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Peer-reviewedCC BY-NC-ND 4.0NPJ Genomic Medicine

Evolutionary history of LRRK2 and PRKN in leprosy and Parkinson’s disease

  • Rachele Cagliani1
  • Uberto Pozzoli1
  • Diego Forni1
  • Alessandra Mozzi1
  • Manuela Sironi2,3
  1. 1Computational Biology Unit, Scientific Institute IRCCS E. MEDEA, Bosisio Parini, Italy
  2. 2School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
  3. 3Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{cagliani2026evolutionary,
  title = {{Evolutionary history of LRRK2 and PRKN in leprosy and Parkinson’s disease}},
  author = {Rachele Cagliani and Uberto Pozzoli and Diego Forni and Alessandra Mozzi and Manuela Sironi},
  journal = {NPJ Genomic Medicine},
  year = {2026},
  month = jul,
  doi = {10.1038/s41525-026-00596-7},
  url = {https://doi.org/10.1038/s41525-026-00596-7},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Evolutionary history of LRRK2 and PRKN in leprosy and Parkinson’s disease
AU  - Rachele Cagliani
AU  - Uberto Pozzoli
AU  - Diego Forni
AU  - Alessandra Mozzi
AU  - Manuela Sironi
PY  - 2026
DA  - 2026/07/11
JO  - NPJ Genomic Medicine
DO  - 10.1038/s41525-026-00596-7
UR  - https://doi.org/10.1038/s41525-026-00596-7
AB  - 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.
SN  - 2056-7944
ER  -