We are investigating the genetic and cellular pathological mechanisms that cause Down Syndrome phenotypes.
Trisomy of human chromosome 21 (Hsa21) occurs in ∼1 in 750 live births, and the resulting gene dosage imbalance gives rise to Down syndrome (DS), the most common known genetic form of mental retardation. DS is a constellation of different phenotypes: while all people with DS have hypotonia, cognitive impairment, neurodegeneration and craniofacial alterations, most also present with a spectrum of other disorders such as heart defects and leukaemia.
We are investigating the genetic and cellular pathological mechanisms that cause Down Syndrome phenotypes. In collaboration with Professor Elizabeth Fisher (Institute of Neurology, UCL) we are interested in identifying dosage-sensitive genes on Hsa21 which, when present in three copies, cause the many different phenotypes seen in DS. We are addressing this using mouse models. We have created a novel mouse strain, termed Tc1, which carries a freely segregating copy of Hsa21. Tc1 mice show defects in memory, synaptic plasticity, locomotor function, heart development and in the craniofacial skeleton (O'Doherty et al, 2005; Morice et al, 2008; Galante et al 2009; Witton et al 2015).
People with DS have increased rates of mekaryoblastic leukaemia, but lower rates of solid tumours. We have shown that Tc1 mice have perturbed megakaryopoiesis, a pathology that may contribute to the increased rates of leukaemia in human DS (Alford et al, 2010). In contrast, studies of Tc1 mice have shown that the reduction in solid tumours may be due to defective angiogenesis (Reynolds et al, 2010).
Currently our main aim is to identify 'dosage-sensitive' genes, which, when present in three copies cause DS phenotypes. To do this we have constructed a series of novel mouse strains with duplications and deletions of regions mouse chromosomes orthologous to Hsa21 (Lana-Elola et al 2016). Analysis of these mouse strains has allowed us to narrow down the region containing the genes that cause congenital heart defects. We are currently working to identify the specific dosage-sensitive genes that cause congenital heart defects, and to understand how increased copy number of these genes leads to pathology.
More broadly, we are also using the same approaches to identify the dosage-sensitive genes that cause cognitive impairment, neurodegeneration and craniofacial abnormalities.