Multiple alleles - ABO blood group, Rh Factor, Erythroblastosis foetalis, Problems

Although individual humans (and all diploid organisms) can only have two alleles for a given gene, multiple alleles may exist at the population level.
“Three or more kinds of gene which occupy the same locus are referred to as multiple alleles.”

1. MULTIPLE ALLELES
1
UNIT II (A): MULTIPLE ALLELES

GENE
 A gene is the basic physical and functional unit of heredity that controls a particular
trait of an organism.
ALLELE
 An Allele is an alternative form of a same gene, located on same locus on the
homologous chromosomes.
 Alleles were first defined by Gregor Mendel in the law of segregation.

NOTE:
 Most genes have two alleles, a dominant allele and a recessive allele. For example: tall
(dominant) and dwarf (recessive).
 If an organism is heterozygous for that trait (possesses one of each allele), then usually
the dominant trait is expressed. A recessive allele is only expressed if an organism is
homozygous for that trait (possesses two recessive alleles).
 Although individual humans (and all diploid organisms) can only have two alleles for a
given gene, multiple alleles may exist at the population level.
2.1 MULTIPLE ALLELES
 According to Altenburg, “Three or more kinds of gene which occupy the same locus are
referred to as multiple alleles.”
 Multiple alleles are defined as three or more alternative form of a same gene, located
on same locus on the homologous chromosomes, coding for certain characteristic in
a population.
 A gene controlled by more than two alleles and following Non-Mendelian pattern of
inheritance and is described as MULTIPLE ALLELISM.
Examples;
1. ABO blood groups
2. Rh factor in Human
3. Coat Colour in Rabbit
4. Eye color in Drosophila

2.2 ABO BLOOD GROUPS
 ABO blood group in Human was discovered by LANDSTEINER in 1901.
 The ABO system is characterized by the presence or absence of antigens on the surface
of Red Blood Cells.
 Individuals will naturally develop antibodies against the ABO antigens they do not
have.
 For example, individuals with blood group A will have anti-B antibodies, and
individuals with blood group O will have both anti-A and anti-B.








RBC Surface
proteins (Ag)
Plasma
Antibody (Ab)
Blood
Type
A b A
B a B
AB -- AB
-- a & b O

2. MULTIPLE ALLELES
2
 The ABO phenotype of any individual is ascertained by mixing a blood sample with
antiserum containing type A or type B antibodies. If the antigen is present on the
surface of Red Blood Cells of the person, then it will react with the corresponding
antibody and cause clumping or agglutination of the Red Blood Cells.

GENETICS OF ABO BLOOD SYSTEM
 The ABO blood type is inherited in an Autosomal Co-Dominant fashion.
 The ABO locus is located on chromosome 9 at 9q34.1-q34.2 consisting 18 kb of
genomic DNA (Exon 7).
 The A and B alleles differ from each other by seven nucleotide substitutions
 The gene controlling ABO blood type is labeled as I.
 The alleles are designated as I
A
, I
B
and I
O
(or i).
Where, I → Isoagglutinogen (antigen)
I
A
→ Allele for A antigen
I
B
→ Allele for B antigen
I
O
→ Allele for o antigen
 Dominance Hierarchy among alleles; I
A =
I
B
> I
O

i.e., Alleles I
A
& I
B
are dominant over I
O

Alleles I
A
& I
B
are Co-dominant

Genotype Antigen
on RBC
Blood
type
I
A
I
A
/ I
A
I
O
A A
I
B
I
B
/ I
B
I
O
B B
I
A
I
B
A & B AB
I
O
I
O
-- O

 Further, studies suggest that I
A
allele may occur in at least FOUR allelic forms;
I
A1
,
IA2
, I
A3
& I
A4

 Thus, Dominance Hierarchy among 6 alleles; I
A
I
A1
>
IA2
> I
A3
> I
A4
]
=
I
B
> I
O


Note:
Recent data reports over 80 ABO alleles.

 The blood groups are defined by the presence of specific carbohydrate sugars
[oligosaccharide chains] on the surface of red blood cells.
 The specificity of A and B antigens are based on the terminal sugars of carbohydrate
group [i.e., precursor molecule - H antigen]
 The H locus is located on chromosome 19 at 19q13.3 (>5 kb of genomic DNA, three
exons), and it encodes a fucosyltransferase that produces the H antigen on RBCs.
 H-antigen consists of 3 sugar molecules; galactose (Gal), N-acetylglucosamine (GlcNAc)
and fucose (Fuc)
 I
A
and I
B
alleles each encode a specific glycosyl-transferring enzyme, which catalyzes
the final step in the synthesis of the A and B antigen.
 The I
A
allele encodes a glycosyltransferase (i.e., N-acetylgalactose transferase) that
produces the A antigen (by adding terminal N-acetylgalactosamine - immunodominant
sugar)
 The I
B
allele encodes a glycosyltransferase (i.e., galactose transferase) that creates the
B antigen (by adding terminal D-galactose - immunodominant sugar).
 The I
O
allele encodes an enzyme with no function (might be, not yet discovered), and
therefore neither A or B antigen is produced, leaving the underlying precursor (the H
antigen) unchanged.

3. MULTIPLE ALLELES
3
Allele
↓translation
Glycosyl
transferase
↓ Function
Terminal-sugar
I
O

↓
---
↓
---
I
A

↓translation
N-acetylgalactose
transferase
↓Function
N-acetyl galactosamine
I
B

↓translation
galactose
transferase
↓Function
D-galactose



Oligosaccharide
chains






Symbolic form of
Antigen








2.3 Rh FACTOR IN HUMAN
 Rh system most polymorphic of all human blood group systems comprised of > 50
independent antigens.
 The Rh factor genetic information is also inherited from our parents, but it is inherited
independently of the ABO blood type alleles.

HISTORY
 The Rh-factor was discovered by K LANDSTEINER in 1940 along with A.S. WEINER.
 They immunized rabbits with blood of a monkey (Macaca rhesus).
 The rabbits developed antibodies that could agglutinate not only rhesus blood, but
also the blood of human beings.
 The antigens of both monkeys and humans were called Rhesus (Rh antigen).
 The antigen responsible for this reaction was consequently called as Rhesus (Rh)
factor.
 Rhesus proteins are expressed only in the membranes of red blood cells and their
immediate precursors.
 The gene is denoted as R-r or Rh-rh.
 Formation of Rh antigen is controlled by dominant gene (R) and its absence by
recipient gene (r).
 People having this antigen with genotype (RR or Rr) were called Rh positive (Rh
+
) and
those whose blood is devoid of it with genotype (rr) were Rh negative (Rh
–
).
 About 95% in India are Rh
+
.
Genotype Rh factor
Rh
+
/Rh
+
Rh
+

Rh
+/Rh
- Rh
+
Rh
-
/ Rh
-
Rh
-

4. MULTIPLE ALLELES
4
CURRENT STATUS
 The Rh system is one of the most complex genetic systems, and certain aspects of its
genetics, nomenclature and antigenic interactions are unsettled.
 The descriptive terms D positive and D negative refer only to the presence or absence
of the red cell antigen "D".
 The terms Rh positive and Rh negative are the old terms used .
 The early name given to the D antigen, "Rho", is less frequently used.

GENETICS OF Rh FACTOR
 The first Rhesus gene, the RHCE gene, was discovered in 1990.
 The RHD gene was found two years later (1992).
 These 2 genes controlling antigen expression are located on Chromosome 1.
 The two Rhesus proteins, RhD and RhCE, are very similar, differing in only 36 of the
417 amino acids, which they each comprise.
 More than 170 alleles have been found on the RHD gene since. The site has still not
been explored fully.
 Depending on the phenotype and their molecular structure, these RHD alleles are
classified as partial D, weak D or DEL….
 The Rh antigens are transmembrane protiens, whose structure is similar to the ion
channels,
 Function of Rh protein is Cation transportation, RBC Membrane stability…

Two systems of nomenclature developed prior to advances in molecular genetics are;

1. WIENER THEORY
 American Dr. Alexander Wiener.
 The Wiener theory postulates that two genes, one on each chromosome of the pairs,
control the entire expression of the Rh system in one individual.
 The Rh gene occurs at one Rh locus, has multiple alleles.
 The two genes at the two loci homozygous or heterozygous.
 There are eight major alleles are called R
O
, R
1
, R
2
, R
z
, r, r', r" and r
y
.

