Mansour S L, Goddard J M, Capecchi M R
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City 84112.
Development. 1993 Jan;117(1):13-28. doi: 10.1242/dev.117.1.13.
We derived mice that carry a targeted insertion of a neor gene in the int-2 (Fgf-3) proto-oncogene coding sequences. The mutation was found to be recessive and mice that were homozygous for the insertion did not often survive to adulthood. The mutant mice had defects in the development of the tail and inner ear that could be correlated with disruption of int-2 expression in the posterior primitive streak and hindbrain or otic vesicle. While the tail phenotype was 100% penetrant, we found that the inner ear phenotype had reduced penetrance and variable expressivity. The variable expressivity could not be attributed to variability in the genetic background of the mutant allele or to leaky expression from the mutant allele. Thus, we conclude that even in a uniform genetic background, stochastic variation in the expression of a developmental circuit can result in dramatic differences in phenotypic consequences.
我们培育出了在int-2（Fgf-3）原癌基因编码序列中携带neoⁿ基因靶向插入的小鼠。发现该突变是隐性的，插入纯合的小鼠通常无法存活至成年。突变小鼠的尾巴和内耳发育存在缺陷，这可能与后原条、后脑或耳泡中int-2表达的破坏有关。虽然尾巴表型的外显率为100%，但我们发现内耳表型的外显率降低且表达具有变异性。这种表达变异性不能归因于突变等位基因遗传背景的变异性或突变等位基因的渗漏表达。因此，我们得出结论，即使在统一的遗传背景下，发育回路表达的随机变化也可能导致表型结果的显著差异。
