Christopher Pearson, PhD
Research Institute
Senior Scientist
Genetics & Genome Biology
University of Toronto
Associate Professor
Dept. of Molecular Genetics
Phone: 416-813-8256
Fax: 416-813-4931
e-mail: cepearson.sickkids@gmail.com
Research Interests
- Mechanisms of Genome Stability
- Trinucleotide Repeat Diseases
- DNA Replication, Repair and Mutation
- DNA Structure and Function
Research Activities
Mechanisms of Genome Stability and Trinucleotide Repeat Diseases
My 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 (the most common form of muscular dystrophy), Huntington's disease, spinocerebellar ataxia types 1, 2, 3, 6 and 7, 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 mode 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. 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 correlation's 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.
Publications
Edamura KN, Leonard MR, Pearson CE. (2005) Role of replication and CpG methylation in fragile X syndrome CGG deletions in primate cells. American Journal of Human Genetics, 76:302-311 (News & Views, American Journal of Human Genetics, 76:i-ii)
Mulvihill DJ, Edamura KN, Hagerman KA, Pearson CE, Wang YH. (2004) Effect of CAT or AGG interruptions and CpG methylation on nucleosome assembly upon trinucleotide repeats of spinocerebellar ataxia type 1 and fragile X syndrome. Journal of Biological Chemistry, 280:4498-4503
Pearson CE. (2003) Slipping while sleeping? Trinucleotide expansions in germ cells. Trends in Molecular Medicine, 11:483-488
Yang Z, Lau R, Marcadier J, Chitayat D, Pearson CE. (2003) Replication inhibitors modulate the instability of an expanded trinucleotide repeat at the DM1 locus in human cells. American Journal of Human Genetics, 73:1092-1105.
Tam M, Montgomery SE, Kekis M, Stollar BD, Price GB, Pearson CE. (2003) Slipped (CTG)(CAG) repeats of the myotonic dystrophy locus: Surface-probing with anti-DNA antibodies. Journal of Molecular Biology, 332:585-600.
Marcadier JL, Pearson CE. (2003) Fidelity of primate cell repair of a double-strand break in a (CTG)(CAG) tract: Effect of structure. Journal of Biological Chemistry, 278:33848-33856.
Jin P, Zarnescu DC, Zhang F, Pearson CE, Lucchesi JC, Moses K, Warren ST. (2003) RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron, 39:739-747.
Cleary JD, Pearson CE. (2003) The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence. Cytogenetics & Genome Research, 100:25-55. (cover photo).
Libby RT, Monckton DG, Fu Y.-H, Martinez RA, McAbney JP, Lau R, Einum DD, Nichol K, Ware CB, Ptacek LJ, Pearson CE, LaSpada AR. (2003) Genomic context drives SCA7 CAG repeat instability, while expressed SCA7 cDNAs are intergenerationally and somatically stable in transgenic mice Human Molecular Genetics, 12:41-50.