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272 PARIS IV. GENETIC ASPECTS < DISCUSSION Dr.. Salome G. f aelsch: It was a great pleasure for me to hear Dr. Neel's presentation of the genetics of abnormal hemoglobins, and I listened to it while still under the impact of the most impressive demonstration by Dr. Ingram on the nature of the gene effect in the case of sickling. Dr. Ingram seems to feel that the hemoglobins are rather direct and primary products of the gene. This reminded me of the time when the biochemical genetics of ne2~rostora was still young and when enzymes were considered primary gene products, a concept which since then has been modified exten- sively. I wonder whether perhaps some caution is not also indicated if one regards hemoglobins as primary gene products. Some of Dr. Neelts data which he presented here today I, at least, feel cannot be reconciled with the idea that hemoglobins are really primary gene products. For example, he reported the very interesting fact, of which I was not aware before, that individuals heterozygous for the sickling gene and for the hemoglobin G gene, do not show the presence of any normal hemoglobin. If hemoglobins are primary gene products, then one would expect normal hemoglobin which is produced by the normal gene in the case of the sickle heterozygote, to be found somewhere in these double heterozygotes, and the same should be true for the hemoglobin G. particularly if the difference be- tween normal and abnormal hemoglobin is only due to the substitution of one amino acid in one of the hemoglobin peptides. In this connection, I might perhaps just call attention to some work that Dr. Ranney and I have been doing on genetically-determined different hemo- globins in the mouse, which, I must admit after having listened to Dr. Neel, is not nearly as good an experimental subject as man. Nevertheless, some of our data seem to indicate at least that there is interaction of primary gene products, if you want to use that term, on a rather early level, and that hemo- globins may perhaps turn out not to be primary gene products after all. I shall be very much interested to hear what Dr. Neel has to say about this. Dr. Neel: I can only endorse wholeheartedly what Dr. Waelsch has just said. As a matter of fact, I think I was fairly careful not to identify hemo- globins with primary gene products. But if ever there was an opportunity to get pretty close to primary gene products, I think we have it in this system. I am as impressed as you are by the apparent failure of hemoglobin A to be formed in the double heterozygote for the genes responsible for hemoglobins S and G. It is that fact which has dissuaded me for the time being from attempting to formulate any biosynthetic sequences. However, when you say that the findings are not consistent with hemoglobins being primary gene products, I am not sure that we know enough about what is consistent with primary gene products to say that this is inconsistent. Dr. Harvey Ita~zo: I echo Dr. Waelsch's concern about this absence of A.

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DISCUSSION 273 However, I would like to point out certain pertinent facts in these cases, namely, there is a pair of siblings, both of whom are supposed to have SG. However, they have different electrophoretic patterns. One of them has three components by moving boundary electrophoresis, and the other has two. More- over, the latter only shows an S spot on paper. Be that as it may, I am still inclined to the view that the amino acid sequence in a hemoglobin molecule reflects exactly the information carried in the genes. If two loci that segregate independently determine sequences in different parts of the molecule, the normal molecule would be an association product which contains both sequences. A doubly heterozygous red ceil would syn- thesize four polypeptides, including a normal and an abnormal polypeptide, corresponding to each of the two loci. These would be potentially capable of associating into four types of molecules, the normal form, two different ab- normal forms, and a doubly abnormal form. One of the SO individuals pre- sumably has a thalassemia allele. If the thalassemia allele is the absence or the complete malfunction of a locus for hemoglobin, at most only three different polypeptides can result from the taco loci. If the two loci correspond to dif- ferent parts of the hemoglobin molecule, the polypeptides corresponding to allelic genes would not associate, and the three nolvPentides could form only two different hemoglobin molecules. 1 , ~ Dr. Neel: With reference to the speculations of Dr. Itano, the possibilities for speculation here are almost infinite. I think most of us should have felt that if the genetic interpretation which I have presented is correct and there is ~ G locus and an S locus, the double heterozyg;otes should show an appreciable quantity of hemoglobin A. The fact is that we did not find appreciable quanti- ties of hemoglobin A. This observation has discouraged me from speculation as to what we should find. I can only express the hope that those of you who are in charge of hematological laboratories will help us dig out the families that will give us facts of this nature, so important in developing an understanding of the biochemical genetics of this situation. Dr. I. Herbert Scheinberg: I would like to ask Dr. Reel a question. If there is some appreciable incidence of spontaneous mutation to the sickle cell gene, is there any way of explaining or speculating as to why this should occur only, or almost only, in Negroes, and Why you should not get some mutation in white people? Dr. Neel: Why don't we find hemoglobin S in persons other than Africans ? This is something that I have speculated on under other circumstances. We have never had the kind of large-scale survey on Caucasians or Mongolians which would tell us just how frequent the hemoglobin S gene may be in these groups. But on indirect grounds, such as the paucity of cases of sickle cell anemia in Caucasians with no known or probable Negro admixture in in~- mediate or remote times, we can infer that it is quite rare. Certainly this sug- gests to me a mutation rate below 10-';, but I don't think we can exclude

