title: Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases.
abstract: Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington's disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Varela
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Curtis
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Andrew G L
authors.initials: AG
authors.lastname: Douglas
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Suzan M
authors.initials: SM
authors.lastname: Hammond
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Aisling J
authors.initials: AJ
authors.lastname: O'Loughlin
authors.affiliation: Fundacion Pública Galega de Medicina Xenómica, Clinical Hospital of Santiago, Travesía da Choupana s/n, Santiago de Compostela, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Sobrido
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Janine
authors.initials: J
authors.lastname: Scholefield
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
mesh_terms: D000483:Alleles; D042622:DNA Repeat Expansion / Q000235:genetics*; D020868:Gene Silencing; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000628:therapy; D015316:Genetic Therapy; D005828:Genetics, Population; D006579:Heterozygote; D006801:Humans; D058990:Molecular Targeted Therapy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics