Mapping Modifiers Affecting Muscularity of the Myostatin Mutant (<i>MstnCmpt-dl1Abc</i>) Compact Mouse

Genetics - Tập 165 Số 1 - Trang 257-267 - 2003
L. Varga1, Géza Müller2, Gyula Szabó1, O. Pinke1, Edit Korom1, Balázs Kovács1, László Patthy3, M. Soller4
1Institute for Animal Biology, Agricultural Biotechnology Center, H-2101 Gödöllö, Hungary
2EGIS Pharmaceuticals, H-1475 Budapest, Hungary
3Institute of Enzymology, Hungarian Academy of Sciences, H-1518 Budapest, Hungary
4Department of Genetics, The Alexander Silberman Life Science Institute, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel

Tóm tắt

AbstractThe hypermuscular Compact phenotype was first noted in a line of mice selected for high body weight and protein content. A new line, based on mice showing the Compact phenotype, was formed and selected for maximum expression of the Compact phenotype. Previously we mapped and identified a 12-bp deletion in the myostatin gene, denoted MstnCmpt-dl1Abc, which can be considered as a major gene responsible for the hypermuscular phenotype. Genetic analysis revealed that full expression of the hypermuscular phenotype requires the action of modifier loci in addition to MstnCmpt-dl1Abc. To map these modifier loci, an interspecific F2 population was generated between Comp9, an inbred line homozygous for MstnCmpt-dl1Abc, and CAST/Ei, an inbred line generated from Mus musculus castaneus. Selective DNA pooling and genotyping, separately by gender, was carried out within a subpopulation of the F2 consisting of individuals homozygous for MstnCmpt-dl1Abc. Significant association with hypermuscularity at a false discovery rate (FDR) of 0.05 was found for markers on chromosomes 3, 5, 7, 11, 16, and X. In all cases, the marker allele derived from the Comp9 parent showed a higher frequency in the hypermuscular group and the CAST/Ei allele in the normal group. The modifier loci apparently exerted their effects on muscularity only in the presence of MstnCmpt-dl1Abc.

Từ khóa


Tài liệu tham khảo

Abreu, 2002, Chordin-like CR domains and the regulation of evolutionarily conserved extracellular signaling systems, Gene, 287, 39, 10.1016/S0378-1119(01)00827-7

Akamatsu, 1999, Subtilisin-like proprotein convertase PACE4 (SPC4) is a candidate processing enzyme of bone morphogenetic proteins during tooth formation, Dev. Dyn., 216, 481, 10.1002/(SICI)1097-0177(199912)216:4/5<481::AID-DVDY16>3.0.CO;2-M

Akamatsu, 2000, Highly regulated expression of subtilisin-like proprotein convertase PACE4 (SPC4) during dentinogenesis, Biochem. Bio-phys. Res. Commun., 272, 410, 10.1006/bbrc.2000.2752

Alfred, 1997, Mapping in the region of Danforth’s short tail and the localization of tail length modifiers, Genome Res., 7, 108, 10.1101/gr.7.2.108

Benjamini, 1995, Controlling the false discovery rate: a practical and powerful approach to multiple testing, J. R. Stat. Soc. B, 57, 289, 10.1111/j.2517-6161.1995.tb02031.x

Bunger, 2001, Inbred lines of mice derived from long-term growth selected lines: unique resources for mapping growth genes, Mamm. Genome, 12, 678, 10.1007/s00335001-3018-6

Chipuk, 2002, The androgen receptor represses transforming growth factor-β signaling through interaction with smad3, J. Biol. Chem., 277, 1240, 10.1074/jbc.M108855200

Constam, 1999, Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases, J. Cell Biol., 144, 139, 10.1083/jcb.144.1.139

Constam, 2000, SPC4/PACE4 regulates a TGFbeta signaling network during axis formation, Genes Dev., 14, 1146, 10.1101/gad.14.9.1146

Cryns, 2002, Vestibular dysfunction in the epistatic circler mouse is caused by phenotypic interaction of one recessive gene and three modifier genes, Genome Res., 12, 613, 10.1101/gr.218402

