Population genetics and allele-specific silencing of the Huntington disease mutation

Huntington disease (HD) is a devastating neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin gene (HTT). A repeat of ≥36 CAG defines the HD mutation and is diagnostic in the presence of motor or psychiatric phenotypes. All patients have an expanded CAG repeat, usually inherited from an affected parent and heterozygous with a normal (≤35) CAG repeat allele. This thesis addresses numerous gaps in our understanding of the HD mutation at the population level, including heterozygote frequency, penetrance, ancestry, the de novo mutation rate, and haplotypes useful for therapeutic gene silencing. Dense SNP genotyping across HTT in HD patients and relatives from Canada, Sweden, France, and Italy allowed definition of the three most common HD mutation haplotypes in populations of European ancestry. All common defining alleles of these haplotypes were identified from the 1000 Genomes Project reference data and validated by direct genotyping of HD patients and their families. Haplotypes of the HD mutation provide mutually exclusive sets of target variants for allele-specific HTT silencing in the maximum number of European ancestry patients. Haplotypes of the HD mutation were investigated in additional HD patient populations worldwide. The HD mutation in Peru occurs most frequently on the A1 HTT haplotype, as in Europe, but on a distinct A1 variant found in Amerindian controls, supporting an indigenous origin of the HD mutation in Latin America. The general population frequency of the HD mutation was estimated from CAG repeat genotyping of 7315 individuals in Canada, the United States, and Scotland, revealing that approximately 1 in 400 people (0.246%) has a CAG repeat of 36 or greater. This frequency of the HD mutation in the general population is higher than expected from clinical prevalence estimates. The normal CAG repeat distribution was characterized in a range of ethnically distinct populations, allowing comparative estimates of the HD new mutation rate. Estimated as a function of intermediate CAG repeat frequencies below the pathogenic range (27-35 CAG), 1 in 5372 births is a new mutation for HD in European ancestry populations, representing 7.1% of HD mutations (≥36 CAG) in the general population.

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