224 PHYSIOLOGIC GENETICS 



discussed in the general section on genes and tissue function, it is important to deter- 

 mine the site of initial genie action in each case. It appears probable that most of the 

 defects are indigenous to bloodforming tissue, but this can only be established by 

 transplants between genotypes affected differently. For these reasons, the development 

 of congenic histocompatible strains differing essentially only in the anemia-producing 

 genes is an important part of our work. 1105 



Since animals of several important genotypes are available only in fetal and new- 

 born stages, it is also very important to develop methods for working with extremely 

 small quantities of tissues and for studying metabolism of fetal hematopoiesis. Forma- 

 tion of hemoglobin is, of course, an essential part of all ery thropoiesis ; and, since many 

 human hereditary anemias have been traced to specific hemoglobinopathies, 619 ' 938 it 

 seems essential to study the nature of hemoglobin associated with different anemic 

 states. Studies of the reactions of normal and affected animals to particular physio- 

 logic stimuli or stresses may be very helpful in identifying metabolic deviations. Several 

 of the genes under study have extensive pleiotropic effects in other tissues. Analyses 

 of these effects will undoubtedly increase knowledge of pathways of genie action, but 

 may also yield clues as to the nature of original genie action in hematopoietic tissue. 

 Attempts are being made to develop each of these approaches in the study of murine 

 anemias, but, except for experiments with the W series, they are still in the stage of 

 potentiality rather than performance. 



CHARACTERIZATION OF ff-SERIES ANEMIAS 



The hematologic phenotype of animals differing in M^-series genes ranges from 

 an ostensibly normal picture in ww, Ww, and W j w animals, 1091, 1102, 1106 to slight 

 macrocytic anemia in W v w, 1091 and severe macrocytic anemia in animals of all double- 

 dominant genotypes. Order of increase in severity of afflication is ww (normal) = 

 Ww = W j w < W v w < W V W V < WW V = W'W V < WW = WW 1 = W j W j . 

 (Animals of the last three genotypes are almost invariably lethal in early postnatal life.) 

 The bone marrow of adult W V W V and WW V individuals has almost exactly the same 

 cellularity as that of their normal littermates, 970 although it produces only slightly 

 more than one-half the normal number of erythrocytes, suggesting a delay in matura- 

 tion of erythroid cells. Careful microscopic study of the marrow confirmed this 

 suggestion, since the ratio of early to late stages in erythropoiesis was significantly 

 higher in the anemic animals. 1110 The first evidence suggesting a biochemical basis 

 for this arrest came from C 14 -glycine-incorporation experiments using anemic and 

 normal littermates. 16, 1097 There was no difference between genotypes in time of 

 appearance of erythrocytes with labelled globin, but in the anemic mice there was a 

 great delay in appearance of cells with labelled protoporphyrin. Subsequent experi- 

 ments showed a similar delay in appearance of labelled protoporphyrin in erythrocytes 

 ofanemics following injection of radioactive (5-amino-levulinic acid, 15 an intermediate 

 on the path leading to protoporphyrin. This delay in heme synthesis, which is still 