Darvasi, 1994, Selective DNA pooling for determination of linkage between a molecular marker and a quantitative trait locus, Genetics, 138, 1365, 10.1093/genetics/138.4.1365

Greenberg, 1993, Linkage analysis of “necessary” disease loci versus “susceptibility” loci, Am. J. Hum. Genet., 52, 135

Grobet, 1997, A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle, Nat. Genet., 17, 71, 10.1038/ng0997-71

Kambadur, 1997, Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle, Genome Res., 7, 910, 10.1101/gr.7.9.910

Lander, 1995, Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results, Nat. Genet., 11, 241, 10.1038/ng1195-241

Langley, 2002, Myostatin inhibits myoblast differentiation by down-regulating MyoD expression, J. Biol. Chem., 277, 49831, 10.1074/jbc.M204291200

Lebowitz, 1987, Trait based designs for determination of linkage between marker loci and quantitative trait loci, Theor. Appl. Genet., 73, 556, 10.1007/BF00289194

Lee, 2002, Application of false discovery rate to quantitative trait loci interval mapping with multiple traits, Genetics, 161, 905, 10.1093/genetics/161.2.905

Letts, 1995, A curly-tail modifier locus, mct1, on mouse chromosome 17, Genomics, 29, 719, 10.1006/geno.1995.9946

Ma, 2001, Characterization of 5′-regulatory region of human myostatin gene: regulation by dexamethasone in vitro, Am. J. Physiol. Endocrinol. Metab., 281, 1128, 10.1152/ajpendo.2001.281.6.E1128

Matin, 2001, Sensitized polygenic trait analysis, Trends Genet., 17, 727, 10.1016/S0168-9525(01)02528-8

McPherron, 1997, Double muscling in cattle due to mutations in the myostatin gene, Proc. Natl. Acad. Sci. USA, 94, 12457, 10.1073/pnas.94.23.12457

McPherron, 1997, Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member, Nature, 387, 83, 10.1038/387083a0

Mosig, 2001, A whole genome scan for quantitative trait loci affecting milk protein percentage in Israeli-Holstein cattle, by means of selective milk DNA pooling in a daughter design, using an adjusted false discovery rate criterion, Genetics, 157, 1683, 10.1093/genetics/157.4.1683

Nadeau, 2001, Modifier genes in mice and humans, Nat. Rev. Genet., 2, 165, 10.1038/35056009

Neumann, 1994, Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice, Nat. Genet., 6, 357, 10.1038/ng0494-357

Ronin, 2003, High-resolution mapping of quantitative trait loci by selective recombinant genotyping, Genetics, 164, 1657, 10.1093/genetics/164.4.1657

Southey, 1998, Controlling the proportion of false positives among significant results in QTL detection, 221

Spiller, 2002, The myostatin gene is a downstream target gene of basic helix-loop-helix transcription factor MyoD, Mol. Cell. Biol., 22, 7066, 10.1128/MCB.22.20.7066-7082.2002

Szabó, 1998, A deletion in the myostatin gene causes the compact (Cmpt) hypermuscular mutation in mice, Mamm. Genome, 9, 671, 10.1007/s003359900843

Varga, 1997, Inheritance and mapping of compact (Cmpt), a new mutation causing hypermuscularity in mice, Genetics, 147, 755, 10.1093/genetics/147.2.755

Weller, 2000, Using the false discovery rate approach in the genetic dissection of complex traits: a response to Zaykin, Genetics, 154, 1919, 10.1093/genetics/154.4.1919

Weller, 1998, A new approach to the problem of multiple comparisons in the genetic dissection of complex traits, Genetics, 150, 1699, 10.1093/genetics/150.4.1699

Woo, 1997, Genetic identification of two major modifier loci of polycystic kidney disease progression in pcy mice, J. Clin. Invest., 100, 1934, 10.1172/JCI119724

Zaykin, 2000, Using the false discovery rate approach in the genetic dissection of complex traits: a response to Weller, Genetics, 154, 1917, 10.1093/genetics/154.4.1917