Dynamic structure of the SPANX gene cluster mapped to the prostate cancer susceptibility locus HPCX at Xq27.
Genetic linkage studies indicate that germline variations in a gene or genes on chromosome Xq27-28 are implicated in prostate carcinogenesis. The linkage peak of prostate cancer overlies a region of approximately 750 kb containing five SPANX genes (SPANX-A1, -A2, -B, -C, and -D) encoding sperm proteins associated with the nucleus; their expression was also detected in a variety of cancers. SPANX genes are >95% identical and reside within large segmental duplications (SDs) with a high level of similarity, which confounds mutational analysis of this gene family by routine PCR methods. In this work, we applied transformation-associated recombination cloning (TAR) in yeast to characterize individual SPANX genes from prostate cancer patients showing linkage to Xq27-28 and unaffected controls. Analysis of genomic TAR clones revealed a dynamic nature of the replicated region of linkage. Both frequent gene deletion/duplication and homology-based sequence transfer events were identified within the region and were presumably caused by recombinational interactions between SDs harboring the SPANX genes. These interactions contribute to diversity of the SPANX coding regions in humans. We speculate that the predisposition to prostate cancer in X-linked families is an example of a genomic disease caused by a specific architecture of the SPANX gene cluster.
Kouprina
Natalay
N
Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, Maryland 20892, USA.
Pavlicek
Adam
A
Noskov
Vladimir N
VN
Solomon
Greg
G
Otstot
John
J
Isaacs
William
W
Carpten
John D
JD
Trent
Jeffrey M
JM
Schleutker
Joanna
J
Barrett
J Carl
JC
Jurka
Jerzy
J
Larionov
Vladimir
V
D001483:Base Sequence; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D003001:Cloning, Molecular; D040461:Gene Components; D020440:Gene Duplication; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D015003:Yeasts
D009687:Nuclear Proteins; C414403:SPANXA1 protein, human; C521014:SPANXA2 protein, human; C521016:SPANXD protein, human