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

• Published in: Human Molecular Genetics
• Main Authors: McFarland, Karen N, Tiwari, Anjana, Hashem, Vera, Zhang, Linwei, Zeng, Desmond, Vincent, Justin, Arredondo, Maria J, Johnson, Kristy L, Gan, Shi Rui, Yabe, Ichiro, Skov, Laurits, Rasmussen, Astrid, Ashizawa, Tetsuo
• Format: Article in Journal/Newspaper
• Language: English
• Published: Oxford University Press (OUP) 2024
• Subjects: Bering Land Bridge
• Online Access: http://dx.doi.org/10.1093/hmg/ddae092; https://academic.oup.com/hmg/advance-article-pdf/doi/10.1093/hmg/ddae092/58082590/ddae092.pdf

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.