title: Sequence-Level Analysis of the Major European Huntington Disease Haplotype.
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 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.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jlee51@mgh.harvard.edu.
authors: Jong-Min
authors: JM
authors: Lee
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Kyung-Hee
authors: KH
authors: Kim
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Aram
authors: A
authors: Shin
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Michael J
authors: MJ
authors: Chao
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Kawther
authors: K
authors: Abu Elneel
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Tammy
authors: T
authors: Gillis
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Jayalakshmi Srinidhi
authors: JS
authors: Mysore
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Julia A
authors: JA
authors: Kaye
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Hengameh
authors: H
authors: Zahed
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Ian H
authors: IH
authors: Kratter
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Aaron C
authors: AC
authors: Daub
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Steven
authors: S
authors: Finkbeiner
authors: Institute for Systems Biology, Seattle, WA 98109, USA.
authors: Hong
authors: H
authors: Li
authors: Institute for Systems Biology, Seattle, WA 98109, USA.
authors: Jared C
authors: JC
authors: Roach
authors: Institute for Systems Biology, Seattle, WA 98109, USA.
authors: Nathan
authors: N
authors: Goodman
authors: Institute for Systems Biology, Seattle, WA 98109, USA.
authors: Leroy
authors: L
authors: Hood
authors: Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
authors: Richard H
authors: RH
authors: Myers
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
authors: Marcy E
authors: ME
authors: MacDonald
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors: James F
authors: JF
authors: Gusella
mesh_terms: D001483:Base Sequence; D019143:Evolution, Molecular; D018703:Founder Effect; D006239:Haplotypes / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins