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OCR for page 272
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.
OCR for page 273
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
OCR for page 274
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
OCR for page 275
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.
Representative terms from entire chapter:
primary gene
