IX. GENETICS AND HUMAN HEMOGLOBIN CHEMISTRY 463 



F gene and a j8 thalassemic gene have been reported (Kraus et al., 1961). 

 The high F gene seems to interact with the Z^"^'' gene; 70% Hb-F and 

 30% Hb-A are present in these individuals. Similar levels of Hb-F are 

 nonnally found in thalassemia major; but the high F/thalassemia 

 condition is of intermediate severity and quite different from thalas- 

 semia major as a pathological entity (Kraus et al., 1961). 



Individuals with the high F sickle-cell condition have levels of Hb-F 

 comparable to some of the sickle-cell anemic patients (Bradley et al., 

 1961 ) ; the ratio Hb-S/Hb-F is, however, quite variable in sickle-cell 

 anemia. Sickle-cell anemia is a severe disease, while the high F/sickle- 

 cell condition is almost asymptomatic (Edington and Lehmann, 1955; 

 Jacob and Raper, 1958; Went and Maclver, 1958). Thompson et al. 

 (1961) and Bradley et al. (1961) have reported that Hb-F is evenly 

 distributed in the red cells of high F and of high F/sickle-cell individuals, 

 in contrast with the uneven distribution of Hb-F in thalassemia major 

 and sickle-cell anemia. This obser^'ation provides a clue to explain the 

 absence of pathological manifestations in the high F/sickle cell condition, 

 as compared to sickle-cell anemia. In sickle-cell anemia the cells with 

 high Hb-S content sickle and lyse at normal physiological oxygen 

 tension, while in the high F/sickle-cell condition the unifomi distribu- 

 tion of Hb-F among the red cells prevents sickling at the same oxygen 

 tension. Hb-F does not participate in the sickling process, since it does 

 not form mixed aggregates with Hb-S (Allison, 1957). 



The uniform distribution of Hb-F in red cells of high F individuals is 

 of more profound significance, since it shows that the synthesis of high 

 amounts of Hb-F is common to all the cells and is not characteristic of 

 particular cellular clones, as it seems to be the case in severe anemias. 

 The synthesis of Hb-F in the high F condition is the primary manifesta- 

 tion of the "high F" gene and does not seem to result indirectly from 

 severe anemia (Thompson et al., 1961). 



Wheeler and Krevans (1961) have reported a child apparently 

 homozygous for the high F gene; the child is in healthy condition and 

 does not possess any detectable Hb-A or Hb-As. The absence of Hb-Aa 

 in this child constitutes the only evidence that the high F gene suppresses 

 the synthesis of ^ and 8 chains at the same time. The Hb-F of this child 

 appears to be identical by fingerprinting to authentic Hb-F from cord 

 blood (C. Baglioni, unpublished). 



The hereditary persistence of Hb-F seems to be a genetic entity com- 

 pletely different from the hereditary anemias in which high levels of 

 Hb-F have been reported. It has been suggested that the high F muta- 

 tion may involve a regulator or operator gene, rather than a structural 

 gene (P. S. Gerald, unpublished; Ceppellini, 1961; Motulsky, 1962; Neel, 



