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. 1996 Dec;144(4):1777–1785. doi: 10.1093/genetics/144.4.1777

Genetic Evaluation of Candidate Genes for the Mom1 Modifier of Intestinal Neoplasia in Mice

K A Gould 1, C Luongo 1, A R Moser 1, M K McNeley 1, N Borenstein 1, A Shedlovsky 1, W F Dove 1, K Hong 1, W F Dietrich 1, E S Lander 1
PMCID: PMC1207727  PMID: 8978063

Abstract

As genetic mapping of quantitative trait loci (QTL) becomes routine, the challenge is to identify the underlying genes. This paper develops rigorous genetic tests for evaluation of candidate genes for a QTL, involving determination of allelic status in inbred strains and fine-structure genetic mapping. For the Mom1 modifier of intestinal adenomas caused by Apc(Min), these tests are used to evaluate two candidate genes: Pla2g2a, a secretory phospholipase, and Rap1GAP, a GTPase activating protein. Rap1GAP passes the first test but is excluded by a single fine-structure recombinant. Pla2g2a passes both tests and is a strong candidate for Mom1. Significantly, we also find that Apc(Min)-induced adenomas remain heterozygous for the Mom1 region, consistent with Mom1 acting outside the tumor lineage and encoding a secreted product.

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Selected References

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  1. Dietrich W., Katz H., Lincoln S. E., Shin H. S., Friedman J., Dracopoli N. C., Lander E. S. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics. 1992 Jun;131(2):423–447. doi: 10.1093/genetics/131.2.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Frankel W. N. Taking stock of complex trait genetics in mice. Trends Genet. 1995 Dec;11(12):471–477. doi: 10.1016/s0168-9525(00)89155-6. [DOI] [PubMed] [Google Scholar]
  3. Gould K. A., Dietrich W. F., Borenstein N., Lander E. S., Dove W. F. Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics. 1996 Dec;144(4):1769–1776. doi: 10.1093/genetics/144.4.1769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Groden J., Thliveris A., Samowitz W., Carlson M., Gelbert L., Albertsen H., Joslyn G., Stevens J., Spirio L., Robertson M. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991 Aug 9;66(3):589–600. doi: 10.1016/0092-8674(81)90021-0. [DOI] [PubMed] [Google Scholar]
  5. Harwig S. S., Tan L., Qu X. D., Cho Y., Eisenhauer P. B., Lehrer R. I. Bactericidal properties of murine intestinal phospholipase A2. J Clin Invest. 1995 Feb;95(2):603–610. doi: 10.1172/JCI117704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hussussian C. J., Struewing J. P., Goldstein A. M., Higgins P. A., Ally D. S., Sheahan M. D., Clark W. H., Jr, Tucker M. A., Dracopoli N. C. Germline p16 mutations in familial melanoma. Nat Genet. 1994 Sep;8(1):15–21. doi: 10.1038/ng0994-15. [DOI] [PubMed] [Google Scholar]
  7. Kim S. H., Roth K. A., Moser A. R., Gordon J. I. Transgenic mouse models that explore the multistep hypothesis of intestinal neoplasia. J Cell Biol. 1993 Nov;123(4):877–893. doi: 10.1083/jcb.123.4.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kinzler K. W., Nilbert M. C., Su L. K., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hedge P., McKechnie D. Identification of FAP locus genes from chromosome 5q21. Science. 1991 Aug 9;253(5020):661–665. doi: 10.1126/science.1651562. [DOI] [PubMed] [Google Scholar]
  9. Kobayashi T., Hirayama Y., Kobayashi E., Kubo Y., Hino O. A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat Genet. 1995 Jan;9(1):70–74. doi: 10.1038/ng0195-70. [DOI] [PubMed] [Google Scholar]
  10. Laird P. W., Jackson-Grusby L., Fazeli A., Dickinson S. L., Jung W. E., Li E., Weinberg R. A., Jaenisch R. Suppression of intestinal neoplasia by DNA hypomethylation. Cell. 1995 Apr 21;81(2):197–205. doi: 10.1016/0092-8674(95)90329-1. [DOI] [PubMed] [Google Scholar]
  11. Leister I., Weith A., Brüderlein S., Cziepluch C., Kangwanpong D., Schlag P., Schwab M. Human colorectal cancer: high frequency of deletions at chromosome 1p35. Cancer Res. 1990 Nov 15;50(22):7232–7235. [PubMed] [Google Scholar]
  12. MacPhee M., Chepenik K. P., Liddell R. A., Nelson K. K., Siracusa L. D., Buchberg A. M. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell. 1995 Jun 16;81(6):957–966. doi: 10.1016/0092-8674(95)90015-2. [DOI] [PubMed] [Google Scholar]
  13. Moser A. R., Dove W. F., Roth K. A., Gordon J. I. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol. 1992 Mar;116(6):1517–1526. doi: 10.1083/jcb.116.6.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Moser A. R., Pitot H. C., Dove W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990 Jan 19;247(4940):322–324. doi: 10.1126/science.2296722. [DOI] [PubMed] [Google Scholar]
  15. Mulherkar R., Desai S. J., Rao R. S., Wagle A. S., Deo M. G. Expression of enhancing factor gene and its localization in mouse tissues. Histochemistry. 1991;96(4):367–370. doi: 10.1007/BF00271358. [DOI] [PubMed] [Google Scholar]
  16. Tischfield J. A., Xia Y. R., Shih D. M., Klisak I., Chen J., Engle S. J., Siakotos A. N., Winstead M. V., Seilhamer J. J., Allamand V. Low-molecular-weight, calcium-dependent phospholipase A2 genes are linked and map to homologous chromosome regions in mouse and human. Genomics. 1996 Mar 15;32(3):328–333. doi: 10.1006/geno.1996.0126. [DOI] [PubMed] [Google Scholar]
  17. Wienecke R., König A., DeClue J. E. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J Biol Chem. 1995 Jul 7;270(27):16409–16414. doi: 10.1074/jbc.270.27.16409. [DOI] [PubMed] [Google Scholar]

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