- Email: [email protected]
Molecular genetics of alpha thalassemia
MedicaiHypoIhcm KJ Longman
(1989) 30,75-79 1989
Group UKLtd
Molecular
Genetics
of Alpha
Thalassemia
E. C. IGBOKWE Biomedical
Research Program,
Southern
University,
Shreveport,
Louisiana 71107, USA
Abstract - Linked duplicte genes in Chromosome 16 condition the production not only of alpha-globin chains in the Hemoglobin A (HbA) molecule, but also of the varied forms of alpha thalassemia in human subjects. Null allelism, not gene deletion, exists at these gene loci. Two codominant alleles occur at each locus; these are characterized as Gb and Ob at one locus, and as Gc and Oc at the second locus. Gb and Gc are genetically active alleles, and either conditions the production of alpha-globin chain. Ob and Oc are null or genetically inert alleles, and neither conditions the production of alpha-globin chain, Gb and Gc are additive in the expression of disease genotype. The number of alpha-globin chains in the HbA molecule, and the absence as well as the varied forms of alpha thalassemia are inherited quantitatively as follows: four alpha-globin chains and the absence of alpha thalassemia result from GbGbGcGc; either GbGbGcOc or GbObGcGc yields three alpha-globin chains and asymptomatic alpha thalassemia minor; any one of three genotypes, GbGbOcOc, GbObGcOc or ObObGcGc, yields two alpha-globin chains and mild alpha thalassemia minor; either GbObOcOc or ObObGcOc yields one alphaglobin chain and severe alpha thalassemia minor; ObObOcOc produces no alpha-globin chain and the fatal alpha thalassemia major. The inheritance of any combination of active and null alleles, and of the associated forms of alpha thalassemia, is deducible from the alpha-globin as well as the disease phenotypes and/or genotypes of parental subjects.
Introduction
The classes of alpha thalassemia have been reviewed amply in various literature (1, 2, 3. 4). Alpha thalassemia results from the absence of one or more alpha-globin chains in the HbA molecule. Two classes of this disorder- are presently recognized, and are characterized as alphathal-1 and alpha-thal-2 respectively. Several clinical forms that differ from one another in severity have been described for each class. Two forms, thalassemia major and thalassemia minor,
have been described for alpha-thal-1. Thalassemia major results in intrauterine death whereas thalassemia minor, classified as either severe or mild, is typically characterized by tissue anoxia, impaired erythropoiesis and hemolytic anemia. Two forms of thalassemia minor have been described for alpha-thal-2; one form is asymptomatic whereas the other is mildly symptomatic and resembles the mild form of alpha-thal-1 minor. From a molecular perspective, alpha thalas75
76
MEDICAL HYPOTHESES
semia major results from the absence of alphaglobin chains in the HbA molecule. The severe form of alpha-thal-1 minor results from the presence of only one alpha-globin chain in the HbA molecule. The mild forms of alpha-thal-1 minor and alpha-thal-2 result from the presence of only two alpha globin chains in the HbA molecule. The .asymptomatic form of alpha-thal-2 results from the presence of only three alpha-globin chains in the HbA molecule. The existing genetic model of alpha thalassemia postulates alpha-globin gene deletion as the basis for the absence or reduced production of alpha-globin chains in the HbA molecule (3, 4, 5, 6). An alternative model is proposed here, and postulates a triad of allelism (codominant, active, null) at linked duplicate gene loci as the basis for the inheritance of alpha-globin chains and of the associated forms of alpha thalassemia. Existing genetic model
The existing genetic model for alpha thalassemia is presented in various literature (3, 5, 6). Production of alpha-globin chains in the HbA molecule is controlled by two alpha-globin genes in Chromosome 16. The allele that conditions the production of alpha-globin chain may be
Alpha-globin Gene Locus
Gl.
-GI
G2.
