21 (1
). The incidence of trisomy is influenced by maternal age and differs between populations (between 1 in 319 and 1 in 1000 live births are trisomic for Hsa21) (2
). Trisomic fetuses are at an elevated risk of miscarriage, and people with DS have an increased risk of developing several medical conditions (7
). Recent advances in medical treatment and social inclusion have significantly increased the life expectancy of people with DS. In economically developed countries, the average life span of people who are trisomic for Hsa21 is now greater than 55 years (8
). In this review, we will discuss novel findings in the understanding of DS and highlight future important avenues of research.
The additional copy of Hsa21, in people with DS, is proposed to result in the increased expression of many of the genes encoded on this chromosome. The imbalance in expression of Hsa21 and non-Hsa21 genes is hypothesized to result in the many phenotypes that characterize DS. However, only some of the Hsa21 genes are likely to be dosage-sensitive, such that the phenotype they confer is altered by gene-copy number. Thus to understand DS, it is crucial both to understand the genomic content of Hsa21 and to evaluate how the expression levels of these genes are altered by the presence of a third copy of Hsa21. There have been a number of recent advances in genomics relevant to DS. For example, the traditional definition of a gene has been modified (Box 1
). A number of fusion transcripts that are encoded by two or more genes previously considered to be separate have been reported, such as the transcript encoded by exons from the Hsa21, DONSON
). Whether these transcripts represent novel genes has yet to be determined. However, the number of genes recognized on Hsa21 is likely to continue to increase from the current count of more than 400 (10
). In particular, as algorithms to identify non-coding RNAs (e.g. microRNAs) improve, the number of recognized genes may increase. Five microRNAs have been identified on Hsa21 (11
). MicroRNAs regulate the expression of other genes (13
), and their role in DS is not fully understood. Spatial and temporal mapping of the Hsa21 gene expression is also critical to the understanding of DS. The increase in expression of some Hsa21 genes caused by trisomy of Hsa21 has been recently shown to lie within the range of natural variations in the expression of these genes in the euploid population (14
). Similar findings have also been reported in the Ts(1716
)65Dn (Ts65Dn) mouse model of DS (Fig. ) (16
This suggests that these genes are unlikely to be candidates for the dosage-sensitive genes underlying DS phenotypes in the tissues investigated.
Box 1:What is a gene?
The definition of a gene has shifted over the past 100 years since it was first coined by Wilhelm Johannsen in 1909, based on the ideas of Mendel, de Vries, Correns and Tschermak. Their original theoretical definition of the gene being ‘the smallest unit of genetic inheritance’ remains the cornerstone of our understanding; however, the definition has grown with our knowledge of molecular biology. The gene has recently been defined as ‘a union of genomic sequences encoding a coherent set of potentially overlapping functional products’ (133
). Splicing generates multiple transcripts from one gene. Moreover, exons from genes previously considered to be separate may be spliced together to generate novel transcripts (9
). How to classify these fusion transcripts is a significant challenge. In addition, alternative transcription start sites that generate novel 5′ untranslated regions continue to be discovered, even for well-characterized genes (134
). Although many of these novel transcripts are rare and their functional importance is not understood, our definition of a gene must encompass the observed diversity of the genome.
Figure 1. Mouse models of Hsa21 trisomy and monosomy. Hsa21 (orange) is syntenic with regions of mouse chromosomes 16 (Mmu16, blue), 17 (Mmu 17, green) and 10 (Mmu10, grey). The Tc1 mouse model carries a freely segregating copy of Hsa21, which has two deleted regions, (more ...)
Trisomy of Hsa21 is associated with a small number of conserved features, occurring in all individuals, including mild-to-moderate learning disability, craniofacial abnormalities and hypotonia in early infancy (17
). Although these phenotypes are always found in people with DS, the degree to which an individual is affected varies. Additionally, trisomy of Hsa21 is also associated with variant phenotypes that only affect some people with DS, including atrioventricular septal defects (AVSDs) in the heart, acute megakaryoblastic leukaemia (AMKL) and a decrease in the incidence of some solid tumours. This phenotypic variation is likely to be caused by a combination of environmental and genetic causes. Genetic polymorphisms in both Hsa21 and non-Hsa21 genes may account for much of this variation. Genome-wide association studies to identify these polymorphisms constitute a promising strategy to gain novel insights into the pathology of DS.
A central goal of DS research is to understand which of the genes on Hsa21, when present in three copies, lead to each of the different DS-associated phenotypes, and to elucidate how increased expression leads to the molecular, cellular and physiological changes underlying DS pathology. Two distinct approaches are being taken to address these issues. First, genomic association studies, such as that recently published by Lyle et al
)., may point to genes that play an important role in pathology. Secondly, a number of animal models of Hsa21 trisomy have been generated. Recent advances in chromosome engineering have led to the establishment of mice trisomic for different sets of mouse genes syntenic to Hsa21, and a mouse strain, Tc(Hsa21)1TybEmcf (Tc1), carrying most of Hsa21, as a freely segregating chromosome (Fig. ) (19
). These strains are being used both to map dosage-sensitive genes on Hsa21 and to understand pathological mechanisms. Here, we review recent advances in the understanding of DS-associated phenotypes and the development of therapeutic strategies to treat them.