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. 2017 Feb;25(3):332-340.
doi: 10.1038/ejhg.2016.169. Epub 2016 Dec 21.

The Targetable A1 Huntington Disease Haplotype Has Distinct Amerindian and European Origins in Latin America

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Free PMC article

The Targetable A1 Huntington Disease Haplotype Has Distinct Amerindian and European Origins in Latin America

Chris Kay et al. Eur J Hum Genet. .
Free PMC article

Abstract

Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin (HTT) gene. HD occurs worldwide, but the causative mutation is found on different HTT haplotypes in distinct ethnic groups. In Latin America, HD is thought to have European origins, but indigenous Amerindian ancestry has not been investigated. Here, we report dense HTT haplotypes in 62 mestizo Peruvian HD families, 17 HD families from across Latin America, and 42 controls of defined Peruvian Amerindian ethnicity to determine the origin of HD in populations of admixed Amerindian and European descent. HD in Peru occurs most frequently on the A1 HTT haplotype (73%), as in Europe, but on an unexpected indigenous variant also found in Amerindian controls. This Amerindian A1 HTT haplotype predominates over the European A1 variant among geographically disparate Latin American controls and in HD families from across Latin America, supporting an indigenous origin of the HD mutation in mestizo American populations. We also show that a proportion of HD mutations in Peru occur on a C1 HTT haplotype of putative Amerindian origin (14%). The majority of HD mutations in Latin America may therefore occur on haplotypes of Amerindian ancestry rather than on haplotypes resulting from European admixture. Despite the distinct ethnic ancestry of Amerindian and European A1 HTT, alleles on the parent A1 HTT haplotype allow for development of identical antisense molecules to selectively silence the HD mutation in the greatest proportion of patients in both Latin American and European populations.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
HTT haplotype distributions in the Peruvian population. (a) The HD mutation in Peru occurs predominantly on the A1 haplotype (73%), of which nearly all are the Amerindian A1 variant haplotype. (b) Haplotypes of the HD mutation differ by geographic region of Peru. HD occurs most frequently on the A1 haplotype in Lima (including Cañete), North Coast, and the Northern Interior regions, but is more frequent on A2 in South Coast, and C1 in the Southern Interior. (c) Control HTT haplotypes in Mestizo Peruvians reflect indigenous ancestry with major European admixture and minor African contributions. (d) Control Amerindian HTT haplotypes reflect low genetic diversity in this subpopulation relative to Mestizo controls, and reveal the Amerindian A1 haplotype in the indigenous population of Peru.
Figure 2
Figure 2
Genome-wide admixture analysis of selected Amerindian controls and mestizo HD patients from Peru relative to the 1000 Genomes Project reference samples. (a) Plotting of principal components 3 and 4 from Amerindian Peruvian individuals reveals extreme clustering by ethnicity and partial overlap with reference Peruvians from the 1000 Genomes Project. Amerindian Peruvian controls are most similar to reference Peruvians, reflecting known heterogeneity of indigenous genetic ancestry across Latin America. (b) ADMIXTURE analysis suggests a nearly exclusive indigenous ancestry among Amerindian Peruvian controls, including all Amerindian individuals with the A1 haplotype. Mestizo Peruvian HD probands show similar levels of admixture as reference Peruvians relative to Europeans from Spain and Portugal (K=5, see Supplementary Figure 1).
Figure 3
Figure 3
European and Amerindian A1 HTT haplotype frequencies across all reference populations of the 1000 Genomes Project. Latin American reference populations have the highest frequency of the Amerindian A1 variant haplotype, constituting the majority of all A1 haplotypes among Colombians (CLM), Mexicans (MXL), and Peruvians (PEL). Amerindian A1 also constitutes a third of all A1 haplotypes among Puerto Ricans (PUR). In contrast, Amerindian A1 is rare in European and South Asian populations where the parent A1 haplotype is common: British (GBR), Finnish (FIN), Iberian (IBS), Toscani Italian (TSI), Utah Caucasian (CEU), Bengali (BEB), Gujarati (GIH), Telugu (ITU), Punjabi (PJL), and Sri Lankan Tamil (STU). The parent A1 haplotype is entirely absent in Black African and East Asian populations, except for one instance in a Gambian individual. European and Amerindian A1 are both found among admixed Africans from the United States (ASW) and Barbados (ACB).
Figure 4
Figure 4
The frequency of European and Amerindian A1 HTT haplotypes differs dramatically between HD chromosomes from Caucasian Canadian patients and mestizo Peruvian patients. The A1 HTT haplotype in mestizo Peruvian HD and control chromosomes is almost exclusively the Amerindian A1 variant. In Amerindian Peruvian controls, the A1 HTT haplotype is exclusively the Amerindian A1 variant. In contrast, the Amerindian A1 haplotype variant occurs rarely in Caucasian Canadian HD chromosomes. The A1 HTT haplotype is defined by variant alleles at rs72239206 (GRCh37 chr4:g.3142661_3142664delACTT), rs149109767 (GRCh37 chr4:g.3230411_3230413delGAG), and rs362307 (GRCh37 chr4:g.3241845C>T). The Amerindian A1 variant haplotype is additionally defined by the C allele at rs12508079 (GRCh37 chr4:g.3080238T>C).
Figure 5
Figure 5
HTT haplotype distribution of HD and control chromosomes in Latin American HD families from the UBC HD BioBank. Amerindian A1 is the most frequent HD haplotype in a collection of patients from across Latin America (47%). The parent A1 haplotype, which could be therapeutically targeted for allele-specific HTT silencing in European patient populations, constitutes the majority (59%) of HD chromosomes in Latin American patients. Latin American control haplotypes reflect indigenous Amerindian and European admixture.

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