.G
present at either gene locus. However, a deletion of either locus may exist and will result in nonproduction of alpha-globin chain. This model infers homozygosity when either corresponding alpha-globin alleles or corresponding deletions occur at a given locus. The presence of a single alpha-globin allele with a corresponding gene deletion at a given locus is taken to represent heterozygosity. Homozygosity for gene deletion at both alphaglobin gene loci results in the total absence of alpha-globin chains in the HbA molecule and in alpha-thalassemia major. Homozygosity for gene deletion at one locus, plus heterozygosity for gene deletion at the second locus, results in the production of only one alpha-globin chain in the HbA molecule and in the severe form of alphathal-1 minor. Heterozygosity for gene deletion at both loci results in the production of only two alpha-globin chains in the HbA molecule and in the mild form of alpha-thal-1 minor which clinically resembles the symptomatic form of alphathal-2 minor. Homozygosity for gene deletion at one locus, plus homozygosity for the alphaglobin allele at the second locus, results in the production of only two alpha-globin chains in the HbA molecule and in the symptomatic form of
GI.
a~1
Gz.
,<2
=l
or
OF
Alpha-globin
1::
Gene deletion
“:
Phenotype
Alpha-globin
G,G,G2G7 :I :I: * :i:
4 alpha-globin
chains/HbA
None
0 alpha-globin
chain/HbA
Alpha-thal
I alpha-globin
chain/HbA
Alpha-thal-I form)
minor
(severe
2 alpha-globin
chains/HbA
Alpha-thal-1 form)
minor
(mild
2 alpha-globin
chains/HbA
Alpha-thal-2 (symptomatic
minor form)
,122
Phenotype
Disease
Alpha-globin/Disease Genotype
major
:‘,:‘;,G,:”
2
_
G
i/i
ix
:ii
,122
G,:‘:,G?” 2 G,G,01*2 “,+,GIG2 Gl”‘lG2G2
3 alpha-glopbin
chains/HbA
$$~~tt~$,$~~~~
GIGIG2”2 Fig. 1 Alignments alpha thalassemia.
of alpha-globin
alleles and gene deletions
in Chromosome
16 as presented in the existing
genetic
model for
MOLECULAR
77
GENETICS OF ALPHA THALASSEMIA
for gene alpha-thal-2 minor. Heterozygosity deletion at one locus, plus homozygosity for the alpha-globin allele at the second locus, results in the production of only three alpha-globin chains in the HbA molecule and in the asymptomatic form of alpha-thal-2 minor. The alignments of alpha-globin alleles and gene deletions as presented in the existing genetic model are shown in Figure 1. Proposed genetic model
Like the existing genetic model, the proposed model is based on duplicate linked genes in chromosome 16. Unlike the existing model, the proposed model precludes gene deletion. In the proposed model, each alpha-globin gene locus contains two codominant alleles; one allele is genetically active’ whereas the other is null or genetically inert. The active allele conditions production of alpha-globin chain whereas the null allele conditions non-production of alphaglobin chain. Thus, one locus contains the alleles Gb and Ob representing the active and null alleles respectively. The second locus contains the alleles Gc and Oc representing the active and null alleles respectively. For any given alpha-globin genotype, the alleles at both alpha-globin loci are additive in determining the number of alpha-globin chains in the HbA molecule and the varied clinical
Alpha-globin/Disease
forms of alpha thalassemia. A genotype comprising four active alleles results in four alpha-globin chains in the HbA molecule and in the absence of alpha thalassemia. Homozygosity for the null allele at both loci results in the total absence of alpha-globin chains in the HbA molecule and in alpha thalassemia major. Homozygosity for the null allele at one locus, plus heterozygosity for the active allele at the second locus, results in only one alpha-globin chain in the HbA molecule and in severe alpha thalassemia minor. Heterozygosity for the null allele at both loci results in only two alpha-globin chains in the HbA molecule and in mild alpha thalassemia minor. SimilarIy, homozygosity for the null allele at one locus, plus homozygosity for the active allele at the second locus, results in only two alpha-globin chains in the HbA molecule and in mild alpha thalassemia minor. Heterozygosity for the null allele at one locus, plus homozygosity for the active allele at the second locus results in only three alpha-globin chains in the HbA molecule and in asymptomatic alpha thalassemia minor. The alignments of active and null alleles in the proposed genetic model are presented in Figure 2. The added advantage of the proposed genetic model is that the probability for the inheritance of any genotypic combination of active and null alleles and of the associated disease phenotype
Alpha-globin Gene Locus
Gb,‘Ob
Alpha-globin Gene Locus
Gc/Oc
Alpha-globin Phenotype
Disease
4 alpha-globin
None
Phenotype
Genotype GbGbGcGc ObObOcOc
alpha-globin
chain/HbA chain/HbA
Alpha-thal
major
ObObGcOc
) )
GbObGcOc ObObGcGc GbGbOcOc
) ) )
2 alpha-globin
chains/HbA
Mild alpha-thal
GbGbGcOc
)
3 alpha-globin
chains/HbA
Asymptomatic minor
GbObOcOc
1 alpha-globin
chain/HbA
Severe
Fig. 2 Alignments of active and null alpha-globin alpha thalassemia.
