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Pages 253-275

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From page 253...
... but with ~ variable component up to 20 per cent of the total of hemoglobin F.58 64, 6s <;nrP hr~m^~7`rctnilc ;nA;`r;` must have received ~ sickle cell gene from both parents, then, with certain very rare exceptions to be discussed later' both parents of a child with this type of sickle cell anemia must exhibit the sickling phenomenon. Tow, one of the appeals of genetics is that one can submit hypotheses to rather rigorous testing.
From page 254...
... NON-SICKLE CELL TRAIT AMONG THE NONANEMIC SIBLINGS OF CHILDREN WITH SICKLE CELL ANEMIA, BOTH PARENTS KNOWN OR ASSUMED TO HAVE THE SICKLE CELL TRAIT. Author Number with s.c.t.
From page 255...
... The modes in the case of Raper's data do not correspond with the values observed ir: the American Negroes, but this may be due to the different techniques employed. The role of the genetic mechanism responsible for this bimodality in the maintenance of the relatively high frequency of the sickle cell gene, a subject to be discussed later, is unknown.
From page 256...
... to be discussed later, we feel that G is better designated a normal variant than an abnormal hemoglobin. The genetic basis of hemoglobin H appears to be somewhat different from that of the other abnormal hemoglobins discussed thus far.
From page 257...
... ~ or several years it has been recognized that ~nd~~-iduals with thalassemia minor might, on moving boundary electrophoresis, exhibit a minor hemoglobin component with mobility slightly greater than hemoglobin A.7~ ~' 60 More recently, Kunkel and Wallenius,30 using "starch block" electrophoresis, have observed the regular occurrence of a minor hemoglobin component, now termed A`', in normal blood, which component is increased in thalassemia minor; this is apparently identical with the just-mentioned fast-moving shoulder seen in thalassemia minor with moving boundary eiectrophoresis. Here may be a "handle" which will make thalassemia minor somewhat easier to work with.
From page 258...
... However, even with the exclusion of the doubtful individuals, the occurrence of normal children and some with thalassemiahemoglobin S disease suggests non-allelism of the two genes. On the other hand, omitting the doubtful individuals, the departure from expectation on the basis of complete independence of the two genes is significant (expectation 11 thalassemia-hemoglobin S or normal: 11 thalassemia minor or sickle cell trait; probability of the observed or a greater deviation as computed from binomial distribution — 0.004~.
From page 259...
... By now we have established the high probability that the genes responsible for hemoglobins S and C are either alleles or linked, and the further probability that at least one of the several possible thalassemia genes is to be found at a different locus, with the possibility that another of the postulated thalassemia genes may either occur at or be linked with the S-C locus. We turn now to a consideration of the relationship of the genes responsible for the remaining abnormal hemoglobins to these two loci.
From page 260...
... Robinson, one of the co-authors, to compare the hemoglobin G in this family with that identified as G by Edington, Lehmann, and Schneider in 1955,19 with agreement in all essential respects.) The propositus for this kindred was a 28-year-old male of Italian extraction who appeared on clinical grounds to have sickle cell anemia.
From page 261...
... GENETICS OF AB N:ORMAL HEMOGLOBINS—NEEL 261 FIG. 2.—Picture pedigree of a family in which hemoglobins S and G and thalassemia were encountered.
From page 262...
... Bus marriage to a completely normal woman, III-4, has thus far resulted in one child whose hemoglobin on electrophoresis shows an AG pattern. The proper genetic interpretation of these findings would appear to be that III-3 has inherited the sickle cell gene from his father and the hemoglobin G gene from his mother, and has, in turn, transmitted the latter gene to his daughter.
From page 263...
... There comes a time in the development of many genetic problems when a symbolic shorthand becomes a great aid to clarity of thought and brevity of expression. That time has arrived with respect to the abnormal hemoglobins.
From page 264...
... In brief, it is suggested that the first locus to be recognized as associated with hemoglobin production be given the locus symbol Hbi. We now recognize three different genes which may occur at that locus, the normal gene, HERA, and the abnormal genes associated with the production of hemoglobins S and C, namely, Hats and Half.
From page 265...
... In view of the apparent differences in amino acid composition between fetal and adult hemoglobin, and in view of the "template" concept of protein synthesis, the biochemical evidence would seem to favor the latter hypothesis, a point of view previously expressed by Itano,24 Singer, Singer, and Goldberg,70 and Huisman, Jonxis, and van der Schaaf.2~ This locus might be designated as Hb3, with the only gene thus far known for this locus being Hb3F. Biochemical Genetics and the Abnormal Hemoglobins.
From page 266...
... If hemoglobins G and S diffe, in amino acid substitutions at diffcrent points in the chain, will some hemoglobin molecules show both types of substitution, and some only one? These are very basic questions in biochemical genetics.
From page 267...
... Since it is a well established tenet of genetics that mutation tends to be recurrent, in any consideration of the population genetics of the abnormal hemoglobins there immediately arises the question of the frequency with which mutation resulting in the hemoglobin genes is occurring. There are a good 'many complications to establishing unequivocally the fact that a mutation has occurred.77 Be that as it may, there are now in the literature a number of reports suggestive of mutation to the sickle cell gene.49' 77' 32 These involve for the most part the failure of a mother of a child with sickle cell anemia to exhibit the sickle cell trait or any other identifiable hemoglobin abnormality.
From page 268...
... He postulates that the relatively recent spread of "slash and burn" agriculture through large parts of Africa has created an ecological situation favorable to an increased importance of the malaria parasite, and hence has lead to an extension of the conditions resulting in selection for the sickle cell gene. There is, then, something of a conflict in evidence, between findings indicating a sufficient mutation rate to account for numerous local origins of the sickle cell gene, and other findings suggesting that much of the present-day distribution of the sickle cell gene can be accc~unted for through relatively recent gene flow and increase with changing selective pressures, with the inference that mutation is extremely rare.
From page 269...
... W., and Neel, J V.: A new inherited abnormality of hemoglobin and its interaction with sickle cell hemoglobin, Blood 6: 1240-1259, 1951.
From page 270...
... B.: Distribution of parasites in the red cells of sickle cell trait carriers infected with Plasmodium falciparum, Tr.
From page 271...
... I Their demonstration in sickle cell anemia and other hematologic disorders by means of alkali denaturation, Blood 6: 413~28, 1951.
From page 272...
... 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.
From page 273...
... 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.
From page 274...
... Whether other factors than malaria pressure 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.
From page 275...
... Our assumption has been that some stress circumstance is necessary for hemoglobin H to become manifest, such a circ~mstance being thalassemia on the other side of the family in our recent occurrence 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.


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