GENIC ACTION IN THE MOUSE 221 



mately 18 crossover units from the WMocus, provided another check upon fetal genotype. 

 Homozygous luxate (Ixlx) fetuses were identifiable as early as the twelfth day of develop- 

 ment by the shape of their abnormal hind feet. 168 This gene was placed in test 

 matings in coupling with W v , so that more than 96 per cent of all fetuses with abnormal 

 hind feet {Ixlx) would also be expected to be severely anemic and potentially sterile 

 (W V W V ). Thus, a closely linked gene with early clear-cut expression proved to be a 

 very useful tool in retrograde analysis. An interesting long-term consequence of the 

 paucity of germ cells in W V W V mice is that all of the females eventually develop 

 ovarian tumors. 1101 The lack of pigmentation in WW and W V W V mice is essentially 

 100 per cent white spotting, involving absence of melanoblasts in the hair follicle. 1207 

 Melanoblasts, which normally migrate from the neural crest to all parts of the body 

 between the eighth and twelfth days of embryonic life, differentiate from explants of 

 the flank area of normal vow 10-day embryos, but do not appear in explants from the 

 same area of WW littermates. 100 The pigment defect of homozygous defective Mi- 

 series mice is thus completely determined very early in embryonic life. 



Homozygous SISl embryos and neonates 74 and adult Sl d Sl d individuals 83 show a 

 triad of pleiotropic effects in bloodforming tissue, germ cells, and hair pigmentation 

 almost identical with that found in IT-series homozygotes. At least 7 separate in- 

 stances of mutation at the H^-locus are known to have occurred spontaneously, in 

 addition to frequent Miseries mutations in radiation experiments. Four separate 

 instances of SI- locus mutations are known. In each case, all three aspects of the triad 

 were simultaneously altered. It is almost impossible to avoid the conclusion that each 

 of the genes at both of these loci acts as a unit, controlling a single process. The 

 process controlled by the W locus and that controlled by the SI locus may be closely 

 related, possibly as different steps in the same synthetic pathway. 



In which of the three severely affected tissues is this series of processes initiated ? 

 It is known to be important in fetal liver and adult marrow hematopoiesis, but no 

 information is available as to possible yolk-sac hematopoietic defect before the twelfth 

 day of embryonic life. Circulation begins at approximately 9.5 days. 1247 The 

 reduced multiplication of germ cells in WW and W V W V embryos is apparent at 9 days 

 and very marked at 10 days, the melanoblast defect at 10 days. The very early 

 appearance of these anomalies makes it relatively improbable that they are dependent 

 for expression upon an anemia resulting from defective yolk-sac hematopoiesis. It 

 seems very much more probable that the W-Sl series of processes is independently of 

 great metabolic significance in primordial germ cells, in melanoblasts or their em- 

 bryonic precursors, and in hematopoietic cells. Unity of genie action for these genetic 

 loci may involve processes specifically important in the metabolism of three different 

 tissues. 



MATERIALS AND METHODS IN MAMMALIAN PHYSIOLOGIC GENETICS 



Review of the examples of genie action in the mouse discussed in this paper may 

 lead to certain generalizations on methodology. The first tool in search for time and 