alleles in Chromosome
alpha-thal
16 as presented
minor
minor alpha-thal
in the proposed
genetic
model
for
78
MEDICAL HYPOTHESES
Table
Modes and probabilities of quantitative inheritance of alpha thalassemia as presented in the proposed
genetic
model
Example
I:
Both parents
Parents: Gametes: Offspring:
GGGO CC, GO GGGG Normal
Probability:
l/4 (25%)
Example
11:
One parent GOGO)
Parents: Gametes: Offspring:
GGGG GG GGOO Asymptomatic alpha thal. minor
Probability:
l/l (100%)
Example
III:
Parents: Gametes: Offspring:
Probability:
One parent thalassemia
have asymptomatic X
is normal x
alpha
thalassemia
minor
(GGGO)
GGGO GG, GO
GGGO Asymptomatic alpha thal. minor
GGOO Mild alpha thal. minor
2/4 (50%)
l/4 (25%)
(GGGG) GGOO GO
whereas or Or Or
or
the other GOGO GG, GO, GGGG Normal
x GGOO GO GGOO Mild alpha thal. minor
l/2 (50%)
l/2 (50%)
or Or
GOGO GG, GO.
Or
GGGG
is deducible from the disease phenotypes/ genotypes of parental subjects. The active alleles, and conversely the null alleles, regardless of the locus with which they are associated, behave similarly both quantitatively and additively in the inheritance of the varied forms of alpha thalassemia. The modes and probabilities of inheritance of different genotypes/phenotypes of alpha thalassemia are presented in Table 1. Discussion
The existing genetic model for alpha thalassemia is beset with conceptual and semantic difficulties. First, the application of the term heterozygous to the alpha-globin genotype containing one alpha-globin allele and a corresponding deletion of this allele at the same locus is inappropriate. If anything, a fitting term for such a genotypic configuration should be “hemizygous”. Second, the existing model attributes alpha thalassemia major to a double deletion affecting both alphaglobin gene loci. This implies a non-existent
minor
(GGOO
or
GGGO Asymptomatic alpha thal. minor
GGOO Mild alpha thal. minor
214 (5W
l/4 (25%)
minor
(GGGO)
whereas
the other
has mild alpha
00 GGGO Asymptomatic alpha thal. minor
GGOO Mild alpha thal. minor
116
216
216
116
(16.7%)
(33.3%)
(33.3%)
(16.7%)
Normal
Or
thalassemia
00
l/4 (25%)
has asymptomatic alpha thalassemia minor (GGOO or GOGO)
GGGO GG, GO GGGO Asymptomatic alpha thal. minor
has mild alpha
GO00 Severe alpha thal. minor
genotype for one of the disease phenotypes. Third, classification of this blood dyscrasia as alpha-thal-1 and alpha-thal-2 is considered inappropriate particularly for alpha-thal-1 minor (mild form) and alpha-thal-2 minor (symptomatic form) both of which share not only the same number of alpha-globin alleles genotypitally, but also correspondent clinical picture. Given that alpha-globin alleles are additive in the expression of disease genotype, the source of allele with respect to gene loci is considered immaterial in the determination of disease genotype and/or phenotype. Thus, classification of this disorder as alpha-thal-1 and alpha-thal-2 is superfluous. In the proposed model, a simpler classification of alpha thalassemia is presented. This classification reflects not only the additive nature of the active alleles in the expression of disease genotype, but also the quantitative inheritance as well as the clinical variants of alpha thalassemia. The classes as presented in the proposed model are namely alpha thalassemia major, severe alpha
MOLECULAR
79
GENETICS OF ALPHA THALASSEMIA
