Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 253
PART IV. GENETIC ASPECTS OF ABNORMAL HEMOGLOBINS
GENETIC ASPECTS
OF ABNORMAL HEMOGLOBINS
NAMES V. N EEL
So much has been written recently concerning the genetic aspects of the
abnormal hemoglobins that you are undoubtedly familiar with the main out-
lines of our present knowledge in this area. Nevertheless, in keeping with my
assignment, I should like to summarize once again, but as briefly as possible,
some of the generally accepted facts and interpretations concerning hemo-
globin genetics, and then devote much of the remainder of my time to a dis-
cussion of a family which my collaborators and I have recently described.
This discussion will illustrate some of the approaches and problems which
arise in attempts to determine the genetic relationships of the various abnormal
hemoglobins to one another. Finally, me shall deal briefly with the implications,
for genetics and for human biology in general, of some current developments
as regards the hemoglobins.
The Genetics of Hemoglobin S. The hypothesis that the sickling phe-
r~omenon (and the formation of hemoglobin S) is determined by a single
gene with different ejects ire homozygotes and heterozygotes is well known
to all Of vou 46, 4`, 4S, ~ TO ;nr1;~;A',olc hPt^'r~7`rccr~c friar that crone ~xr;1-h thy
. ~ ~ ~ ~
~ J. ~ 1 A ~ ~A ~ 1 ~ ~~ Arm ~— ~ V~} 8~ REV ~ V ~ ~~ ~ ~~AA~~ ~ ~ ~ %4 ~
sickle cell trait, some 30 to 40 per cent of the hemoglobin is type S. the re-
mainder being hemoglobin A. In individuals homozygous for the gene, with
sickle cell anemia, no hemoglobin A is present, the hemoglobin being pre-
dominantly hemoglobin S. 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. In the case of a marriage of a sickle cell trait x normal, we expect
sickle cell wait and normal children in the ratio of exactly 1 :1. In the case
of a marriage of two persons with the sickle cell trait, we expect normal,
sickle cell trait, and sickle cell anemia children in the ratio of exactly 1 :2 :1.
These ratios may be distorted by the manner in which these families come to
our attention. The most extensively studied type of sibship to date is that
~J111~— ~~ AA1~A V ~ w
~ Much of the original world herein referred to has been collaborative, involving
particularly Dr. Wolf Zuelzer, Mr. Abner Robinson, Mr. Frank Livingstone, Dr.
lIarvey Itano, and Dr. Eugene Kaplan. We are greatly indebted to the U. S. Public
Health Service and the Rockefeller Foundation for financial support.
~ Reviews: Cherno$, 1955 ;~2 Gatto, 1956 ;~i Itano, 1955,~5 1956 ,~6 Itano, Bergren
and Sturgeon, 1956;2S Lehmann, 1957;34 Neel, 1956,50 1957;;): Singer 1955~66 White
and Heaven, 1954;79 Zuelzer, Neel, and Robinson, 1956.S°
253
OCR for page 254
254
PART IV. GENETIC ASPECTS
in which the propositus for the sibship has sickle cell anemia and segregation is
studied among the non-anemic siblings of the propositus, both parents being
either known or assumed to have the sickle cell trait. Here a ratio of 2 sickle
cell trait: ~ normal is expected. Table I summarizes the results in four series.
Agreement with hypothesis is satisfactory. It will be noted that such de-
parture from expectation as exists is in the direction of a deficiency of sicklers.
TABLE I
SEGREGATION FOR SICKLE CELL TRAIT VS. NON-SICKLE CELL TRAIT AMONG THE NON-
ANEMIC SIBLINGS OF CHILDREN WITH SICKLE CELL ANEMIA, BOTH PARENTS KNOWN OR
ASSUMED TO HAVE THE SICKLE CELL TRAIT.
Author
Number with s.c.t.
Number
examined Observed ~ Expected
Number normal
Observed ~ Expected
Neel, 19514S
Lambotte-Legrands,
195 13i
Banks, Scott and
Simmons, 19524
Vandepitte, 1955~0
98 62 65.4 36
70 45 46.7 25 23.3
33 15 22.0 18
208 141 138.7 67
32.6
110
69.3
409 i 263 ~ 272.8 ~ 146 ~ 13 6.2
X- 1.023 D.F. 1 0.50 > P > 0.30
In my own experience with a number of other types of segregating sib-
ships,48 there was a similar deficiency, with x~ for the entire group of cases
studied by myself significant at the 1 per cent level. However, it must be re-
membered that both discrepancies between legal and biological paternity, and
the occurrence in the series of some of the variants of sickle cell anemia
(as sickle cell-thalassemia disease; see below) would be expected to procure
departures in this direction, for which reason the over-all agreement with
hypothesis should be regarded as satisfactory.
Bunny and Sandier and Novitski63 have raised the possibility that there
may be an abnormal segregation ratio with respect to the genes responsible
for the sickling phenomenon and for thalassemia, in consequence of which
there is an excess of individuals with the abnormality over expectation in
segregating sibships. They have introduced this as a possible contributory
factor in the relatively high frequency of these genes in certain parts of the
world. The departure from expectation in the sickle cell data, such as it is, is
actually opposite in direction to expectation on this hypothesis, although, as
Sandler and Novitski point out, large numbers are necessary for a critical
test of the hypothesis.
In American Negroes with the sickle cell trait, the amount of abnormal
OCR for page 255
GENETICS OF ABNORMAL HEMOGLOBINS NEEL 255
hemoglobin revealed by moving boundary electrophoresis varies from approx-
imately 22 to 45 per cent of the total, with modal values at 3~36 per cent
and 40-42 per cent. There are significant intrafamily correlations ire this
respect; it has been suggested these can be explained through the action of
segregating genetic modifiers.7S 54 An alternative hypothesis, that the correla-
tions may be due to the occurrence of different "iso-alleles" of the normal allele
of the hemoglobin S gene, seems not to be borne out by the data. It is worth
emphasizing that, if our limited experience is typical, these modifiers are
common in the American Negro population. Allisont and Raper,6t using
paper electrophoresis have also encountered two modal values in the amount
of abnormal hemoglobin in African Negroes with the sickle cell trait. 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.
