Extended haplotype with rs41524547-G defines the ancestral origin of SCA10

Author:

McFarland Karen N123ORCID,Tiwari Anjana4,Hashem Vera4,Zhang Linwei5,Zeng Desmond12,Vincent Justin4,Arredondo Maria J4,Johnson Kristy L6,Gan Shi Rui78,Yabe Ichiro910,Skov Laurits11,Rasmussen Astrid6,Ashizawa Tetsuo124

Affiliation:

1. Department of Neurology , College of Medicine, The McKnight Brain Institute, , 1149 South Newell Drive, Gainesville, FL 32610 , United States

2. University of Florida , College of Medicine, The McKnight Brain Institute, , 1149 South Newell Drive, Gainesville, FL 32610 , United States

3. Center for Translational Research in Neurodegeneration, University of Florida , 1275 Center Drive, Gainesville, FL 32610 , United States

4. Neuroscience Research Program and Department of Neurology, Houston Methodist Hospital and Weill Cornell Medicine , 6560 Fannin Street, Houston, TX 77030 , United States

5. Department of Neurology, China-Japan Friendship Hospital , Yinghua East Street 2, Chaoyang, Beijing 100029 , China

6. Genes and Human Disease Research Program, Oklahoma Medical Research Foundation , 825 N.E. 13th Street, Oklahoma City, Oklahoma 73104 , United States

7. Department of Neurology and Institute of Neurology , First Affiliated Hospital, , 20 Cha Zhong Lu, Tailing District, Fuzhou 362000 , China

8. Fujian Medical University , First Affiliated Hospital, , 20 Cha Zhong Lu, Tailing District, Fuzhou 362000 , China

9. Department of Neurology , Faculty of Medicine and Graduate School of Medicine, , 7 Chome Kita 15 Jonishi, Kita Ward, Sapporo 060-8638 , Japan

10. Hokkaido University , Faculty of Medicine and Graduate School of Medicine, , 7 Chome Kita 15 Jonishi, Kita Ward, Sapporo 060-8638 , Japan

11. Bioinformatics Research Centre, Aarhus University , Universitetsbyen 81, 3., Building 1872, Aarhus C. DK-8000 , Denmark

Abstract

Abstract Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5′-end by the minor allele of rs41524547, located ~35 kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia—a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.

Publisher

Oxford University Press (OUP)

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