thalassemia minor, mild alpha thalassemia alpha thalassemia minor, and asymptomatic minor. Alpha-thal-1 minor and alpha-thal-2 minor as presented in the existing model are considered by the proposed model as representing the same disease phenotype, namely mild alpha thalassemia minor; unlike the existing model, the proposed model considers this disease phenotype as accruing from any one of three disease genotypes (Fig. 2). The proposed model offers null allelism as the alternative to gene deletion as presented in the existing model. The alternate to the null allele is the active allele which conditions production of alpha-globin chain. Thus, each alpha-globin or the associated disease genotype may be described appropriately as heterozygous if only one of either null or active allele is present. A parallel to the concept of codominant, active or null allelism as presented in the proposed model is found in the model for the inheritance of ABO blood group antigens. Three multiple, codominant alleles (A, B, 0) are associated with the gene locus for the ABO blood group antigens. Either A or B. representing genetically active alleles, conditions production of a blood group antigen, whereas 0, representing a null or genetically inert allele, conditions non-production of blood group antigen.
null allele conditions non-production of alphaglobin chain. The active alleles at both loci, and conversely the null alleles, are additive in the determination of the number of alpha-globin chains in the HbA molecule, and in the expression of disease genotype. Only four phenotypes of alpha thalassemia are recognized in the alternative model as proposed here. Differing from one another in clinical presentation, the four phenotypes are namely alpha thalassemia major, severe alpha thalassemia minor, mild alpha thalassemia minor and asymptomatic alpha thalassemia minor. Alpha thalassemia major is characterized by the absence of alpha-globin chains in the HbA molecule whereas severe alpha thalassemia minor, mild alpha thalassemia minor and asymptomatic alpha thalassemia minor are characterized by the presence of one alpha-globin chain, two alpha-globin chains and three alpha-globin chains in the HbA molecule respectively. The inheritance of any combination combination of active and null alleles, and of the associated forms of alpha thalassemia, is deducible from the alpha-globin as well as the disease phenotypes and/or genotypes of parental subjects. Acknowledgements I
Conclusion
An alternative model is proposed for the molecular genetics of alpha thalassemia. This model is based on linked duplicate genes present in Chromosome 16 and conditioning the production of alpha-globin chains in the HbA molecule. The presence of gene deletion at the linked gene loci, as offered in the existing genetic model for alpha thalassemia, is rejected. Instead, null allelism and active allelism at these gene loci are proposed. Thus, the alternative genetic model as proposed here favors the existence of two codominant alleles, one genetically active and the other genetically null or inert, at each gene locus. The alleles are designed as Gb and Ob at one locus, and as Gc and Oc at the second locus; Gb and Gc are active alleles whereas Ob and Oc are inert alleles at their respective loci. The active allele conditions production of alpha-globin chain whereas the
am grateful to Mrs. Barbara Bobo for secretarial assistance, and to Mrs. Joyce Buggs and Mrs. Regina Robinson for reading this manuscript.
