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Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease.

ABSTRACT: Background:The huntingtin gene (HTT) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments. Objective:This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions. Methods:Across 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing. Results:Heterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the mHTT allele in 61% (95% high density interval: 55%, 67%) of individuals. Conclusions:These results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD.

SUBMITTER: Claassen DO

PROVIDER: S-EPMC7249892 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease.

Claassen Daniel O DO Corey-Bloom Jody J Dorsey E Ray ER Edmondson Mary M Kostyk Sandra K SK LeDoux Mark S MS Reilmann Ralf R Rosas H Diana HD Walker Francis F Wheelock Vicki V Svrzikapa Nenad N Longo Kenneth A KA Goyal Jaya J Hung Serena S Panzara Michael A MA

Neurology. Genetics 20200514 3

<h4>Background</h4>The huntingtin gene (<i>HTT</i>) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments.<h4>Objective</h4>This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions.<h4>Methods</h4>Across 7 US sites, 202 individuals with HD prov ...[more]

PMID: 32548276

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Project description:BackgroundA large single nucleotide polymorphism (SNP) dataset was used to analyze genome-wide diversity in a diverse collection of watermelon cultivars representing globally cultivated, watermelon genetic diversity. The marker density required for conducting successful association mapping depends on the extent of linkage disequilibrium (LD) within a population. Use of genotyping by sequencing reveals large numbers of SNPs that in turn generate opportunities in genome-wide association mapping and marker-assisted selection, even in crops such as watermelon for which few genomic resources are available. In this paper, we used genome-wide genetic diversity to study LD, selective sweeps, and pairwise FST distributions among worldwide cultivated watermelons to track signals of domestication.ResultsWe examined 183 Citrullus lanatus var. lanatus accessions representing domesticated watermelon and generated a set of 11,485 SNP markers using genotyping by sequencing. With a diverse panel of worldwide cultivated watermelons, we identified a set of 5,254 SNPs with a minor allele frequency of ≥ 0.05, distributed across the genome. All ancestries were traced to Africa and an admixture of various ancestries constituted secondary gene pools across various continents. A sliding window analysis using pairwise FST values was used to resolve selective sweeps. We identified strong selection on chromosomes 3 and 9 that might have contributed to the domestication process. Pairwise analysis of adjacent SNPs within a chromosome as well as within a haplotype allowed us to estimate genome-wide LD decay. LD was also detected within individual genes on various chromosomes. Principal component and ancestry analyses were used to account for population structure in a genome-wide association study. We further mapped important genes for soluble solid content using a mixed linear model.ConclusionsInformation concerning the SNP resources, population structure, and LD developed in this study will help in identifying agronomically important candidate genes from the genomic regions underlying selection and for mapping quantitative trait loci using a genome-wide association study in sweet watermelon.

Dataset Information

Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease.

Publications

Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease.

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