The Genetics of Hemoglobin C. Like hemoglobin S. the presence of
hemoglobin C seems to be determined by a single gene which, when heterozy-
gous, results in some 30 to 40 per cent of the hemoglobin being abnormal in
type, and when homozygous, in all the hemoglobin being abnormal save for a
variable but usually small component of hemoglobin F.'`' '9, ·~6' 7~, ·36 Because
of the greater difficulties involved in studying the inheritance of hemoglobin
C, in that one must rely on electrophoresis rather than such a simple procedure
as a sickling test, there is not yet available a large body of data for a critical
evaluation of the precise ratios in segregating families. Such data as are
available, as summarized in Zuelzer, Neel, and Robinson, ~ 9 reveal no de-
, . . . . .
partures from the expected ratios.
The Genetic Relationship of Hemoglobins 5 and C. The first papers on
hemoglobin C raised the obvious question of the genetic relationship of this
hemoglobin to hemoglobin S and pointed out the information necessary to a
decision. Critical data were soon supplied by Ranney, Larson, and McCor-
mack<;° and by Smith and Conley (unpublished), on the basis of which it
may be concluded that the two genes concerned are either alleles or linked.
In brief, this evidence consists of the observation that the children of a mar-
riage involving a normal person and a person simultaneously heterozygous for
both the abnormal genes all either possess the sickle cell trait or the hemo-
globin C trait. The basis for this statement is indicated in figure 1. However,
the number of children studied is small, and further data on this point are
highly desirable.
The Inheritance of Hemoglobins D, E, G. I, and I. The relatively
limited material available concerning the inheritance of hemoglobins D, E, G.
I and J (cf. reviews quoted in footnote to introduction) suggest that each of
these abnormal hemoglobins owes its presence to a single gene which in the
OCR for page 256
256
PART INT. GENETIC ASPECTS
ALLELiC GENES INDEPENDENT GENES
R A r lo
LINKED GENES
FIG. 1. Diagrammatic representation of expectation on the basis of i) allelism of
two genes, A and B; 2) independence (location on different chromosomes) of the two
genes; or 3 ) linkage, with less than 50 per cent crossing-over, of the two genes.
( From Human Heredity, by J. V. Neel and W. J. Schull, University of Chicago
Press, 1954).
heterozygous state results in some 30 to 40 per cent of the hemoglobin being
of an abnormal type. Hemoglobin ~ is an exception to this generalization, in
that in the family reported by Thorup, Itano, Wheby, and Leavell,73 as
well as in the material reported by us under the designation of Liberian 1,6-'
the abnormal component in heterozygotes amounted to 60 per cent of the
total. Individuals homozygous for the gene producing hemoglobin E are
characterized by the fact that all of their hemoglobin is of the abnormal type
save for a small and variable type F component.~3 39' 40 An individual all of
whose hemoglobin was type D has been presented as the probable result of
homozygosity for the hemoglobin D gene.8 While this may be the case, there
there no family studies, and experience with the manner in which the thalas-
semia and possibly other genes may interact with the genes responsible for the
abnormal hemoglobins has emphasized the absolute necessity of family studies in
reaching conclusions concerning genotype.
The father of the proband for the family in which hemoglobin G was first
discovered appeared on paper electrophoresis to have only hemoglobin G.
Ten of his 11 children showed the hemoglobin G trait; the eleventh is a
parentage exclusion on the basis of exhibiting the sickling phenomenon.
These findings are highly suggestive of homozygosity as regards the gene
responsible for this abnormal hemoglobin.~9 It is noteworthy that this presumed
homozygote showed no anemia. On the basis of this finding, as well as our
oven experience with hemoglobin G. 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. This hemoglobin
has been observed only in individuals who are also heterozygous for the thalas-
semia gene, suggesting that this latter gene somehow "potentiates" the appear-
ance of hemoglobin H.44 It will be difficult to conduct detailed studies in
man of the genetics of a trait which is only expressed on a specific genetic
background.
OCR for page 257
GENETICS OF ABNORMAL HEMOGLOBINS NEEL 257
The Genetics of Thalassemia. Before turning to a consideration of the
genetic relationships of the genes responsible for hemoglobins D, E, G. I, and ~
so one another and to the genes responsible for hemoglobins S and C, we
must, for reasons which will become apparent, consider at this point the gene-
tics of thalassemia. As in the case of the abnormal hemoglobins, thalassemia
has been extensively reviewed recently (cf. refs. p. 2j3), and we shall con-
fine our attention here to the main outlines. The data on the familial dis-
tribution of thalassemia are in general consistent with the hypothesis that the
mild form of this disease, known as thalassemia minor, is due to heterozygosity
for a gene which in the homozygous condition produces the much more serious
and fatal disorder known as thalassemia major.~°, 'I i4 75 53 Recently, as no-
ted earlier, several workers have raised the possibility that there may be art
abnormality in genetic segregation in connection with the thalassemia gene,
comparable to that know-e for the T locus in the mouse, and resulting in an
excess of thalassemia major and minor over expectation in segregating matings.
The data as summarized by several authors53 ~ do not appear to lend support to
. .
t Ifs suggestion.
In diagnosing the presence of an abnormal hemoglobin, the basis of the
diagnosis is a rather specific alteration in the behavior of a well known and
extensively studied protein. The diagnosis of thalassemia has until recently
lacked this specificity, depending rather on morphological criteria involving
.. . . . . ~ , . . . . . . . ..
erythrocyte size arid shape. ~ 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 hemo-
globin component, now termed A`', in normal blood, which component is
increased in thalassemia minor; this is apparently identical with the just-men-
tioned 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.
Recently several investigators have emphasized on clinical and biochemical
grounds the possibility that there may be not one but several thalassemias.79 28
This opinion is based in part on the wide range in the expression of the heter-
ozygote, but to an even greater extent in the variability in the results of com-
bining a thalassemia gene with the gene responsible for either hemoglobin S
of hemoglobin C.
~ decision concerning the obvious question of the relationship of the
thalassemia gene or genes to the locus associated with the production of hemo-
globins S and C depends, of course, on the study of the type of children emerg-
ing from a marriage of a normal individual and an individual heterozygous
for the thalassemia gene and also either the gene resulting in hemoglobin S or
C. Here again, we encounter a paucity of data This is in part because many
OCR for page 258
258
PART IV. GENETIC ASPECTS
individuals simultaneously heterozygous for the genes responsible for thalas-
semia and hemoglobin S suffer from a severe, chronic hemolytic anemia
which may be clinically indistinguishable from sickle cell anemia, and thus
results in early death and impaired reproduction. I have been able to find in the
literature a description of only seven marriages involving a normal person
and one with thalassemia-hemoglobin S disease. The results are shown in
table II. Most of the evidence suggesting non-allelism is supplied by the
TABLE II
A SUMMARY OF THE TYPES OF CHILDREN RESULTING FROM 1\IARRIAGES BETWEEN A
l\.CRMAL INDIVIDUAL AND ONE WITH BOTH THE THALASSEMIA GENE AND THE GENE
RESPONSIBLE F R HEMCGL~BIN S.