References 1. Weatherall D J. Other anemias resulting from defective red cell maturation: The Thalassemias. In: Oxford Textbook of Medicine. 1st Ed., Vol. 2, ed. by Weatherall D J. Ledingham J C, Warrell D A, Oxford University Press, Oxford. p. 19.40. 1983. 2. Nienhaus A W. The Thalassemias. In: Textbook of Medicine, 16th Ed.. ed. by Wyngaarden J B, Smith L H, W.B. Saunders Company. Philadelphia, p. 882. 1982. .3 Thompson J S. Thompson M W. Genetics in Medicine. 3rd Ed., W.B. Saunders Company, Philadelphia. p, 109. 19x0. 4. Weatherall D 1. Clegg J B. The Thalassemia Syndromes, 3rd Ed.. Blackwell Scientific Publications. Oxford, 1081. 5. Weatherall D J. Clegg J B. Recent developments in the molecular genetics of human hemoglobin. Cell 16: 467. 1979. 6. Weatherall D J. The molecular genetics of haemoglobin: The Thalassemias. In: Recent Advances in Haematology. ed. Hoffbrand A V. Churchill Livingstone. Edinburgh, 1982.
(1989) 30,75-79 1989
Group UKLtd
Molecular
Genetics
of Alpha
Thalassemia
E. C. IGBOKWE Biomedical
Research Program,
Southern
University,
Shreveport,
Louisiana 71107, USA
Abstract - Linked duplicte genes in Chromosome 16 condition the production not only of alpha-globin chains in the Hemoglobin A (HbA) molecule, but also of the varied forms of alpha thalassemia in human subjects. Null allelism, not gene deletion, exists at these gene loci. Two codominant alleles occur at each locus; these are characterized as Gb and Ob at one locus, and as Gc and Oc at the second locus. Gb and Gc are genetically active alleles, and either conditions the production of alpha-globin chain. Ob and Oc are null or genetically inert alleles, and neither conditions the production of alpha-globin chain, Gb and Gc are additive in the expression of disease genotype. The number of alpha-globin chains in the HbA molecule, and the absence as well as the varied forms of alpha thalassemia are inherited quantitatively as follows: four alpha-globin chains and the absence of alpha thalassemia result from GbGbGcGc; either GbGbGcOc or GbObGcGc yields three alpha-globin chains and asymptomatic alpha thalassemia minor; any one of three genotypes, GbGbOcOc, GbObGcOc or ObObGcGc, yields two alpha-globin chains and mild alpha thalassemia minor; either GbObOcOc or ObObGcOc yields one alphaglobin chain and severe alpha thalassemia minor; ObObOcOc produces no alpha-globin chain and the fatal alpha thalassemia major. The inheritance of any combination of active and null alleles, and of the associated forms of alpha thalassemia, is deducible from the alpha-globin as well as the disease phenotypes and/or genotypes of parental subjects.
Introduction
The classes of alpha thalassemia have been reviewed amply in various literature (1, 2, 3. 4). Alpha thalassemia results from the absence of one or more alpha-globin chains in the HbA molecule. Two classes of this disorder- are presently recognized, and are characterized as alphathal-1 and alpha-thal-2 respectively. Several clinical forms that differ from one another in severity have been described for each class. Two forms, thalassemia major and thalassemia minor,
have been described for alpha-thal-1. Thalassemia major results in intrauterine death whereas thalassemia minor, classified as either severe or mild, is typically characterized by tissue anoxia, impaired erythropoiesis and hemolytic anemia. Two forms of thalassemia minor have been described for alpha-thal-2; one form is asymptomatic whereas the other is mildly symptomatic and resembles the mild form of alpha-thal-1 minor. From a molecular perspective, alpha thalas75
76
MEDICAL HYPOTHESES
semia major results from the absence of alphaglobin chains in the HbA molecule. The severe form of alpha-thal-1 minor results from the presence of only one alpha-globin chain in the HbA molecule. The mild forms of alpha-thal-1 minor and alpha-thal-2 result from the presence of only two alpha globin chains in the HbA molecule. The .asymptomatic form of alpha-thal-2 results from the presence of only three alpha-globin chains in the HbA molecule. The existing genetic model of alpha thalassemia postulates alpha-globin gene deletion as the basis for the absence or reduced production of alpha-globin chains in the HbA molecule (3, 4, 5, 6). An alternative model is proposed here, and postulates a triad of allelism (codominant, active, null) at linked duplicate gene loci as the basis for the inheritance of alpha-globin chains and of the associated forms of alpha thalassemia. Existing genetic model
The existing genetic model for alpha thalassemia is presented in various literature (3, 5, 6). Production of alpha-globin chains in the HbA molecule is controlled by two alpha-globin genes in Chromosome 16. The allele that conditions the production of alpha-globin chain may be
Alpha-globin Gene Locus
Gl.
