The Evolution of Genetic Variability at the LRRK2 Locus

Abstract

Leucine-rich repeat kinase 2 (LRRK2) c.6055G>A (p.G2019S) is a frequent cause of Parkinson's disease (PD), accounting for >30% of Tunisian Arab-Berber patients. LRRK2 is widely expressed in the immune system and its kinase activity confers a survival advantage against infection in animal models. Here, we assess haplotype variability in cis and in trans of the LRRK2 c.6055G>A mutation, define the age of the pathogenic allele, explore its relationship to the age of disease onset (AOO), and provide evidence for its positive selection.

Keywords: LRRK2; Parkinson’s disease; evolution.

Figure 1

Three clades defined by the variability in 5 SNPs (rs2638245, rs10878199, rs2638271, rs2708438, and rs1388587) were identified within this sample. (a) An unrooted maximum likelihood phylogenic tree shows three prominent clades in this Tunisian cohort. These three clades are defined by: TTCA[G/C], n = 41, freq = 0.24; CTG[A/G]G, n = 73, freq = 0.43; and TT[C/G]GC, n = 54, freq = 0.32, respectively. (b) The age of initial symptom onset for affected heterozygotes in each of the three trans clades. No significant difference was observed (z = 0.40, p = 0.69).

Figure 2

Absolute value of elevated iHSs > 2.5 across chromosome 12. A cluster of elevated iHSs can be observed within the 39.8–41.0 Mb range, which encompasses LRRK2 p.G2019S haplotypes and is consistent with positive selection within the region. LRRK2 p.G2019S is encoded by GRCh38 NC_000012.12:g.40340400G>A (‘A’ is the mutant allele, as boxed above).