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
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
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DOI：
10.1534/genetics.103.020495
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发表时间：
2004-08-01
期刊：
影响因子：
3.3
通讯作者：
Threadgill, DW
中科院分区：
文献类型：
--
作者：
Strunk, KE;Amann, V;Threadgill, DW
小鼠表皮生长因子受体（Egfr(tm1Mag)）的零等位基因的纯合性引起的致死时间在很大程度上依赖于遗传背景。最初试图利用来自瑞士的远交CD-1小鼠绘制背景修饰因子的遗传图谱，但没有成功。为了研究影响Egfr（tm1Mag）纯合子胚胎存活的遗传结构，我们利用129S6/SvEvTAC-Egfr（tm1Mag）与9个瑞士衍生的自交系的杂交，对Egfr（tm1Mag）突变体的生存能力进行了划分，从而对远交系群体中分离的遗传变异性进行了划分。ALR/LtJ、ALS/LtJ、APN、APS、ICR/HaRos、NOD/LtJ、NON/LtJ、SJL/J和SWR/J观察发现，这些菌株支持不同水平的Egfr（tm1Mag）纯合子胚胎存活，提示CD-1群体内部的遗传异质性导致了最初缺乏Egfr（tm1Mag）修饰子检测。与来自瑞士的杂交相似，来自129S6/SvEvTAC、AKR/J、APN、BALB/cJ、BTBR-T+ tf/tf、C3H/HeJ、C57BL/6J、DBA/2J和nrB/NJ自交系背景的9个基因菌株也支持不同水平的Egfr（tm1Mag）突变体的存活。通过基因系杂交制备F-1杂交胚胎，发现不同遗传背景具有互补的修饰子。对基因系的分析表明，远交系背景的杂种优势不利于Egfr（tm1Mag）表型变异。对杂交的详细分析表明，修饰语在三个不同的发展阶段起作用。一类修饰因子支持Egfr（tm1Mag）纯合子胚胎的存活到妊娠中期，另一类修饰因子支持妊娠中期胚胎从卵黄囊向胎盘来源的营养来源的发育，第三类修饰因子支持妊娠后期的存活。利用野生型和Egfr（tm1Mag）突变胎盘的RNA进行的微阵列分析数据支持广泛的遗传异质性的存在，并表明它可以进行分子划分。这种方法应该是普遍有用的划分异质性贡献其他复杂性状。
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.