-GI
G2.
.G
present at either gene locus. However, a deletion of either locus may exist and will result in nonproduction of alpha-globin chain. This model infers homozygosity when either corresponding alpha-globin alleles or corresponding deletions occur at a given locus. The presence of a single alpha-globin allele with a corresponding gene deletion at a given locus is taken to represent heterozygosity. Homozygosity for gene deletion at both alphaglobin gene loci results in the total absence of alpha-globin chains in the HbA molecule and in alpha-thalassemia major. Homozygosity for gene deletion at one locus, plus heterozygosity for gene deletion at the second locus, results in the production of only one alpha-globin chain in the HbA molecule and in the severe form of alphathal-1 minor. Heterozygosity for gene deletion at both loci results in the production of only two alpha-globin chains in the HbA molecule and in the mild form of alpha-thal-1 minor which clinically resembles the symptomatic form of alphathal-2 minor. Homozygosity for gene deletion at one locus, plus homozygosity for the alphaglobin allele at the second locus, results in the production of only two alpha-globin chains in the HbA molecule and in the symptomatic form of
GI.
a~1
Gz.
,<2
=l
or
OF
Alpha-globin
1::
Gene deletion
“:
Phenotype
Alpha-globin
G,G,G2G7 :I :I: * :i:
4 alpha-globin
chains/HbA
None
0 alpha-globin
chain/HbA
Alpha-thal
I alpha-globin
chain/HbA
Alpha-thal-I form)
minor
(severe
2 alpha-globin
chains/HbA
Alpha-thal-1 form)
minor
(mild
2 alpha-globin
chains/HbA
Alpha-thal-2 (symptomatic
minor form)
,122
Phenotype
Disease
Alpha-globin/Disease Genotype
major
:‘,:‘;,G,:”
2
_
G
i/i
ix
:ii
,122
G,:‘:,G?” 2 G,G,01*2 “,+,GIG2 Gl”‘lG2G2
3 alpha-glopbin
chains/HbA
$$~~tt~$,$~~~~
GIGIG2”2 Fig. 1 Alignments alpha thalassemia.
of alpha-globin
alleles and gene deletions
in Chromosome
16 as presented in the existing
genetic
model for
MOLECULAR
77
GENETICS OF ALPHA THALASSEMIA
for gene alpha-thal-2 minor. Heterozygosity deletion at one locus, plus homozygosity for the alpha-globin allele at the second locus, results in the production of only three alpha-globin chains in the HbA molecule and in the asymptomatic form of alpha-thal-2 minor. The alignments of alpha-globin alleles and gene deletions as presented in the existing genetic model are shown in Figure 1. Proposed genetic model
Like the existing genetic model, the proposed model is based on duplicate linked genes in chromosome 16. Unlike the existing model, the proposed model precludes gene deletion. In the proposed model, each alpha-globin gene locus contains two codominant alleles; one allele is genetically active’ whereas the other is null or genetically inert. The active allele conditions production of alpha-globin chain whereas the null allele conditions non-production of alphaglobin chain. Thus, one locus contains the alleles Gb and Ob representing the active and null alleles respectively. The second locus contains the alleles Gc and Oc representing the active and null alleles respectively. For any given alpha-globin genotype, the alleles at both alpha-globin loci are additive in determining the number of alpha-globin chains in the HbA molecule and the varied clinical
Alpha-globin/Disease
forms of alpha thalassemia. A genotype comprising four active alleles results in four alpha-globin chains in the HbA molecule and in the absence of alpha thalassemia. Homozygosity for the null allele at both loci results in the total absence of alpha-globin chains in the HbA molecule and in alpha thalassemia major. Homozygosity for the null allele at one locus, plus heterozygosity for the active allele at the second locus, results in only one alpha-globin chain in the HbA molecule and in severe alpha thalassemia minor. Heterozygosity for the null allele at both loci results in only two alpha-globin chains in the HbA molecule and in mild alpha thalassemia minor. SimilarIy, homozygosity for the null allele at one locus, plus homozygosity