l l Children t
Authors
Ethnic
background
-
Tha, assemia-
sickle cell
disea se
Normal
Thal-
assem~a
Sickle
cell
Trait
Silvestroni and
Bianco, 195265
Powell, Rodarte,
and Neel, 1950;'$3
Neel, Itano, and
Lawrence, 19535-'
Neel, 1951,4S kin-
dred 60
Ceppellinili
Italian
(Italy) 1 0 0 0
Italian
(USA) 0 0 2 0
Greek
(USA) 0 0 0 1
American
Negro 1 ~ 1? 2 1 + 1 ? 1 7
American
Negro 0 0 4 3 7
Greek
(USA) 0 0 1 2
Italian
(Italy) 0 0 1 2
2 + 1? 2 9 ~ 1? 9
2
1
3
3
filmily which I described in 1951. In this family the stigmata of thalassemia
minor were very minor indeed, leading to some difficulties in classification.
Furthermore, the interaction of the thalassemia and sickling genes was very
much less than usual. However, even with the exclusion of the doubtful in-
dividuals, the occurrence of normal children and some with thalassemia-
hemoglobin 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~. This suggests either linkage or heterc-
geneity of the material (i.e., two, or more, thalassemia loci).
OCR for page 259
GENETICS OF ABNORMAL HEMOGLOBINS NEEL 259
In addition to the data of table II, Silvestroni and Bianco65 in 1952 des-
cribed a marriage between an individual with sickle cell-thalassemia disease
and an individual with the sickle cell trait, from which among 7 children who
could be studied or on whom there were medical records, there was one normal
child, again suggestive of non-allelism. Finally, Singer et al.69 have reported
the birth of a normal child to a woman with thalassemia-hemoglobin C dis-
ease whose husband was deceased and hence of unknown genotype. This sug-
gests non-allelism of the gene responsible for these two traits, to be expected
if hemoglobins S and C for their part are due to allelic genes. Further data on
this point are highly desirable. At present the evidence for the heterogeneity of
the thalassemia trait is growing.
A comparable situation may exist with respect to the elliptocytosis trait, a
morphological abnormality of the erythrocyte which in several dozens of
pedigrees has behaved as if due to a dominant gene. But now it has been shown
that in some pedigrees this gene appears to be rather closely linked to the
Rh LOCUS' whereas in other pedigrees there is no evidence for linkage frets. in
Morton43~. There is some evidence for linkage between the thalassemia gene
and the genes responsible for the Lewis and Secretor characteristics;7 an ex-
tension of these data, with particular attention to the question of hetero-
geneity of the material, would seem indicated. It will also be of interest to
determine whether the A2 component is accentuated in some pedigrees of
thalassemia and not in others, in relation to this heterogeneity problem.
The Relationship of the Genes Responsible for Hemoglobins D, E, G.
0,1, and I, to One Another and to the Genes Responsible for Hemoglobins
S and C. 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. A number of investigators
have postulated that several more or even all of the genes responsible for the
abnormal hemoglobins may fall into the S-C series of multiple alleles.24, 9' 45'
3~, 35 This opinion is based in part on the apparent absence of normal hemo-
globin in persons heterozygous for two of these genes, as S-D. In the final
analysis, however, these genetic relationships can only be established with
certainty from the study of fertile marriages in which one of the marital
partners is simultaneously heterozygous for two or more of the genes con-
cerned. Indeed, as will become apparent in the family we are now to consider,
we know too little about biochemical genetics to draw inferences from the
type of factor interaction as to the formal relationships of the genes involved.
Recently I have been so fortunate as to be associated in the study of a
family in which the genes responsible for thalassemia and hemoglobins S and
OCR for page 260
260
PART IV. GENETIC ASPECTS
G were present.64 Not only was it a stroke of luck to encounter such a family,
but the types of individuals observed in the family were such as to yield almost
a maximum of possible genetic information. The details of the family are
complicated and will require constant reference to table III and figure 2.
(I should mention that since our paper on this family went to press it has
been possible for Mr. Robinson, one of the co-authors, to compare the hemo-
globin 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. Fifteen members
of the family were available for study. Although it is customary to begin the
description of a family with the propositus, it will in this case be somewhat
less confusing if we begin with III-5. She was a 14-year-old girl with the
hematological findings of thalassemia minor; her hemoglobin in both its solu-
bility and electrophoretic behavior corresponded to type A. Her father, II-6,
had no hematological abnormality. Her mother, II-7, showed in unequivocal
fashion the findings of thalassemia minor. On both Tiselius and paper electro-
phoresis, essentially all the hemoglobin appeared to be type G. although Tise-
lius studies revealed a small and equivocal "shoulder" with a mobility cor-
responding to 2.7 ~ 10-;' cm.~/sec./volt. This is the approximate position of
the "thalassemia shoulder" of hemoglobin As which was referred to earlier.
There was no significant increase in the amount of fetal hemoglobin. Although
the electrophoretic findings would by analogy with what is known concerning
the results of homozygosity for the genes responsible for hemoglobins S. C,
and E suggest that II-7 was homonymous for the G gene. the fact that her
1 1 ~ ~ ~
J ~ ~
aaugnrer was nor sound to rave any hemoglobin G would seem to rule out
that explanation. A second factor ruling out this explanation is the fact that
I-3, II-7's father, is completely normal hematologically, and hence could
scarcely have made the contribution of a hemoglobin G gene necessary if his
daughter were homozygous. The most reasonable interpretation of these
findings would seem to be that they are due to simultaneous heterozygosity
for the thalassemia and G genes.
We turn now to II-5, sister to II-7, whose findings differ from those of
her sister only in the presence of a distinct, minor hemoglobin component
which migrates with a speed of 2.7 x 10-' cm.~/sec./volt, the rate shown by
hemoglobins D and S. This amounts to about 20 per cent of the total, and
appears to be an accentuation of the "shoulder" observed in the electrophoretic
pattern of II-7. We will assume on the basis of the cytological findings that
this woman is heterozygous for the thalassemia gene, and on the basis of the
O
electrophoret~c findings that she Is either homozygous or heterozygous for the
G gene. Again, however, as in the case of II-7, the absence of hemoglobin G
in her father renders homozygosity unlikely, and suggests the most probable
OCR for page 261
GENETICS OF AB N:ORMAL HEMOGLOBINS—NEEL 261
FIG. 2.—Picture pedigree of a family in which hemoglobins S and G and thalas-
semia were encountered. The crescent and dot-withir~-circle symbols represent the
sickling and thalassemia traits, respectively. The letters refer to the hemoglobin
phenotypes. (Reproduced from Blood 1~?: 239, 1957, by permission of Grune and
Stratton, Inc.).
