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CHAPTER 32 



Qf-specifying cistrons might be found joined 

 to either of the two different products of the 

 j8-specifying cistrons. In this event, the di- 

 hybrid under discussion would prove to have 

 all four of the following types of globin: 

 a?°--/3?, ar'^/3t, af^t a^f^t This has been 

 found to be the case (see References at end 

 of Chapter). 



The results, showing that sickle cell hetero- 

 zygotes make normal 7 chains and defective 

 (3 chains, suggest that three different cistrons 

 are involved — one making a chains, one /3, 

 and one 7. What working relationship might 

 these three cistrons have? Subsequent to 

 birth, the cistron that makes 7 chains normally 

 has its action turned off, so to speak, and that 

 for /3 chains is turned on. In the case of 

 thalassemia major, the 7 cistron is turned off, 

 and the /3 turned on, as in normal people, but 

 the a cistron often fails to be turned on ; when 

 the a cistron is turned on, hemoglobin A is 

 produced, and when it is not, hemoglobin H 

 (/St) is produced. (One might expect the t. 

 major fetus to have 7^ and 0^7^ hemo- 

 globin since the /3 chains are not being pro- 

 duced. One would also expect that an adult 

 with hemoglobin I, alfS^, would also pro- 

 duce abnormal fetal hemoglobin of type 



All results support the view that each differ- 

 ent polypeptide chain is specified by a single 

 but different cistron. However, because of 

 the rarity of heterozygotes, for mutants in 

 different cistrons specifying hemoglobin, and 

 the paucity of linkage data in man, it is 

 difficult to obtain precise data on the relative 

 positions of the different cistrons. For the 

 same reasons, it is difficult to study the allel- 

 ism of hemoglobin mutants affecting the same 

 chain, which presumably involve defects in 

 the same cistron. What kind of study would 

 we like to be able to make in this respect? 



Heterozygotes for two mutants in the same 

 cistron would usually have received one mu- 

 tant from each parent. If the cistron was 

 identical to, or smaller than, the recon, the 



genotype could be written — > the mutants 



would always segregate (barring mutation, 

 including nondisjunction), and all gametes 

 would receive either /Wi or W2 but never both 

 or neither. This kind of result would prove 

 the mutants were reconically allelic (see 

 Chapter 22). If, however, the cistron was 

 larger than a recon, being composed of a 

 number of recons, the mutations involved 

 would sometimes have been in two different 

 recons of a cistron. In this case the heterozy- 

 gote hypothesized would be reconically dihy- 



brid 



nil + 



and crossing over would, on rare 



occasions, give rise to gametes of mi m2 type 

 and of + + type. (To obtain evidence for 

 intracistron recombination one would prefer 

 to test individuals who are heterozygous for 

 both hemoglobins S and E, say, rather than 

 those that are heterozygous for S and G. For 

 the latter might involve adjacent recons be- 

 tween which crossing over might be very rare, 

 and one might fail to obtain the crossover and 

 conclude incorrectly that these mutants were 

 reconic alleles. One would certainly not 

 choose heterozygotes for S and C hemo- 

 globins for this purpose, for it is likely that 

 these are, in fact, reconic alleles.) 



As indicated, the lack of appropriate num- 

 bers of heterozygotes for mutants in the 

 same cistron has thus far prevented us from 

 making this test in man. This question can 

 be investigated in Neurospora, however, 

 which is a more suitable organism than is 

 man for crossover studies. It was already 

 mentioned that a large number of inde- 

 pendently occurring point mutations, defect- 

 ing adenylosuccinase, had been localized to 

 the same region of a chromosome. We would 

 like to know whether this enzyme contains 

 only a single, very long polypeptide (which 

 would be specified by one cistron), several 

 polypeptides (which would be specified by 

 several cistrons in the same general area of 

 the chromosome), or many polypeptides. 



