A Pipeline to Assess Disease-Associated Haplotypes in Repeat Expansion Disorders: The Example of MJD/SCA3 Locus

Frontiers in Genetics
Inês P D CostaSandra Martins

Abstract

At least 40 human diseases are associated with repeat expansions; yet, the mutational origin and instability mechanisms remain unknown for most of them. Previously, genetic epidemiology and predisposing backgrounds for the instability of some expanding loci have been studied in different populations through the analysis of diversity flanking the respective pathogenic repeats. Here, we aimed at developing a pipeline to assess disease-associated haplotypes at oligonucleotide repeat loci, combining analysis of single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs). Machado-Joseph disease (MJD/SCA3), the most frequent dominant ataxia worldwide, was used as an example of a detailed procedure. Thus, to identify genetic backgrounds that segregate with expanded/mutated alleles in MJD, we selected a set of 26 SNPs and 7 STRs flanking the causative CAG repeat. Key criteria and steps for this selection are described, and included (1) haplotype blocks minimizing the occurrence of recombination (for SNPs); and (2) match scores to increase potential for polymorphic information content of repetitive sequences found in Tandem Repeats Finder (for STRs). To directly assess SNP haplotypes in phase with MJD expansions, we optimized...Continue Reading

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Citations

Jun 14, 2019·European Journal of Human Genetics : EJHG·Reuven SharonyCarlos R Gordon
Jun 6, 2020·NAR Genomics and Bioinformatics·Mengge ZhaoKai Wang
Oct 23, 2020·Science Translational Medicine·Mercedes PrudencioLeonard Petrucelli

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Methods Mentioned

BETA
genotyping
PCR

Software Mentioned

PHASE
BLAST
GeneMapper
Primer3Plus
Tandem Repeats Finder
AutoDimer
Ensembl

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