TABLE III~
A SUMMARY OF THE HEMATOLOGICAL AND BIOCHEMICAL
FINDINGS IN A FAMILY IN WHICH THE GENES RESPONSIBLE FOR
HEMOGLOBINS S .AND G AND THALASSEMIA WERE SEGREGATING.
o
.~
:- ~
~ or
.~ .~
q~
c;
˘-Q
I-3
II-7
II-5
II-4
II-6
III-1
III-2
III-3
III-4
III-5
IV-1
IV-2
5
=>
.. X
_ ~ ~
F.C. hI
B.H. F
F.H. F~
F`.S. M
M.H. M
V.S. M
C.S. F
G.S. M
M.S. F
Fr.H. F
S.S. M
I.S. F~
. ~ .~ .=
~ . '= ~ ~, _ ~- ~ ulubility
76 _ _ _ A A oo A
39 + _ + G G oo A
45 ~ _ ~ G G oo A
52 _ + _ AS AS AS —
45 _ _ _ A A oo
28 + + + S GS AS
24 _ _ _ A A oo A
26 _ + _ GS GS AS ~-
25 _ _ _ A A co A
14 + _ _ A A oo A
1 + _ _ A A _
5 _ AG AG ~ A
Heweglobin Type
. .
._ . ~
0 0
~ ~ ~ tl
-
A A
G G
G G
AS AS
A A
S GS
A A
GS GS
A A
A A
A A
AG AG
~0
o~
c,
._ ~
~ .0
,~ 0
. <=
<1.0
<1.0
<1.0
1.1
1.2
3.9
<1.0
1.2
<1.0
1.8
4.1
1.4
* Reproduced from Blood 1~: 240, 1957, by permission oŁ Grune and Stratton, Ine.
b4
5=
~Q ~_
112
114
85
241
96
121
130
OCR for page 262
262
PART IV. GENETIC ASPECTS
interpretation to be that she, like her sister, is simultaneously heterozygous
for the G and thalassemia genes.
This woman (II-5) married a man who had the sickle cell trait, as did
all three of his siblings available for testing. This marriage, then, involves
three different genes responsible for erytnrocytic variation, namely, the genes
responsible for hemoglobins G arid S. and the thalassemia gene. The marriage
resulted in two sons. One, III-3, exhibits the sickling phenomenon but has no
anemia, thus appearing to have only the sickle cell trait. However, electro-
phoretically his hemoglobin is a mixture of S and G with G comprising about
~ r~ . r . 1 . . 1 T T · · .
~ 1 3
ou per cent or tne total. 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. Note the ~nn~rent l~h~7sin1~ic;31 e~lliv~lence of
hemoglobin G to hemoglobin A.
Errs i- ~--~ -~-
III-1, the individual who originally brought this family to our attention,
has, in contrast to his brother, a severe, chronic hemolytic anemia in all
respects answering to the description of sickle cell anemia, even though on
Tiselius electrophoresis his hemoglobin is quite similar to his brother's, ap-
parently consisting of approximately equal proportions of G and S. On paper
electrophoresis the pattern is essentially that of S alone, thus illustrating the
discrepancies which occasionally occur between paper and moving-boundary
electrophoresis. The only son of III-1, aged 1 year, exhibits morphologic ab-
normalities of his erythrocytes consistent with thalassemia minor, although it
must be recognized that this is an age when mild iron deficiency anemias are
not uncommon. Since III-2, the mother of this child, is hematologically
normal, the thalassemia gene which appears to be present in the child must
have been inherited from our propositus, his father. The presence of a thalas-
semia gene in the propositus would also explain the marked difference between
his findings and those of his brother, who has the S and C genes, but ap-
parently not the thalassemia gene. We are thus led to the conclusion that
I I I- 1 possesses three different genes resulting in hematologic abnormality,
namely, those responsible for thalassemia and hemoglobins G and S.
If this interpretation of the pedigree is correct, then two important genetic
conclusions are automatic:
1. The genes responsible for hemoglobins G and S cannot be alleles
otherwise IV-1, the son of the propositus, would have received one or the
other of the genes from his father.
2. The genes responsible for hemoglobins G and thalassemia cannot be
alleles otherwise the propositus could not have received both of these genes
from his mother, as analysis of the pedigree seems to demonstrate.
We have already considered briefly the evidence that the genes responsible
OCR for page 263
GENETICS OF ABNORMAL HEMOGLOBINS NEEL 263
for hemoglobins S and C, on the one hand, are not allelic with at least one of
tile several possible thalassemia genes. It therefore becomes necessary to
postulate at least three different genetic loci involved in hemoglobin produc-
tion, with the relationship of the genes responsible for hemoglobins D, E, H.
I; and ~ to these loci yet to be determined.
There are two more points concerning this family which deserve emphasis.
The finding that an individual simultaneously heterozygous for the genes
responsible for hemoglobins S and G annarentlv produces no hemoglobin A,
. . ..
~ ~ J AL ~
even though these genes are non-allelic, demonstrates the fallibility of this
criterion of allelism. Secondly, we must consider the theoretical implications of
the finding, in II-5 and II-7, of a minor hemoglobin component with the
mobility of hemoglobin D or S. This component is unaccompanied by sickling.
Although it could be the "thalassemia shoulder," it was not observed in III-5
c, IV-1, who also have the thalassemia gene. Conceivably, it might be the
result of an inheritance from I-4, who was not studied. There is, on the other
hand, the possibility that this component is not the result of a specific gene,
but is rather a genetic interaction product. It has been demonstrated that
when pigeons of two species are crossed, the hybrids possess certain erythrocyte
antigens not present in either parent (cf. Irwin, 1951,23 for summary). Can
this component be regarded as such a "hybrid substance?" And, in this same
context, would hemoglobin H also qualify as a hybrid substance?
As I pointed out earlier, this family has an almost incredibly high "infor-
mation content." The segregants in each of the four marriages in the pedigree
which could be studied in detail in each instance shed critical light on the
hypothesis under test. Although I shall undoubtedly continue to pursue pedi-
grees as long as I live, I cannot escape the feeling that no family I shall ever
study in the future can be quite as exciting as this one.
