416 



CHAPTER 32 



marj effect of gene action. We would also 



like to decide whether one or more genes 

 are involved in hemoglobin A synthe- 

 sis. Several lines of evidence point to 

 an independent specification of a and fi 

 chains: 



1. Mutants that change the f3 chain (pro- 

 ducing hemoglobins S, C\ E, or G ) 

 produce no change in the a chain. 



2. Mutants that change the a chain (pro- 

 ducing hemoglobins 1 or Hopkins-2 ) 

 produce no change in the (3 chain. 



Further evidence consistent with the inde- 

 pendent specification of a and /3 chains 

 comes from the study of individuals pos- 

 sessing both Hopkins-2 and S hemoglobins. 

 Such known individuals have one parent 

 like themselves and the other of normal 

 blood type (hemoglobin A). Also, these 

 individuals have siblings with Hopkins-2 but 

 not S hemoglobin, and others with the re- 

 verse. Consequently, such Hopkins-2 + S 

 persons cannot be monohybrid and must be 

 dihybrid, since the abnormal hemoglobins 

 can occur separately or together in different 

 siblings. Because the number of siblings 

 who must be recombinant is quite large, the 

 two loci are either unlinked or, if linked, 

 cannot be very close together. We can 

 write the genotype of these dihybrids as 



a Uo ~a A /? s /i A . 



The two a and the two (3 chains in a 

 given globin molecule are identical, even in 

 heterozygotes. Since the Hopkins-2 -f S in- 

 dividuals are dihybrid for mutants at widely 

 separated loci, it seems reasonable that the 

 two a chains specified by gene «""- (that 

 is, a"""-) or by gene a A (a£) are produced 

 independently of the two (3 chains specified 

 by gene /i s fjSf) or by gene /i A (p A ). If 

 so, either product of the two different a- 

 specifying genes should be found joined to 

 either of the two different products of the 

 /^-specifying genes. Accordingly, the dihy- 



brid under discussion is expected to have 

 all four of the following types of globin: 

 a n "--^. o' 1 "-'.^. a£j8f, «\i). This is found 

 to be the case. 7 



Hemoglobin A 2 . The Hb-A u tetramer 

 present in normal adults can be dissociated 

 into two dimers and fingerprinted sepa- 

 rately. One dimer is identical with a.}\ the 

 other dimer is called 8;}-. The 8 A - chain 

 is very similar to the /i A chain, only 4 (or 

 possibly 8 ) amino acid differences occur- 

 ring among the 146 residues. Hb-A L . is rep- 

 resented as « A 8 A -. Certain individuals are 

 found s to produce only about half the nor- 

 mal amount of Hb-A L .. In place of the 

 missing component is an equal amount of 

 a new hemoglobin Hb-B 2 . When finger- 

 printed, the chains of Hb-B;. prove to have 

 two a and two 8 chains in the tetramer. 

 Further analysis shows that the a chains are 

 a;} — that is, normal — but a single amino 

 acid is substituted in the 8 chain which 

 probably involves a change of Gly -> Arg 

 at position 16. Hb-Bj can, therefore, be 

 written «. A 8^ 2 . 



It should be noted that a person with 

 Hb-B;. makes normal Hb-A, thus leaving 

 the f3 A chain unaffected. The 8 chain is 

 presumably specified by a gene, 8, which is 

 nonallelic to either the a A or f3 A genes. 

 Moreover, a person that makes both Hb-A;. 

 and Hb-B L . presumably is genetically hybrid 



_ S A 2g B 2 . 



One study involved a man who made 

 some Hb-S (o£j8f) and Hb-B-, (a£&f») 

 and married a normal woman (with Hb-A, 

 Hb-A;.). They had six children; those that 

 made Hb-S did not make Hb-B;.., and vice 

 versa. Since one of the hemoglobin defects 

 in the father's hemoglobin was present in 

 each of his parents, the simplest explana- 

 tion is that the 8 and \3 genes are linked and 

 that no crossover recombinants occurred in 



7 See H. A. Itano and E. A. Robinson (1960). and 

 ( . Baglioni ( 1963). 

 3 Bj K- Ceppellini. 



