title: Copy number variants in the kallikrein gene cluster.
abstract: The kallikrein gene family (KLK1-KLK15) is the largest contiguous group of protease genes within the human genome and is associated with both risk and outcome of cancer and other diseases. We searched for copy number variants in all KLK genes using quantitative PCR analysis and analysis of inheritance patterns of single nucleotide polymorphisms. Two deletions were identified: one 2235-bp deletion in KLK9 present in 1.2% of alleles, and one 3394-bp deletion in KLK15 present in 4.0% of alleles. Each deletion eliminated one complete exon and created out-of-frame coding that eliminated the catalytic triad of the resulting truncated gene product, which therefore likely is a non-functional protein. Deletion breakpoints identified by DNA sequencing located the KLK9 deletion breakpoint to a long interspersed element (LINE) repeated sequence, while the deletion in KLK15 is located in a single copy sequence. To search for an association between each deletion and risk of prostate cancer (PC), we analyzed a cohort of 667 biopsied men (266 PC cases and 401 men with no evidence of PC at biopsy) using short deletion-specific PCR assays. There was no association between evidence of PC in this cohort and the presence of either gene deletion. Haplotyping revealed a single origin of each deletion, with most recent common ancestor estimates of 3000-8000 and 6000-14 000 years for the deletions in KLK9 and KLK15, respectively. The presence of the deletions on the same haplotypes in 1000 Genomes data of both European and African populations indicate an early origin of both deletions. The old age in combination with homozygous presence of loss-of-function variants suggests that some kallikrein-related peptidases have non-essential functions.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Lindahl
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Säll
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.forename: Anna M
authors.initials: AM
authors.lastname: Johansson
authors.forename: Hans
authors.initials: H
authors.lastname: Lilja
authors.forename: Christer
authors.initials: C
authors.lastname: Halldén
mesh_terms: D001483:Base Sequence; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007610:Kallikreins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D010375:Pedigree; D011471:Prostatic Neoplasms / Q000235:genetics; D017384:Sequence Deletion; D044465:White People / Q000235:genetics
chemical_list: D005819:Genetic Markers; D007610:Kallikreins
references.citation: Nature. 2010 Apr 1;464(7289):713-20
references.pmid: 20360734
references.citation: Nat Genet. 2010 May;42(5):385-91
references.pmid: 20364136
references.citation: Nature. 2010 Apr 1;464(7289):704-12
references.pmid: 19812545
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Nat Genet. 2011 Dec 04;44(1):78-84
references.pmid: 22138692
references.citation: Biol Chem. 2012 Dec;393(12):1365-90
references.pmid: 23667899
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Nat Rev Cancer. 2008 Apr;8(4):268-78
references.pmid: 18337732
references.citation: Endocr Rev. 2010 Aug;31(4):407-46
references.pmid: 20103546
references.citation: Nat Rev Genet. 2011 May;12(5):363-76
references.pmid: 21358748
references.citation: Am J Hum Genet. 2005 Mar;76(3):449-62
references.pmid: 15700229
references.citation: Cancer Prev Res (Phila). 2010 May;3(5):611-9
references.pmid: 20424135
references.citation: Biol Chem. 2006 Jun;387(6):637-41
references.pmid: 16800724
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: Science. 2008 Apr 25;320(5875):539-43
references.pmid: 18369103
references.citation: Genetics. 1973 Sep;75(1):199-212
references.pmid: 4762875
references.citation: Nucleic Acids Res. 1999 Jan 15;27(2):573-80
references.pmid: 9862982
references.citation: Ann Hum Genet. 2010 Mar;74(2):117-25
references.pmid: 20070851
references.citation: BMJ. 2010 Sep 14;341:c4521
references.pmid: 20843935
references.citation: Science. 2012 Feb 17;335(6070):823-8
references.pmid: 22344438
references.citation: J Med Genet. 2004 Jun;41(6):445-9
references.pmid: 15173230
references.citation: Nat Genet. 2008 Sep;40(9):1107-12
references.pmid: 19165925
references.citation: Eur J Hum Genet. 2008 Oct;16(10):1225-34
references.pmid: 18414511
references.citation: Nat Rev Genet. 2013 Feb;14(2):125-38
references.pmid: 23329113
references.citation: Genome Res. 2009 Sep;19(9):1682-90
references.pmid: 19592680