Since coming to these meetings, I have learned of a family being studied by
Drs. Torbert and Smith,74 in which there occurs an individual possessing
hemoglobin S in combination with a "fast component," married to an indi-
vidual possessing neither of these components. The issue of the marriage in-
cludes children of such a type as to suggest non-allelism of the genes respon-
sible for the two hemoglobins. The relationship of this "fast component"
gene to the thalassemia and hemoglobin G loci is unknown, but it is perhaps
not too soon to start to think of the possibility of still another genetic locus
involved in hemoglobin production.
Terminology. 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. Thus far in this presentation, we have avoided the use of gene
symbols only by rather cumbersome circumlocutions. Two years ago Allison2
and I'd independently advanced terminological systems which were quite
similar. Last year we were able to meet and resolve such differences as did
OCR for page 264
264
PART IV. GENETIC ASPECTS
exist. Subsequently, at the sixth meeting of the International Society of Hema-
tology in 1956, I presented a compromise nomenclature which at a later dis-
cussion seemed to find rather general acceptance.52 At least, it did not elicit
any violent controversy, which in matters terminological is about as close as
one can come to a seal of approval. The chief merits of the system are that it
follows accepted usage in experimental genetics, and is elastic and descriptive.
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 recog-
nize 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. The second locus to be identified will be
designated as He,, with the two alleles thus far known being identified as
HERA and Hb9G. Finally, it is suggested that the thalassemia locus be desig-
nated by the symbol Th, with the thalassemia gene being known as Thy and
its normal allele as ThN. When and if it is definitely shown that there are
several thalassemia loci, then they may be designated as Thi, The, etc. With
respect to these three loci, the genotype of a normal person is HbiA/Hbi~;
Hb~/Hb.~; Th~/Th~-. The genotypes encountered in the pedigree we have
just considered in some detail are interpreted to be as shown in Fig. 3.
The woes and shortcomings of terminological systems are proverbial. In
this instance, one is, for example, immediately confronted by the problem of
the genetic basis of the minor hemoglobin components we have been dis-
cussing yesterday arid today. Does each of these imply the existence of a
?
31
Hb 1'Hb, / \
Hb 2 / Hb 2 ( )
ThN/ThN ~ /
I T
m: ;~> 31 ' at ' 1 me| fib, /Hb, |
( Hb2/Hb2 ~ ( ~b2 /~b2 ~ Hb2 /Hb2 Hb ^/Rb ( ~b2C/Hb2 ~ Hb2 /Hb2 ( Hb2G/Hb2
ma/ Aim T h / T h ~~ T h / T h
111
IV
| Hb, /Hb' | 35;: b1 1 ~:
Hb2G/Hb2A (:i Hb 2G/Hb2A ~ ( Hb2 /~b2
T b / T h 4/ T h / r h \~/ my
1 ^z A
Hb 2 / ~ b 2
Thr/ rh:Q
me,
( Ht2/Hb2 )
FIG. 3. The genetic interpretation of the family shown in figure 2 and described
in detail in the text.
OCR for page 265
GENETICS OF ABNORMAL HEMOGLOBINS—NEEL 265
separate locus, and if so, what is the relation of these to the loci we have just
been discussing? A related problem concerns the genetic control of the forma-
tion of hemoglobin F. Thus far, no inherited abnormalities of hemoglobin F
leave been identified, so that the possibility of a direct attack on the problem
does not exist. We are left with some indirect considerations, which, as we
have already seen, are to be pursued with caution in this field. Be that as it
may, two a priori possibilities seem outstanding. On the one hand, the hy-
pothesis may be entertained that the genetic basis of hemoglobin F produc-
tion is the same as that for hemoglobin A, with the oxygen tension in the
hematopoietic tissues controlling a switch-over mechanism. The persistence of
small amounts of hemoglobin ~ through life could imply that this switch-
over is never quite complete. The apparently normal adults with substantial
proportions of hemoglobin F who have been encountered f rom time to
timers 5' would then be individuals in whom the switch-over mechanism divas
for some reason imperfect. On the other hand, we must consider the possi-
biiity that there is a separate locus involved in the production of hemoglobin
if, which locus is active (with some degree of suppression of activity at the
loci responsible for hemoglobin A) under conditions of relative tissue anoxia.
In view of the apparent differences in amino acid composition between fetal
and adult hemoglobin, and in view of the "template" concept of protein syn-
thesis, 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. Thus far we
have been largely concerned with the formal genetics of the abnormal hemo-
globins. Some time must be devoted to a consideration of the opportunities
provided by this system for precisely defining the nature of gene action, and
for the further opportunities for quantitative genetics. The elegant localization
of the difference between sickle cell and normal hemoglobin to a single amino
acid which Dr. Ingram has just presented constitutes a genetic milestone. As
the precise biochemical basis for the other abnormal hemoglobins is worked
out, there will emerge a detailed picture of the effects of gene substitutions
which should open a new chapter in physiological genetics. Elsewhere, in
discussing the manifestations of hemoglobins C and E, ~ have raised the
possibility that "the basic defect is the same in these two conditions, the slight
dissimilarities being due to small normal differences between the globin
portion of the hemoglobin molecule in Negroes and Orientals, differences
which only come to light under these circumstances."~° The opportunity to
test this hypothesis with respect to these and other abnormal hemoglobins has
come sooner than could be anticipated.
This system provides an opportunity to test another very basic question.
This has to do with the matter of "invisible" mutations, i.e., mutations which
OCR for page 266
266
PART IV. GENETIC ASPECTS
at the time of their occurrence have no anT~arent effects heca~ise the. alte.rations
1 1
they induce are not reflected in the phenotype as it is usually studied. It is
conceivable that some amino acid substitutions in tI,e chains which comprise a
hemoglobin molecule are not critical, in the sense of producing clinical effects
of altering hemoglobin behavior by any of our current tests. 1 heir importance
lies in the fact that they may be cumulative or else may find expression when
environmental factors alter. The task of analyzing the hemoglobin of as many
as a thousand individuals by Dr. Ingram's techniques will be extremely la-
borious, but yet would supply significant insight `-~ri~h respect to human vari-
ability in regards to just one of the many proteins of the body. Furthermore,
in the field of quantitative genetics, an obvious question is the nature and
amount of the abnormal hemoglobin found in E'b~s/FIb~-i, Hk 0/Hk ~ indi-
viduals. If hemoglobins G and S diffe, in amino acid substitutions at dif-
fcrent 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.
