Intracisternal A particle genes: Distribution in the mouse genome, active subtypes, and potential roles as species-specific mediators of susceptibility to cancer.
Rodents, mice and rats in particular, are the species of choice for evaluating chemical carcinogenesis. However, different species and strains often respond very differently, undermining the logic of extrapolation of animal results to humans and complicating risk assessment. Intracisternal A particles (IAPs), endogenous retroviral sequences, are an important class of transposable elements that induce genomic mutations and cell transformation by disrupting gene expression. Several lines of evidence support a role of IAPs as mouse-specific genetic factors in responses to toxicity and expression of disease phenotypes. Since multiple subtypes and copies of IAPs are present in the mouse genome, their activity and locations relative to functional genes are of critical importance. This study identified the major "active" subtypes of IAPs (subtype 1/1a) that are responsible for newly transposed IAP insertions described in the literature, and confirmed that (1) polymorphisms for IAP insertions exist among different mouse strains and (2) promoter activity of the LTRs can be modulated by chemicals. This study further identified all the genes in the C57BL/6 mouse genome with IAP subtype 1 and 1a sequences inserted in their proximity, and the major biofunctional categories and cellular signaling networks of those genes. Since many "IAP-associated genes" play important roles in the regulation of cell proliferation, cell cycle, and cell death, the associated IAPs, upon activation, can affect cellular responses to xenobiotics and disease processes, especially carcinogenesis. This systemic analysis provides a solid foundation for further investigations of the role of IAPs as species- and strain-specific disease susceptibility factors.
Qin
Chunhua
C
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Wang
Zhibin
Z
Shang
Jin
J
Bekkari
Kavitha
K
Liu
Rong
R
Pacchione
Stephen
S
McNulty
Kathleen A
KA
Ng
Alan
A
Barnum
John E
JE
Storer
Richard D
RD
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D053263:Gene Regulatory Networks; D007426:Genes, Intracisternal A-Particle / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D016678:Genome / Q000235:genetics*; D023281:Genomics / Q000379:methods; D051379:Mice / Q000235:genetics*; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009369:Neoplasms / Q000235:genetics*; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity