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Christopher E. Pearson
 
     
 
 
     
 

Christopher E. Pearson completed a Ph.D. (McGill University, 1994) studying mammalian DNA replication and protein interactions with cruciform-DNAs, proceeded to a post-doc (Texas Medical Center) elucidating the newly identified disease-mutation of trinucleotide repeat instability. During this time, Christopher discovered the elusive slipped-strand DNAs. Christopher is a Senior Scientist at The Hospital for Sick Children, Department of Genetics; an Associate Professor at the University of Toronto, Department of Medical Genetics & Microbiology; and a member of the Canadian Genetic Diseases Network.

 
     
 
Dr. Pearson's research concerns the molecular mechanism(s) of genetic mutations involving trinucleotide repeat sequences. The mutation responsible for at least 21 serious human genetic diseases has been traced to the genetic variation in the lengths of specific trinucleotide repeats in DNA. Many of the diseases associated with this form of mutation affect the neurological or neuromuscular systems and include myotonic dystrophy type 1 (the most common form of muscular dystrophy), Huntington's disease, spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 12 and fragile X (the most common form of inherited mental retardation).
 
     
 
Depending upon the disease gene the unstable repeats can be located in the 5'-UTR, the 3'-UTR, the intronic region, or the coding region (coding for glutamine residues). Repeat expansions can cause disease by altered transcription, altered transcript processing or an altered protein product. While the modes of disease may differ, common to each disease is the expansion mutation. To prevent or treat these diseases at the DNA level it is imperative to understand the molecular details of the mechanism of instability.
 
     
 
Our research focuses on the mechanisms and factors (cellular and genetic) that regulate the genetic instability of trinucleotide repeats. Mutations in tandemly repeated sequences may occur either during the process of DNA replication (genome duplication) or as a result of error-prone DNA repair or through DNA recombination.
 
     
 

Considerable evidence supports a role for DNA replication in repeat instability. Taking advantage of this knowledge, we used drugs specifically affect the process of DNA replication and treated DM1 patient-derived cell lines. The expectation was to attempt to modulate the disease-causing mutation. We have successfully targeted alterations in mutations at the DM1 locus CTG expansion that did not affect the normal allele or other regions of the genome. These are promising first steps towards identifying factors that can specifically arrest or reverse the disease-causing mutation.

 
     
 
Strand slippage between direct repeats during replication can result in insertions or deletions of repeat units. My colleagues and I have demonstrated that trinucleotide repeats can easily form slipped-strand DNA structures. The ability to form slipped-structures is affected by both the length of the repeat tract as well as by the purity of the repeat tract - factors that are known to affect the genetic stability of the repeat tracts and disease in humans.
 
     
 
These correlations provide strong evidence that slipped-structures are mutagenic intermediates in the process of trinucleotide repeat expansion. Furthermore, we have shown that in addition to protein factors (such as DNA mismatch repair) genetic and epigenetic factors can contribute to the disease-associated repeat instability. Current research is aimed at 1) understanding the roles of human DNA replication and repair systems in trinucleotide instability; 2) understanding the formation and cellular processing of slipped-strand DNA structures; and 3) repeat instability in various patient-derived cell lines.
 
     
 

Intellectual Property / Licensing Opportunities

 
 
  • Methylation of Unstable Sequences

 
     
 
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