Evolutionary history of LRRK2 and PRKN in leprosy and Parkinson's disease.

LRRK2 (leucine-rich repeat kinase 2) and Parkin (PRKN) act in shared pathways and are implicated in Parkinson's disease (PD), leprosy, and other diseases. While leprosy likely imposed strong evolutionary pressure, PD's relatively late onset renders it largely invisible to natural selection. We examined the evolutionary history of LRRK2 and PRKN in primates and human populations and found evidence of positive selection on both genes, alongside strong constraint at LRRK2 disease-associated sites. Gibbons were found to carry a pathogenic PRKN mutation (R33Q) causing protein instability. Using ancient DNA, we traced the dynamics of LRRK2 and PRKN variants in Europe and showed that the common PD risk allele LRRK2 G2019S-also protective against salmonellosis-was absent in Paleolithic populations but rose rapidly during the Early Neolithic, likely driven by selection from emerging human-adapted Salmonella. Four leprosy susceptibility variants in PRKN and other loci increased in frequency before the Middle Ages, with little evidence of strong selection during the medieval epidemic itself. Together, these results link a major PD mutation to ancient infectious pressures and suggest that pathogen-driven selection shaped leprosy susceptibility in Europe prior to its medieval peak.