Objective: To determine the generational age of the most recent common ancestor (MRCA) of patients homozygous for PINK1 p.L347P, to 1) Test the hypothesis that PINK1 EOPD in the Pacific resulted from a founder effect; 2) Provide an origin story for patients.

Background: Mutations in the PINK1 gene cause autosomal recessive early-onset Parkinson’s disease (EOPD)¹, with a global prevalence of 1% to 7% in (largely European) EOPD patients^1,2,3. To date our studies have shown that a pathogenic p.L347P PINK1 variant that is not found in European, African or Chinese populations, is the cause of over 70% of EOPD in Pacific patients in New Zealand. This variant has only been reported in populations across the Pacific^3,4,5,6 – probably due to a founder effect – but to date there is no evidence that it impacts New Zealand Māori.

Method: Twenty samples, homozygous for p.L347P, of Malay, Chamorro, Tokelauan, Samoan, and Tongan ancestries were genotyped on the Infinium Global Diversity chip v1.0.

HapMap markers associated with the p.L347P variant were defined by continuous sharing of homozygosity. Common Haplotype lengths were used to calculate generational age of the MRCA using the Genetic Mutation Age Estimator Tool^7,8.

Results: Assuming a correlated genealogy, the p.L347P mutation arose 106.3 generations ago, (CI=9.6-204.8). Depending on the time span used for generation age (20 or 25 years), this equates to a mutation age of 2120-2650 years before present (YBP; CI=200-5125 years).

Conclusion: Our results confirm the hypothesis that p.L347P arose from a founder ancestor who lived approximately 2120-2650 years ago, whose descendants migrated across the western Pacific and thus provides patients with an origin story for their Parkinson’s disease. It is postulated that migration routes from maritime South East Asia into the Pacific occurred 3000-3500 YBP, with subsequent migration into Eastern Polynesia occurring 730-1200 YBP⁹. The dating suggests that p.L347P arose after the initial Western Polynesian migration. It is possible that the variant didn’t reach deep into Polynesia early enough for it to be carried on the Eastern Pacific migration explaining the low rates in Eastern Polynesian peoples (including NZ Māori). Future work is underway to refine these findings and further explore PINK1 genetics in Pacific populations.

References: 1. Valente EM, Salvi S, Ialongo T, et al.( 2004) PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol;56(3):336-341.
2. Healy DG, Abou-Sleiman PM, Gibson JM, et al. (2004) PINK1 (PARK6) associated Parkinson disease in Ireland. Neurology;63(8):1486-1488.
3. Rogaeva E, Johnson J, Lang AE, et al.( 2004) Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. Arch Neurol;61(12):1898-1904.
4. Patel SG, Buchanan CM, Mulroy E, et al. (2021) Potential PINK1 founder effect in Polynesia causing early-onset Parkinson’s disease. Mov Disord;36(9):2199-2200.
5. Tan AH, Lohmann K, Tay YW, et al. (2020) PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases. Parkinsonism Relat Disord;79:34-39.
6. Steele JC, Guella I, Szu-Tu C, et al. (2015) Defining neurodegeneration on Guam by targeted genomic sequencing. Ann Neurol77(3):458-468.
7. Gandolfo LC, Bahlo M, Speed TP (2014) Dating rare mutations from small samples with dense marker data. Genetics 197, 1315-1327.
8. https://shiny.wehi.edu.au/rafehi.h/mutation-dating/
9. Matisoo-Smith E (2015) Ancient DNA and the human settlement of the Pacific: a review. J Hum Evol 79: 93-104.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lighting-the-torch-dating-the-most-common-recent-ancestor-of-the-pink1-p-l347p-variant-linked-to-parkinsons-disease-in-pacific-populations/