Sequence-Level Analysis of the Major European Huntington Disease Haplotype.

TitleSequence-Level Analysis of the Major European Huntington Disease Haplotype.
Publication TypeJournal Article
Year of Publication2015
AuthorsLee J-M, Kim K-H, Shin A, Chao MJ, Abu Elneel K, Gillis T, Mysore J S, Kaye JA, Zahed H, Kratter IH, Daub AC, Finkbeiner S, Li H, Roach JC, Goodman N, Hood L, Myers RH, MacDonald ME, Gusella JF
JournalAm J Hum Genet
Date Published2015 Sep 03
KeywordsBase Sequence, European Continental Ancestry Group, Evolution, Molecular, Founder Effect, Haplotypes, Heterozygote, Humans, Huntington Disease, Molecular Sequence Data, Nerve Tissue Proteins, Pedigree, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Trinucleotide Repeat Expansion
Abstract<p>Huntington disease (HD) reflects the dominant consequences of a CAG-repeat expansion in HTT. Analysis of common SNP-based haplotypes has revealed that most European HD subjects have distinguishable HTT haplotypes on their normal and disease chromosomes and that ∼50% of the latter share the same major HD haplotype. We reasoned that sequence-level investigation of this founder haplotype could provide significant insights into the history of HD and valuable information for gene-targeting approaches. Consequently, we performed whole-genome sequencing of HD and control subjects from four independent families in whom the major European HD haplotype segregates with the disease. Analysis of the full-sequence-based HTT haplotype indicated that these four families share a common ancestor sufficiently distant to have permitted the accumulation of family-specific variants. Confirmation of new CAG-expansion mutations on this haplotype suggests that unlike most founders of human disease, the common ancestor of HD-affected families with the major haplotype most likely did not have HD. Further, availability of the full sequence data validated the use of SNP imputation to predict the optimal variants for capturing heterozygosity in personalized allele-specific gene-silencing approaches. As few as ten SNPs are capable of revealing heterozygosity in more than 97% of European HD subjects. Extension of allele-specific silencing strategies to the few remaining homozygous individuals is likely to be achievable through additional known SNPs and discovery of private variants by complete sequencing of HTT. These data suggest that the current development of gene-based targeting for HD could be extended to personalized allele-specific approaches in essentially all HD individuals of European ancestry.</p>
Alternate JournalAm. J. Hum. Genet.
PubMed ID26320893
PubMed Central IDPMC4564985
Grant ListGM076547 / GM / NIGMS NIH HHS / United States
P50NS016367 / NS / NINDS NIH HHS / United States
U01 NS082079 / NS / NINDS NIH HHS / United States
T32 GM007618 / GM / NIGMS NIH HHS / United States
R01 NS039074 / NS / NINDS NIH HHS / United States
R01 NS091161 / NS / NINDS NIH HHS / United States
P50 NS016367 / NS / NINDS NIH HHS / United States
X01 HG007750 / HG / NHGRI NIH HHS / United States
R01NS091161 / NS / NINDS NIH HHS / United States
P50 GM076547 / GM / NIGMS NIH HHS / United States
U01NS082079 / NS / NINDS NIH HHS / United States