24-4 PHYSIOLOGIC GENETICS 



embryo will have a particular malformation, but whether or not a given embryo 

 actually has the defect depends on intra-uterine variables that so far remain an almost 

 complete mystery. It has been suggested that one of the variables might be segregation 

 of genetic modifiers that may persist in spite of the intense inbreeding that occurs in 

 the development and maintenance of inbred lines. However, the microphthalmia 

 that occurs in the G57BL/6/Fr subline of mice is just as frequent in the offspring of un- 

 affected mothers as it is in the offspring of their microphthalmic sisters, which argues 

 strongly against genetic segregation in this case (Fraser, unpublished data) . 



Trasler 1328 has reported that the spontaneous cleft lip that occurs in the A/Jax 

 strain is more likely to appear in the embryo adjacent to the ovary than in embryos at 

 other uterine sites. This directs attention to the nature of the relevant factors that 

 make the juxta-ovarian site different from other sites, but so far no such factors have 

 been identified. It would seem that the genetic constitution of an A/Jax embryo 

 (and mother, or both) makes its lip-closing mechanism susceptible to disturbance by 

 rather subtle variations in the uterine environment. What are the variations and 

 what is there about an A/Jax labial primordium that makes it so sensitive to environ- 

 mental disturbance? Answers to these questions will eventually require coming to 

 grips with the problem of intralitter variability in biochemical terms. Perhaps some 

 light could be thrown on the subject by observing the effects of agents with known 

 pharmacologic properties, particularly antimetabolites, on the frequencies of defects 

 occurring spontaneously in inbred lines. This approach has been well demonstrated 

 by Landauer 748 in chickens. 



7. Interaction of genes and teratogens. — It should be obvious from the foregoing 

 discussion that the genetic constitutions of the embryo and its mother are influential in 

 determining the response of the embryo to a teratogen. This fact, which will be no 

 surprise to geneticists, is significant for a number of reasons. For one thing, it may 

 account for the differences in nature and frequency of defects reported by different 

 workers using the same teratogen but different strains or substrains of animals. It also 

 emphasizes the fact that even when an environmental teratogen is clearly implicated 

 as a cause of congenital malformations, the genetic constitution may determine whether 

 an embryo exposed to the teratogen will be malformed. This, for instance, is a possible 

 explanation for the fact that some offspring of mothers having rubella in the early 

 weeks of pregnancy do not have the characteristic malformations shown by others. 



As previously mentioned, the study of inbred strains that differ widely in the 

 frequency of a malformation produced by a teratogen, and of crosses between them, 

 can be useful in clarifying the intricate interaction of factors that determine whether or 

 not a given embryo is malformed. Our studies of cortisone-induced cleft palate in the 

 A/Jax and C57BL strains, F x hybrids and backcrosses to the A/Jax strain demonstrated 

 the importance of both fetal and maternal genotype in determining the embryonic 

 response to the teratogen. Studies of the embryology of cortisone-induced cleft palate 

 in strains with both a high and a low frequency of induced clefts demonstrated, far 

 better than a study of either strain separately would have done, that delay in movement 



