The Evolution of Genetic Variability at the LRRK2 Locus

Dylan T Guenther; Jordan Follett; Rim Amouri; Samia Ben Sassi; Faycel Hentati; Matthew J Farrer

doi:10.3390/genes15070878

The Evolution of Genetic Variability at the LRRK2 Locus

Genes (Basel). 2024 Jul 3;15(7):878. doi: 10.3390/genes15070878.

Authors

Dylan T Guenther¹, Jordan Follett¹, Rim Amouri², Samia Ben Sassi², Faycel Hentati², Matthew J Farrer¹

Affiliations

¹ Department of Neurology, University of Florida, Gainesville, FL 32610, USA.
² Mongi Ben Hamida National Institute of Neurology, Av. de la Rabta, Tunis 1007, Tunisia.

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.

MeSH terms

Adult
Age of Onset
Aged
Alleles
Evolution, Molecular
Female
Genetic Predisposition to Disease
Genetic Variation
Haplotypes*
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / genetics
Male
Middle Aged
Mutation
Parkinson Disease* / genetics
Selection, Genetic
Tunisia

Substances

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2 protein, human

Grants and funding

This analysis and report was funded by a Canadian Excellence Research Chair to M.J.F. (CIHR/IRSC 275675 [2010–17]) and by the Lee and Lauren Fixel Chair in Parkinson’s research to M.J.F. [2020-2024].