The Population Genetics of the Abnormal HemGgIobins. In bringing
this talk to a conclusion, I feel obligated to say a few words about the popu-
lation genetics of the genes we have been discussing. Unlike so ready of the
inherited biochemical abnormalities which have been a source of instruction to
biochemist and geneticist alike, the genes under discussion today are no rare
oddities, but in various parts of the world attain very considerable frequencies.
Thus, in parts of Africa 40 per cent of the inhabitants are heterozygous for
the sickle cell gene, and in other parts, 20 per cent for the hemoglobin C gene.
I;requencies of heterozygotes for the hemoglobin E gene of 12 per cent have
been reported from Thailand. In parts of Cyprus and Italy, thalassemia
minor frequencies of 15 per cent or even higher are known. Gene frequencies
of this magnitude do not arise by chance, but indicate that the gene in ques-
tion makes some positive contribution to the fitness of the population. The
search for this fitness factor is currently attracting considerable attention.
The outstanding hypothesis to date, applicable at the moment only to the
sickle cell gene, is that individuals possessing this gene enjoy a relative im-
munity to P. falciparum malaria which, up to a point, can offset the increased
death rate of persons homozygous for the gene (summary in Allison).3 If this
is so, then in an analysis of the detailed mechanism whereby this immunity is
conferred, we have an opportunity for the precise dissection of a problem in
population genetics which is not to be exceeded in any other species.
Three possible (non-alternative) mechanisms have been suggested: 1) Alli-
soni and Mackey and Vivarelli4i have postulated that the falciparum parasite
may not be able to metabolize hemoglobin S as readily as hemoglobin A. 2)
Mackey and Vivarelli4i have suggested that the presence of the malaria para-
site, with its oxygen demands, may induce sickling in the cells of individuals
with the sickle cell trait, with destruction of both the cells and the parasites.
OCR for page 267
GENETICS OF ABNORMAL HEMOGLOBINS NEEL 267
Miller, Neel, and Livingstone42 have pointed out the tendency of erythrocytes
containing the falcipar2~m parasite to adhere to blood vessel walls. Such cells,
being handicapped in the renewal of their oxygen supply, would in parasitized
persons with the sickle cell trait have an added reason for sickling and prema-
ture destruction. 3) Livingstone'37 3s has suggested that, because of 2), the
placentae of women with the sickle cell trait who have falciparz~m malaria
will not be parasitized to the same extent as the placentae of normal women.
This might be expected to result in a greater birth weight for the children of
women with the sickle cell trait; there is some evidence that this is indeed the
case. Under African conditions, one might (within limits, of course) expect
heavier babies to have a better chance of survival than the lighter ones. A1-
though no decision between the relative contributions of these three possibilities'
can be reached at present, it is apparent that it should be feasible to collect
the data necessary for a decision.
Whatever the mechanism responsible for maintaining the relatively high
frequencies of these genes, it is a fact that these genes must have a point of
origin through mutation. 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 litera-
ture 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. It is very doubtful whether all these possible cases of mutation
actually are examples of mutation. Some of them may be attributed to a well
disguised thalassemia gene. However, taking the data at their face value, the
observed frequency of possible mutation is still clearly less than the rate
required to account for the gene frequencies observed in certain parts of
Africa, but yet sufficient to suggest that a mutation rate of ~ x 10-5/locus/
generation is possible.
On the other hand, there is increasing evidence to suggest that the distri-
bution of the sickle cell gene in Africa is to be explained primarily, not in
terms of local origins through mutation with subsequent increase in fre-
quency through selection, but in terms of the introduction of the gene through
migration with subsequent increase in frequency when conditions are favor-
able. The case for spread through migration is especially clear in West Africa
blest of Nigeria (see especially Livingstone3S). Last year I speculated on the
possibility that "the mutations responsible for these hemoglobin types arise
very infrequently but under special circumstances then become widely dis-
seminated. Either the mutation is very rare or the 'special circumstances' are,
geologically speaking, of recent origin otherwise, one would expect the
OCR for page 268
268
PART IV. GENETIC ASPECTS
genes to be much more widely disseminated." Since that time, Livingstone38
has argued that the conditions which favor malaria endemicity are much more
those that accompany the "slash and burn" type of agriculture than those
which charactize a hunting economy. 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 ac-
cc~unted for through relatively recent gene flow and increase with changing
selective pressures, with the inference that mutation is extremely rare. A very
careful scrutiny of all apparent cases of mutation is called for.
In concluding, I should like only to express my appreciation of the occasion
which brings biochemist, clinician, and geneticist together. Under slightly
different circumstances, our gathering might have included the epidemiologist
and anthropologist. I know of no field of inquiry today which better illustrates
the fundamental unity of science.
REFEREN CES
1. Allison, A. C.: Protection afforded by sickle-cell trait against subtertian malarial
infection, Brit. Med. J., ~ (Feb. 6) : 290-294, 1954.
2. Allison, A. C.: Notation for hemoglobin types and genes controlling their syn-
thesis, Science 122: 640-641, 1955.
3. Allison, A. C.: Aspects of polymorphism in man, Cold Spring Harbor Symp. on
4.
Quant. Biol. 20: 239-252, 1955.
Banks, L. O., Scott, R. B., and Simmons, J.: Studies in sickle cell anemia, Am.
Dis. Child. 84: 601-608, 1952.
5. Beet, E. A.: The genetics of the sickle cell trait in a Bantu tribe, Ann. Eug. 14:
279-284, 1949.
6. Bianco, I., Montalenti, G., Silvestroni, E., and Siniscalco, M.: Further data on
genetics of microcythemia or thalassemia minor and Cooley's disease or thal-
assemia major, Ann. Fug. 16: 299 - 315, 1952.
7. Bianco, I., Ceppellini, R., Silvestroni, E., and Siniscalco, M.: Data for the study
of linkage in man. Microcythemia and the Lewis-Secretor characters, Ann.
Human Genet. 19: 81-89, 1954.
8. Bird, G. W. G., and Lehmann, H.: The finding of haemoglobin D disease in a
Sikh, Man 56: 1-3, 1956.
9. Bird, G. W. G., Lehmann, H., and Mourant, A. E.: A third example of haemo-
globin D, Trans. Roy. Soc. Trop. Med. & Hyg. 49: 399-400, 1955.
10" Caminopetros, J.: Recherches sur l'anemie erythroblastique infantile, des peoples
de la Mediteranee orientate, Am. Med. 43: 27-61, 104-125, 1938.
11. Ceppellini, R.: Genetica delle emoglobinopatie. Atti 14° Cong. Soc. It. Ematologia,
Roma, Ottobre, 1955. Suppl. Folia Haematologica, in press.
