Our research is broadly aimed at understanding the molecular turnover and role of simple sequence microsatellite repeats in the human genome and their relationship to human variation and genetic disease. In particular, ongoing work is focused on the CTG•CAG repeat expansions that are associated with the inherited human disorders myotonic dystrophy and Huntington disease. In both of these disorders the CTG•CAG repeat is polymorphic in size between normal individuals, but expanded in length in patients. Once into the disease range, the repeat becomes highly unstable during both germline transmission and somatic development. However, the molecular mechanisms underlying repeat instability and the role of cis- and trans-acting modifiers of instability are currently not well understood. Our research is focused on analysing the germline and somatic dynamics of the expansion process and identifying the cis-acting and trans-acting genetic and environmental modifiers of repeat stability using human samples, transgenic mice, in vitro and in silico modelling. We are also developing new next generation sequencing based approaches to genome wide microsatellite genotyping and mutation detection with a view to uncovering the drivers of germline and somatic mutation in man and the implications for understanding the role of genetic instability in inherited disease, ageing and cancer.
Image 1 - Repeat length variation in the blood DNA of a myotonic dystrophy patient
Image 2 - Variant repeat alleles in myotonic dystrophy patients