Premium
Deep sequencing of the LRRK2 gene in 14,002 individuals reveals evidence of purifying selection and independent origin of the p.Arg1628Pro mutation in Europe
Author(s) -
Rubio Justin P.,
Topp Simon,
Warren Liling,
St. Jean Pamela L.,
Wegmann Daniel,
Kessner Darren,
Novembre John,
Shen Judong,
Fraser Dana,
Aponte Jennifer,
Nangle Keith,
Cardon Lon R.,
Ehm Margaret G.,
Chissoe Stephanie L.,
Whittaker John C.,
Nelson Matthew R.,
Mooser Vincent E.
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22075
Subject(s) - biology , positive selection , genetics , selection (genetic algorithm) , negative selection , mutation , gene , dna sequencing , computational biology , evolutionary biology , genome , artificial intelligence , computer science
Genetic variation in LRRK2 predisposes to Parkinson disease (PD), which underpins its development as a therapeutic target. Here, we aimed to identify novel genotype–phenotype associations that might support developing LRRK2 therapies for other conditions. We sequenced the 51 exons of LRRK2 in cases comprising 12 common diseases ( n = 9,582), and in 4,420 population controls. We identified 739 single‐nucleotide variants, 62% of which were observed in only one person, including 316 novel exonic variants. We found evidence of purifying selection for the LRRK2 gene and a trend suggesting that this is more pronounced in the central (ROC–COR–kinase) core protein domains of LRRK2 than the flanking domains. Population genetic analyses revealed that LRRK2 is not especially polymorphic or differentiated in comparison to 201 other drug target genes. Among Europeans, we identified 17 carriers (0.13%) of pathogenic LRRK2 mutations that were not significantly enriched within any disease or in those reporting a family history of PD. Analysis of pathogenic mutations within Europe reveals that the p.Arg1628Pro (c4883G>C) mutation arose independently in Europe and Asia. Taken together, these findings demonstrate how targeted deep sequencing can help to reveal fundamental characteristics of clinically important loci. Hum Mutat 33:1087–1098, 2012. © 2012 Wiley Periodicals, Inc.