12. Chernoff, A. I.: The human hemoglobins in health and disease, N. Engl. J. Med.
251: 322-331, 365-374, 416-423, 1955.
OCR for page 269
GENETICS OF ABNORMAL HEMOGLOBINS—NEEL 269
13. Chernoff, A. I., Minnich, V. M., Chongchareonsuk, S., Na-Nakorn, S., and Cher-
noff, R.: Clinical, hematological, and genetic studies of hemoglobin E, J. Lab.
Sz Clin. Med. 44: 780, 1954.
14. Dameshek, W.: Familial Mediterranean target-oval cell syndromes, Am. J. Med.
Sci. 205: 643-660, 1943.
15. Dunn, L. C.: Variations in the segregation ratio as causes of variation of gene
frequency, Acta Genet. et Statist. lMed., 4: 139-147, 1953.
16. Dunn, L. C., and Morgan, A'. C., Jr.: Segregation ratios of mutant alleles from
wild populations of Mus musculus, Am. Nat. 87: 327-329, 1953.
17. Edington, G. M.: The pathology of sickle-cell disease in West Africa, Trans.
RoY. Soc. TroD. Med. & Hop. 49: 253-267. 1955.
, ., .=, ,
18. Edington, G. M., and Lehmann, H.: Expression of the sickle-cell gene in Africa,
Brit. Med. J., Nov. 26, p. 1328, 1955.
1'>. Edington, G. M., Lehmann, H., and Schneider, R. G.: Characterization and
genetics of haemoglobin G. Nature 175: 850, 1955.
20. Gatto, I.: Ricerche sui familiar) di bambini affetti da malattia di Cooley, Soc.
ital. Ped.-sez. Sicilia occid. 14-XII-1947. Ref. medic. infant. 1~: 17 e Rivista di
Clin. Ped., 40: 184, 1942.
21. Gatto, I.: Anemic emolitiche da anomalie ereditarie dell'hb, Acta Genet. NIed. et
Gemell. 5: 427~61, 1956.
22. Huisman, T. H. J., Jonxis, J. H. P., and van der Schaaf, P. C.: Amino-acid com-
position of four different kinds of human hemoglobin, Nature 175: 902, 1955.
23. Irwin, M. R.: Genetics and immunology. In: Gcrzetics in the Twentieth Century,
L. C. Dunn, ea., Macmillan Co., New York, 1951, pp. xi and 634.
24. Itano, PI. A.: Qualitative and quantitative control of adult hemoglobin synthesis
a multiple allele hypothesis, Am. J. Human Genet. 5: 34 45, 1953.
25. Itano, H. A.: Clinical states associated with alterations of the hemoglobin mole-
cule, (The Minot Lecture), Arch. Int. Med. 96: 287-297, 1955.
26. Itano, H. A.: The hemoglobins, Ann. Rev. Biochem. 25: 331 - 348, 1956.
27. Itano, H. A., and Neel, J. V.: A new inherited abnormality of human hemoglobin,
Proc. Nat. Acad. Sci. 36: 613 - 617, 1950.
28. Itano, H. A., Bergren, W. R., and Sturgeon, P.: The abnormal human hemo-
globins, Medicine 35: 121-159, 1956.
29. Kaplan, E., Zuelzer, W. W., and Neel, J. V.: A new inherited abnormality of
hemoglobin and its interaction with sickle cell hemoglobin, Blood 6: 1240-1259,
1951.
30. Kunkel, H. G., and Wallenius, G.: New hemoglobin in normal adult blood,
Science 122: 288, 1955.
31. Lambotte-Legrand? J., and Lambotte-Legrand, C.: L'anemie a hematies falciforme~.
chez l'enfant indigene do gas-Congo, Memoirs Institut Royal Colonial Belge,
v. 19, no. 7, pp. 93, 1951.
3 A.
33.
Lambotte-Legrand, J., and Lambotte-Legrand, C.: Unpublished data.
Lehmann, H.: Human haemoglobins, St. Bartholomew s Hosp. Journal 60: 237-
242, 1956.
34. Lehmann, H.: Haemoglobin and its abnormalities, Practitioner 178: 198 - 214, 1957.
3 5. Lehmann, H., Story, P., and Thein, H.: Haemoglobin E in Burmese, Brit. Med.
J., 1: 54 - 547, 1956.
36. Levin, W. C., Schneider, R. G., Cudd, J. A., and Johnson, R. E.: A family with
homozygous hemoglobin C and sickle cell trait union: a clinical, hematological,
and electrophoretic study, J. Lab. & Clin. Med. 42: 918-919, 1953.
37. Livingstone, F`. B.: Sickling and malaria, Brit. Med. J. 1: 762-763, 1957.
OCR for page 270
270 PART IV. GENETIC ~ SPECTS
38. Livingstone, F. B.: Ph.D. thesis: The explanation of the distribution of the sickle
cell gene in West Africa, with particular reference to Liberia. University of
Michigan, 1957.
42.
39. Luan Eng, L.-I.: Penjelidikan hemoglobin patologik di Indonesia, Thesis, Uni-
versitas Indonesia di Djakarta, 1956.
40. Luan Eng, L., and Giok, O. H.: Homozygous hemoglobin-E disease in Indonesia,
Lancet, Jan. 5, pp. 20-23, 1957.
41. Mackey, J. P., and Vivarelli, F.: Sickle-cell anaemia, Brit. Med. J., ~ (Jan. 30):
276, 1954. (From Dar es Salaam.)
Miller, M. J., Neel, J. V., and Livingstone, F. B.: Distribution of parasites in the
red cells of sickle cell trait carriers infected with Plasmodium falciparum, Tr.
Roy. Soc. Trop. Med. & EIyg. 50: 294 - 296, 1956.
43. Morton, N. E.: The detection and estimation of linkage between the genes for
elliptocytosis and the Rh blood type, Am. J. Human Genet. 3: 80-96, 1956.
44. Motulsky, A. G.: Genetic and haematological significance of haemoglobin II,
Nature 178: 1055—1056, 1956.
45. Mourant, A. E.: Some aspects of the congenital abnormalities of hemoglobin syn-
thesis, Proc. Fifth Int. Congr. Blood Transfusion, Paris, 1955.
46. Neel, J. V.: The clinical detection of the genetic carriers of inherited disease,
Medicine, 26: 115-153, 1947.
47^ Neel, J. V.: The inheritance of sickle cell anemia, Science 110: 64 - 66, 1949.
48. Neel, J. V.: The inheritance of the sickling phenomenon, with particular refer-
ence to sickle cell disease, Blood 6: 389-412, 1951.
