Abstract
The most common cause of the monogenic form of Parkinson’s disease known so far is the G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene. Its frequency varies greatly among ethnic groups and geographic regions ranging from less than 0.1% in Asia to 40% in North Africa. This mutation has three distinct haplotypes; haplotype 1 being the oldest and most common. Recent studies have dated haplotype 1 of the G2019S mutation to about 4000 years ago, but it remains controversial whether the mutation has a Near-Eastern or Moroccan-Berber ancestral origin. To decipher this evolutionary history, we genotyped 10 microsatellite markers spanning a region of 11.27 Mb in a total of 57 unrelated Moroccan PD patients carrying the G2019S mutation for which the Berber or Arab origin was established over 3 generations based on spoken language. We estimated the age of the most recent common ancestor for the 36 Arab-speaking and the 15 Berber-speaking G2019S carriers using the likelihood-based method with a mutation rate of 10−4. Data analysis suggests that the shortest haplotype originated in a patient of Berber ethnicity. The common founder was estimated to have lived 159 generations ago (95% CI 116–224) for Arab patients, and 200 generations ago (95% CI 123–348) for Berber patients. Then, 29 native North African males carrying the mutation were assessed for specific uniparental markers by sequencing the Y-chromosome (E-M81, E-M78, and M-267) and mitochondrial DNA (mtDNA) hypervariable regions (HV1 and HV2) to examine paternal and maternal contributions, respectively. Results showed that the autochthonous genetic component reached 76% for mtDNA (Eurasian and north African haplogroups) and 59% for the Y-chromosome (E-M81 and E-M78), suggesting that the G2019S mutation may have arisen in an autochthonous DNA pool. Therefore, we conclude that LRRK2 G2019S mutation most likely originated in a Berber founder who lived at least 5000 years ago (95% CI 3075–8700).
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative disorder after Alzheimer’s disease, affecting about 1–2% of people over 60 years of age [1]
In addition to the fact that 80% (4/5) of patients homozygous for the G2019S mutation were homozygous for the 261bp allele, this particular allele was found in 48% (49/102) of chromosomes in PD patients and in only 8% (13/154) of chromosomes in control individuals; whereas the frequency of the 257bp allele was 18% (18/102) and 20% (31/154) for these groups, respectively (S1 and S2 Tables)
The results suggest that the majority of patients with the G2019S mutation were from Arab-speaking families 63% (36/57) and only 26% (15/57) were from Berber-speaking families for the last three generations
Summary
Parkinson’s disease (PD) is the most common neurodegenerative disorder after Alzheimer’s disease, affecting about 1–2% of people over 60 years of age [1]. Mutations in the LRRK2 gene are the most frequently identified as monogenic causes of PD. They have been found in about 1.8% of healthy controls, 3.6% of sporadic PD cases and 10% of autosomal dominant familial PD cases [1]. 80 variants have been identified in LRRK2 gene so far [5]. Of these variants, 7 mutations are thought to be pathogenic but the most common one remains the G2019S mutation, which accounts for 5–6% of familial and 1–2% of sporadic PD cases [1,6]. The highest frequencies are those recorded in Ashkenazi Jews and North African populations reaching up to approximately20% and 40% of PD patients respectively [7]
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