- THIS ARTICLE
- Full Text
- Full Text (PDF)
- Alert me when this article is cited
- Alert me if a correction is posted
- SERVICES
- Email this article to a friend
- Similar articles in this journal
- Similar articles in PubMed
- Alert me to new issues of the journal
- Download to citation manager
- Reprints & Permissions
- CITING ARTICLES
- Citing Articles via HighWire
- Citing Articles via Google Scholar
- GOOGLE SCHOLAR
- Articles by Strunk, K. E.
- Articles by Threadgill, D. W.
- Search for Related Content
- PUBMED
- PubMed Citation
- Articles by Strunk, K. E.
- Articles by Threadgill, D. W.
Genetics, Vol. 167, 1821-1832, August 2004, Copyright © 2004
doi:10.1534/genetics.103.020495
Phenotypic Variation Resulting From a Deficiency of Epidermal Growth Factor Receptor in Mice Is Caused by Extensive Genetic Heterogeneity That Can Be Genetically and Molecularly Partitioned
Karen E. Strunk*,
,1,
Vicky Amann* and
David W. Threadgill*,,2
* Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37221
Department of Genetics and the Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599
2 Corresponding author: Department of Genetics, CB#7264, MBRB Room 4340, University of North Carolina, Chapel Hill, NC 27599.
E-mail: dwt{at}med.unc.edu
The timing of lethality caused by homozygosity for a null allele of the epidermal growth factor receptor (Egfrtm1Mag) in mice is strongly dependent on genetic background. Initial attempts to genetically map background modifiers using Swiss-derived, outbred CD-1 mice were unsuccessful. To investigate the genetic architecture contributing to survival of Egfrtm1Mag homozygous embryos, the genetic variability segregating within the outbred population was partitioned by surveying viability of Egfrtm1Mag mutants using intercrosses between 129S6/SvEvTAC-Egfrtm1Mag and nine Swiss-derived, inbred strains: ALR/LtJ, ALS/LtJ, APN, APS, ICR/HaRos, NOD/LtJ, NON/LtJ, SJL/J, and SWR/J. The observations showed that these strains support varying levels of survival of Egfrtm1Mag homozygous embryos, suggesting that genetic heterogeneity within the CD-1 stock contributed to the original lack of Egfrtm1Mag modifier detection. Similar to the Swiss-derived intercrosses, nine congenic strains, derived from 129S6/SvEvTAC, AKR/J, APN, BALB/cJ, BTBR-T+ tf/tf, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ inbred backgrounds, also supported varying levels of survival of Egfrtm1Mag mutants. By intercrossing the congenic lines to create hybrid F1 embryos, different genetic backgrounds were found to have complementary modifiers. Analysis of the congenic lines argues against heterosis of outbred backgrounds contributing to Egfrtm1Mag phenotypic variability. A detailed analysis of the crosses suggests that modifiers function at three distinct stages of development. One class of modifiers supports survival of Egfrtm1Mag homozygous embryos to mid-gestation, another class supports development through the mid-gestation transition from yolk-sac to placental-derived nutrient sources, and a third class supports survival through later stages of gestation. Data from microarray analysis using RNA from wild-type and Egfrtm1Mag mutant placentas support the existence of extensive genetic heterogeneity and suggest that it can be molecularly partitioned. This method should be generally useful to partition heterogeneity contributing to other complex traits.
This article has been cited by other articles:
 |
|
 |
|
  C. J. Barrick, R. B. Roberts, M. Rojas, N. M. Rajamannan, C. B. Suitt, K. D. O'Brien, S. S. Smyth, and D. W. Threadgill Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H65 - H75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Gelling, W. Yan, S. Al-Noori, A. Pardini, G. J. Morton, K. Ogimoto, M. W. Schwartz, and P. J. Dempsey Deficiency of TNF{alpha} Converting Enzyme (TACE/ADAM17) Causes a Lean, Hypermetabolic Phenotype in Mice Endocrinology, December 1, 2008; 149(12): 6053 - 6064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Takahashi, K. Shimomura, and V. Kumar Searching for Genes Underlying Behavior: Lessons from Circadian Rhythms Science, November 7, 2008; 322(5903): 909 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Li, K. Boyd, P. J. Dempsey, and D. A. A. Vignali Non-Cell Autonomous Expression of TNF-{alpha}-Converting Enzyme ADAM17 Is Required for Normal Lymphocyte Development J. Immunol., April 1, 2007; 178(7): 4214 - 4221. [Abstract] [Full Text] [PDF]
|
|