49. Neel, J. V.: Data pertaining to the population dynamics of sickle cell disease, Am.
J. Human Genet. 5: 154 - 167, 1953.
50. Neel, J. V.: The genetics of human hemoglobin differences: problems and per-
spectives, Ann. Human Genet. 21: 1-30, 1956.
5 1. Neel, J. NT.: Human hemoglobin types: their epidemiological implications, New
Engl. J. Med. 256: 161 - 171, 1957.
52. Neel, J. V.: The genetic control of hemoglobin synthesis. Proc. Sixth Meeting,
International Soc. of Hematology, in press.
53. Neel, J. V., and Valentine, W. N.: Further studies on the genetics of thalassemia,
Genetics 32: 38-63, 1947.
54. Neel, J. V., Wells, I. C., and Itano. H. A.: Familial differences in the proportion
of abnormal hemoglobin present in the sickle cell trait, I. Clin. Invest. 30: 1120-
1124, 1951.
55. Neel, J. V., Itano, H. A., and Lawrence, J. S.: Two cases of sickle cell disease
presumably due to the combination of the genes responsible for thalassemia and
sickle cell hemoglobin, Blood 8: 43~443, 1953.
56. Neel, J. V., Kaplan, E., and Queller, W. W.: Further studies on hemoglobin C.
I. A description of three additional families segregating for hemoglobin C and
sickle cell hemoglobin, Blood 8: 720734, 1953.
A. Neel, J. V., Hiernaux, J., Linhard, J., Robinson, A. R., Zuelzer, W. W., and Liv-
ingstone, F'. B.: Data on the occurrence of hemoglobin C and other abnormal
hemoglobins in some African populations, Am. J. Human Genet. 8: 138-150,
1956.
5g. Pauling, L., Itano, H. A., Singer, S. J., and Wells, I. C.: Sickle cell anemia, a
molecular disease, Science 110: 543-548, 1949.
59. Powell, W. N., Rodarte, J. G., and Neel, J. V.: The occurrence in a family of
Sicilian ancestry of the traits for both sickling and thalassemia, Blood 5: 887-
897, 1950.
OCR for page 271
GENETICS OF ABNORMAL HEMOGLOBINS—NEEL 271
^ Ranney, H. M., Larson, D. L., and McCormacl<, G. H., Jr.: Some clinical, bio-
chem~cal, and genetic observations on hemoglobin
1277-1284, 1953.
61. Raper, A. 13.: The significance of sicklaemia in Uganda. Proc. Fifth Int. Congr.
Of Blood Transfusion, Paris, 1955.
62. Robinson, A. R., Zuelzer, W. W., Neel, J. V., Lie ingstone, F. B., and Miller,
NI. J.: Two "fast" hemoglobin components in Liberian blood samples, Blood
11: 902-906, 1956.
Sandler, L., and Novitski, E.: Meiotic drive as an evolutionary force, Amer. Nat.
9f: 105-110, 1957.
64. Schwartz, H. C., Spaet, T. H., Zuelzer, W. W., Neel, l. V., Robinson, A. R., and
Kaufman, S. F.: Combinations of hemoglobin G. hemoglobin S. and thalassemia
occurring in one family, Blood 12: 238-250, 1957.
65. Silvestroni, E., and Bianco, I.: Genetic aspects of sickle cell anemia and micro-
drepanocvtic disease, Blood 7: 429~35, 1952.
66. Singer, K.: Hereditary hemolytic disorders associated with abnormal hemo-
globins, Am. J. Med. 15: 633-652, 1955.
67. Singer, K, Chernoff, A. I., and Singer, L.: Studies on abnormal hemoglobins. I.
Their demonstration in sickle cell anemia and other hematologic disorders by
means of alkali denaturation, Blood 6: 413~28, 1951.
68. Singer, E;:., Chernoff, A. I., and Singer, L.: Studies on abnormal hemoglobins. lI.
Their identification by means of the method of fractional denaturation, Blood
6: 429~35, 1951.
69. Singer, K., Kraus, A. P., Singer, L., Rubinstein, H. M., and Goldberg, S. R.:
Studies on abnormal hemoglobins. X. A new syndrome: hemoglobin C-thalas-
semia disease, Blood 9: 1032-1046, 1954.
70. Singer, K., Singer, L., and Goldberg, S. R.: Studies on abnormal hemoglobins. XI.
Sickle cell-thalassemia disease in the Negro. The significance of the S+A+F
and S+A patterns obtained by hemoglobin analysis, Blood 10: 405~15, 1955.
71. Spaet, T. H., Alway, R. PI., and Ward, G.: lIomozygous type "C" hemoglobin,
Pediatrics 1~?: 483~90, 1953.
72. Sturgeon, P., Itano, H. A., and Valentine, W. N.: Chronic hemolytic anemia
associated with thalassemia and sickling traits, Blood 7: 350 - 357, 1952.
73. Thorup, O. A., Itano, H. A., Wheby, M., and Leavell, B. S.: Hemoglobin J.
Science 123: 889—890, 1956.
74. Torbert, J. V., Jr., and Smith, E. W.: Simultaneous inheritance of three adult
hemoglobins determined at two genetic loci, Clin. Res. Proc. 5: 138, 1957.
75. Valentine, W. N., and Neel, I. V.: Hematologic and genetic study of the trans-
mission of thalassemia, Arch. Int. Med. 74: 185—196, 1944.
76. Vandepitte, J.: Aspects quantitatifs et genetiques de l'anomalie falciforme a
Leopoldville. Proc. Fifth Int. Confer. Blood Transfusion, Paris, 1955.
77. Vandepitte, J. M., Zuelzer, W. W., Neel, J. V., and Colaert, J.: Evidence con-
cerning the inadequacy of mutation as an explanation of the frequency of the
sickle cell gene in the Belgian Congo, Blood 10: 341-350, 1955.
78. Wells, I. C., and Itano, If. A.: Ratio of sickle-cell anemia hemoglobin to normal
hemoglobin in sicklemics, l. Biol. Chem. 188: 65-74, 1951.
79. White, J. C., and Beaven, G. H.: A review of the varieties of human haemoglobin
in health and disease, J. Clin. Path. 7: 175 - 200, 1954.
80. Zuelzer, W. W., Neel' J. V., and Robinson, A. R.: Abnormal hemoglobins. In:
Progress in Hematology, L. M. Tocantins, ea., pp. 91-137. Grune and Stratton,
New Yor}:, 1956.
C, J. Clin. Invest. 32:
Representative terms from entire chapter:
abnormal hemoglobins
