Phenotypic variation resulting from a deficiency of epidermal growth factor receptor in mice is caused by extensive genetic heterogeneity that can be genetically and moleculaidy partitioned

The timing of lethality caused by homozygosity for a null allele of the epidermal growth factor receptor (Egfr(tm1Mag)) 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 Egfr(tm1Mag) homozygous embryos, the genetic variability segregating within the outbred population was partitioned by surveying viability of Egfr(tm1Mag) mutants using intercrosses between 129S6/SvEvTAC-Egfr(tm1Mag) 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 Egfr(tm1Mag) homozygous embryos, suggesting that genetic heterogeneity within the CD-1 stock contributed to the original lack of Egfr(tm1Mag) 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 nrB/NJ inbred backgrounds, also supported varying levels of survival of Egfr(tm1Mag) mutants. By intercrossing the congenic lines to create hybrid F-1 embryos, different genetic backgrounds were found to have complementary modifiers. Analysis of the congenic lines argues against heterosis of outbred backgrounds contributing to Egfr(tm1Mag) 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 Egfr(tm1Mag) 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 wildtype and Egfr(tm1Mag) 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.