for the active allele at the second locus, results in only two alpha-globin chains in the HbA molecule and in mild alpha thalassemia minor. Heterozygosity for the null allele at one locus, plus homozygosity for the active allele at the second locus results in only three alpha-globin chains in the HbA molecule and in asymptomatic alpha thalassemia minor. The alignments of active and null alleles in the proposed genetic model are presented in Figure 2. The added advantage of the proposed genetic model is that the probability for the inheritance of any genotypic combination of active and null alleles and of the associated disease phenotype
Alpha-globin Gene Locus
Gb,‘Ob
Alpha-globin Gene Locus
Gc/Oc
Alpha-globin Phenotype
Disease
4 alpha-globin
None
Phenotype
Genotype GbGbGcGc ObObOcOc
alpha-globin
chain/HbA chain/HbA
Alpha-thal
major
ObObGcOc
) )
GbObGcOc ObObGcGc GbGbOcOc
) ) )
2 alpha-globin
chains/HbA
Mild alpha-thal
GbGbGcOc
)
3 alpha-globin
chains/HbA
Asymptomatic minor
GbObOcOc
1 alpha-globin
chain/HbA
Severe
Fig. 2 Alignments of active and null alpha-globin alpha thalassemia.
alleles in Chromosome
alpha-thal
16 as presented
minor
minor alpha-thal
in the proposed
genetic
model
for
78
MEDICAL HYPOTHESES
Table
Modes and probabilities of quantitative inheritance of alpha thalassemia as presented in the proposed
genetic
model
Example
I:
Both parents
Parents: Gametes: Offspring:
GGGO CC, GO GGGG Normal
Probability:
l/4 (25%)
Example
11:
One parent GOGO)
Parents: Gametes: Offspring:
GGGG GG GGOO Asymptomatic alpha thal. minor
Probability:
l/l (100%)
Example
III:
Parents: Gametes: Offspring:
Probability:
One parent thalassemia
have asymptomatic X
is normal x
alpha
thalassemia
minor
(GGGO)
GGGO GG, GO
GGGO Asymptomatic alpha thal. minor
GGOO Mild alpha thal. minor
2/4 (50%)
l/4 (25%)
(GGGG) GGOO GO
whereas or Or Or
or
the other GOGO GG, GO, GGGG Normal
x GGOO GO GGOO Mild alpha thal. minor
l/2 (50%)
l/2 (50%)
or Or
GOGO GG, GO.
Or
GGGG
is deducible from the disease phenotypes/ genotypes of parental subjects. The active alleles, and conversely the null alleles, regardless of the locus with which they are associated, behave similarly both quantitatively and additively in the inheritance of the varied forms of alpha thalassemia. The modes and probabilities of inheritance of different genotypes/phenotypes of alpha thalassemia are presented in Table 1. Discussion
The existing genetic model for alpha thalassemia is beset with conceptual and semantic difficulties. First, the application of the term heterozygous to the alpha-globin genotype containing one alpha-globin allele and a corresponding deletion of this allele at the same locus is inappropriate. If anything, a fitting term for such a genotypic configuration should be “hemizygous”. Second, the existing model attributes alpha thalassemia major to a double deletion affecting both alphaglobin gene loci. This implies a non-existent
minor
(GGOO
or
GGGO Asymptomatic alpha thal. minor
GGOO Mild alpha thal. minor
214 (5W
l/4 (25%)
minor
(GGGO)
whereas
the other
has mild alpha
00 GGGO Asymptomatic alpha thal. minor
GGOO Mild alpha thal. minor
116
216
216
116
(16.7%)
(33.3%)
(33.3%)
(16.7%)
Normal
Or
thalassemia
00
l/4 (25%)
has asymptomatic alpha thalassemia minor (GGOO or GOGO)
GGGO GG, GO GGGO Asymptomatic alpha thal. minor
has mild alpha
GO00 Severe alpha thal. minor
genotype for one of the disease phenotypes. Third, classification of this blood dyscrasia as alpha-thal-1 and alpha-thal-2 is considered inappropriate particularly for alpha-thal-1 minor (mild form) and alpha-thal-2 minor (symptomatic form) both of which share not only the same number of alpha-globin alleles genotypitally, but also correspondent clinical picture. Given that alpha-globin alleles are additive in the expression of disease genotype, the source of allele with respect to gene loci is considered immaterial in the determination of disease genotype and/or phenotype. Thus, classification of this disorder as alpha-thal-1 and alpha-thal-2 is superfluous. In the proposed model, a simpler classification of alpha thalassemia is presented. This classification reflects not only the additive nature of the active alleles in the expression of disease genotype, but also the quantitative inheritance as well as the clinical variants of alpha thalassemia. The classes as presented in the proposed model are namely alpha thalassemia major, severe alpha
