Sequence-Level Analysis of the Major European Huntington Disease Haplotype

American Journal of Human Genetics
Jong-Min LeeJames F Gusella

Abstract

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...Continue Reading

References

Mar 3, 2009·American Journal of Human Genetics·Simon C WarbyMichael R Hayden
Mar 23, 2010·BMC Systems Biology·Jong-Min LeeVanessa C Wheeler
Jun 15, 2011·Nature Genetics·Donald F ConradUNKNOWN 1000 Genomes Project
Oct 4, 2011·Bioinformatics·Gustavo GlusmanJared C Roach
Oct 6, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jeffrey B CarrollMichael R Hayden
Mar 6, 2012·American Journal of Human Genetics·Jong-Min LeeJames F Gusella

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Citations

May 12, 2018·PLoS Genetics·Michael J ChaoJong-Min Lee
Aug 24, 2017·European Journal of Human Genetics : EJHG·Michael J ChaoJong-Min Lee

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