228 PHYSIOLOGIC GENETICS 



place of original genie action is a retrograde analysis. Transplantation and extirpation 

 may be very useful in determining organ localization of the primary defect. Com- 

 parison of growth of normal and affected tissues or organs in vitro may also prove very 

 useful if culture conditions are sufficiently physiologic to allow deduction as to relation 

 of observed differences to genotype. Linked genes may assist in genotypic identifica- 

 tion, particularly in fetal material. Detailed microscopic analysis, sometimes com- 

 bined with other approaches, helps to distinguish the cells primarily affected. 

 Replacement therapy, isotope incorporation, and tests of functional capacity are 

 useful in determining the nature of intracellular processes affected by particular genie 

 substitutions. Comparison of the effects of different genes in a multiple allelic series 

 and study of dominance relations may provide valuable clues, as may pleiotropic 

 effects of single-gene substitutions. 



Studies of genie action are usually limited to unit genes with clear-cut effects, since 

 their effects may most easily be traced. These unit genes tend to affect one or a very 

 few types of cells, probably because the reactions they control are especially important 

 in these cells. (It should be recognized that our methods of detection favor recognition 

 of unit genes with tissue-limited effects; others may either be cell lethal or so diffuse in 

 their effect as to escape detection. Many gene-controlled reactions must alter slightly 

 the metabolism of many kinds of cells.) The characters observed as a result of genie 

 action may be very close to original genie action, as in determination of hemoglobin 

 pattern, or very far removed, as in choreic behavior as a result of defective induction of 

 the middle ear or ovarian tumorigenesis as a result of deficiency of primordial germ 

 cells. It is seldom possible to predict the number of processes between original genie 

 action and observed characteristic; nor is it always possible to be sure when one has 

 reached the end of the road. 



Although the examples in this dissertation have tended to be restricted to effects 

 of single-gene substitutions, characteristics of inbred strains form an important part of 

 available material. Comparison of mice from different inbred strains has demon- 

 strated existence of many inherited characteristics depending upon the interaction of 

 polygenic factors the individual effects of which cannot now and may never be identi- 

 fied. Since it is probable that the interacting genes work in different ways, it is 

 unlikely that the paths of genie action lying behind a multigenic character can be 

 traced very far. Provided the limitations are understood, however, it is frequently 

 possible to design excellent experiments identifying terminal stages of the pathway. 

 Chai's work with endocrine level and response, Heston's studies with genetics of 

 neoplasia, and Gowen's studies of disease resistance are excellent examples of such 

 analyses. These cases must be studied if physiologic genetics is to be put to use in 

 the service of man. Any study which traces a segment of a pathway between gene or 

 genotype and observed character, however far this segment may be from original 

 genie action, is a contribution to physiologic genetics. 



Although this point has not been stressed in our presentation, it is very clear that 

 for successful analysis of the action of a unit gene it is very desirable to have it segregating 