MOLECULAR
79
GENETICS OF ALPHA THALASSEMIA
thalassemia minor, mild alpha thalassemia alpha thalassemia minor, and asymptomatic minor. Alpha-thal-1 minor and alpha-thal-2 minor as presented in the existing model are considered by the proposed model as representing the same disease phenotype, namely mild alpha thalassemia minor; unlike the existing model, the proposed model considers this disease phenotype as accruing from any one of three disease genotypes (Fig. 2). The proposed model offers null allelism as the alternative to gene deletion as presented in the existing model. The alternate to the null allele is the active allele which conditions production of alpha-globin chain. Thus, each alpha-globin or the associated disease genotype may be described appropriately as heterozygous if only one of either null or active allele is present. A parallel to the concept of codominant, active or null allelism as presented in the proposed model is found in the model for the inheritance of ABO blood group antigens. Three multiple, codominant alleles (A, B, 0) are associated with the gene locus for the ABO blood group antigens. Either A or B. representing genetically active alleles, conditions production of a blood group antigen, whereas 0, representing a null or genetically inert allele, conditions non-production of blood group antigen.
null allele conditions non-production of alphaglobin chain. The active alleles at both loci, and conversely the null alleles, are additive in the determination of the number of alpha-globin chains in the HbA molecule, and in the expression of disease genotype. Only four phenotypes of alpha thalassemia are recognized in the alternative model as proposed here. Differing from one another in clinical presentation, the four phenotypes are namely alpha thalassemia major, severe alpha thalassemia minor, mild alpha thalassemia minor and asymptomatic alpha thalassemia minor. Alpha thalassemia major is characterized by the absence of alpha-globin chains in the HbA molecule whereas severe alpha thalassemia minor, mild alpha thalassemia minor and asymptomatic alpha thalassemia minor are characterized by the presence of one alpha-globin chain, two alpha-globin chains and three alpha-globin chains in the HbA molecule respectively. The inheritance of any combination combination of active and null alleles, and of the associated forms of alpha thalassemia, is deducible from the alpha-globin as well as the disease phenotypes and/or genotypes of parental subjects. Acknowledgements I
Conclusion
An alternative model is proposed for the molecular genetics of alpha thalassemia. This model is based on linked duplicate genes present in Chromosome 16 and conditioning the production of alpha-globin chains in the HbA molecule. The presence of gene deletion at the linked gene loci, as offered in the existing genetic model for alpha thalassemia, is rejected. Instead, null allelism and active allelism at these gene loci are proposed. Thus, the alternative genetic model as proposed here favors the existence of two codominant alleles, one genetically active and the other genetically null or inert, at each gene locus. The alleles are designed as Gb and Ob at one locus, and as Gc and Oc at the second locus; Gb and Gc are active alleles whereas Ob and Oc are inert alleles at their respective loci. The active allele conditions production of alpha-globin chain whereas the
am grateful to Mrs. Barbara Bobo for secretarial assistance, and to Mrs. Joyce Buggs and Mrs. Regina Robinson for reading this manuscript.
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