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274 PART IV. GENETIC ASPECTS mutation rate of 10-' in Caucasian and Mongolian populations. Increasingly, my oven thinking is that, despite certain cases of apparent mutation and I have published some of them probably the sickle cell mutation is a rela- tively rare one by our present standards, even in Negro populations. It must be regarded as a mutation which may have occurred infrequently in the history of the human race and which confers a special advantage, and so flourishes, under a particular set of circumstances, namely, those encountered in regions where malaria pressure is intense. Whether other factors than malaria pres- sure are of importance in maintaining a high f requency of the sickle cell gene is still an open question. This is the best that I think anyone can do at the present time. It is be- cause of this indirect evidence that the sickle cell mutation is rare that I em- phasized the necessity of studying apparent cases of mutation with every tool at our disposal. We have found too many of them to reconcile with this other evidence that makes us think the mutation must be a very rare one. At the moment, it appears as if some of these apparent mutations are instead to be explained by our old friend the thalassemia gene, very well disguised. Dr. DVilliam R. Bergren: Recently in our laboratory we have had another blood sample from Dr. Sturgeon's clinic containing hemoglobin H. This occurrence follows very closely the reported case of Rigas and his associates' in that there is no evidence in the parents of the presence of the fast hemoglobin. In this particular case, as with Rigas, there is thalassemia on one side of the family, with the hemoglobin ~ presumably coming from the other. Seventeen members of the non-thalassemia side have been studied, with no funding of hemoglobin H beyond that in the propositus. These results parallel what has been mentioned by Rigas, by Gouttas, and, at this Conference, by Motulsky. The studies on the present family add to the data from two previous occur- rences of hemoglobin H at our hospital. I would like to go back a couple of years to work in our laboratory which has not been reported as yet except informally. In late 1954 we observed on a paper electrophoresis run a hemoglobin with a mobility considerably higher at pH S.6 than that of the normal hemoglobin A. Naturally this was very exciting, but we were cautious in feeling that our observation was a new one, for we had heard through Dr. Itano that Dr. Jensen and Dr. Rucknagel at Duke University had been working with a fast hemoglobin. On cross-checking samples with Dr. Jensen, it was found that our hemoglobin was different from the Duke material (which is now known as hemoglobin I). Meanwhile, we had heard that Dr. Rigas had been studying a fast hemoglobin and that Dr. Motulsky also had two occurrences of a similar one. On crost;-checking sam- ples, it was found that our occurrence checked very closely with the hemo- globin H of Rigas. A second independent occurrence of a fast hemoglobin in our laboratory checked out identically. Meanwhile, cross checks also were

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DISCUSSION 275 made against the fast hemoglobin found by Dr. Thorup and Dr. Itano (now hemoglobin J.). It is of interest that our early occurrences of hemoglobin H seem quite different in family relationship from our recent one or from those reported by others. In each of the two early cases, the hemoglobin H was found in elderly men, and in neither instance was there any Oriental connection in the family. The first case was a 76-year-old man of Scottish ancestry. He had been robust and healthy until age 70, at which time he underwent ~,enitourinary tract surgery. Soon thereafter an anemia developed, and the condition progressed until supportive transfusions there necessary every few weeks. We studied his three children, six grandchildren and a sister. In no case was the fast hemo- globin found, and similar results were had with two correlative lines of the family. Although a genetic relationship could not be established, neither divas it ruled out. The interesting point is that nothing in our study or in history of the family suggested the presence of thalassemia. The second occurrence was in ~ man of about the same age. No family re- mained to be studied, but nothing in our examination of him or of his history divas suggestive of thalassemia. Our assumption has been that some stress cir- cumstance is necessary for hemoglobin H to become manifest, such a cir- c~mstance being thalassemia on the other side of the family in our recent oc- currence and in the published instances. In the two early cases, we considered the possibility of the stress of age as an evocative circumstance for the fast hemoglobin production, provided that the genetic possibility is present. Of course, this concept of a geriatric hemoglobin has only speculative grounds on the basis of present information. It is apparent now that it was a mistake on my part to use an alphabetical designation as a provisional dame for our first occurrence of a fast hemo- globin. The term hemoglobin X has crept into the literature through personal communication, 2 and it has not been clear that hemoglobin X corresponds to hemoglobin H. It would have been much better to designate the new hemo- globin by a noncommittal term such as Los Angeles No. 1, pending compara- tive study. Recently this practice has been followed by Dr. Zuelzer and his colleagues with their fast hemoglobins from Africa, and it has been adopted by Dr. Chernoff for his apparently new fast hemoglobin, that which he has referred to in this Conference as Durham No. 1. . :REFEREN CES 1. Rigas, Demetrios A., Koler, Robert D., and Osgood, Edwin E.: Hemoglobin H: Clinical, laboratory, and genetic studies of a family with a previously un- described hemoglobin, J. Lab. Clin. Med. 47: 51, 1956. 2. Rucknagel, D. L., Page, E. B., and Jensen, W. N.: Hemoglobin I: An inherited hemoglobin anomaly, Blood 10: 999, 1955.