2. FISHER-RACE THEORY : CDE Terminology
 Two British workers, Ronald Fisher and R.R. Race (1940's)
 Although too simplistic to explain this complex system, the theory is useful to explain
routine inheritance of D, C, E, c, and e genes.
 The main tenets of the theory are as follows:
1. Rh inheritance is controlled by 3 closely linked loci on each chromosome of a
homologous pair. (pseudoalleles)
2. Each locus has its own set of alleles which are Dd, Cc, and Ee.
3. The D gene is dominant to the d gene, but Cc and Ee are co-dominant.
4. The 3 loci are so closely linked that crossing-over does NOT occur, and the 3 genes
on one chromosome are always inherited together.
 Gene complex; DCE, DCe, DcE, Dce, dCE, dCe, dcE, dce,

5. MULTIPLE ALLELES
5
PREGNANCY COMPLICATIONS WITH Rh FACTOR
 If a woman who is Rh-negative and a man who is Rh-positive conceive a baby.
 The child inherits the Rh+ trait from the father.
 Rh-incompatibility usually isn't a problem if it's the mother's first pregnancy. Because,
unless there's some sort of abnormality, the fetus's blood does not normally enter the
mother's circulatory system during the course of the pregnancy.
 However, during delivery, the mother's and baby's blood can intermingle.
 If this happens, the mother's body recognizes the Rh-protein as a foreign substance
and can begin producing antibodies (protein molecules in the immune system that
recognize, and later work to destroy, foreign substances) against the Rh -proteins
introduced into her blood.
 Rh antibodies are harmless until the mother's second or later pregnancies.
 If she is ever carrying another Rh-positive child, her Rh-antibodies will recognize the
Rh-proteins on the surface of the baby's blood cells as foreign, and pass into the
baby's bloodstream and attack those cells.
 This can lead to haemolysis of the normal blood cells.
 A baby's blood count can get dangerously low when this condition, known as
haemolytic disease of the newborn, “Erythroblastosis foetalis” occurs.

6. MULTIPLE ALLELES
6
2.4 GENETIC PROBLEMS RELATED

QUESTION NO: 1
A father of blood type A and a mother of blood type B have a child of type O. What blood
types are possible in their subsequent children?
SOLUTION:
 Because type O blood results from the homozygous recessive genotype (i i ), the only
way to produce a type O child is if both parents provide an O allele (i ).
 Since the father has blood type A, he must be heterozygous (I
A
i ).
 Similarly, since the mother has blood type B, she must be heterozygous as well, but
with the B and O alleles (I
B
i ).
CROSS:
Parents : A blood type Father X B Blood type Mother
Genotype: I
A
i X I
B
i
I
A
i

I
B

I
A
I
B
AB Blood Type
I
B
i
B Blood Type

i
I
A
i
A Blood Type
ii
O Blood Type
RESULT: These parents may produce offspring with the following blood type phenotypes:
AB, A, B, and O.



QUESTION NO: 2
A father of blood type B and a mother of blood type O have a child of type O. What are the
chances that their next child will be blood type O? Type B? Type A? Type AB?
SOLUTION:
 Because type O blood results from the homozygous recessive genotype (i i ), the only
way to produce a type O child is if both parents provide an O allele (i ).
 Since the father has blood type B, he must be heterozygous (I
B
i ).
 Because the mother has blood type O, she must be homozygous for the O allele (i i).
CROSS:
Parents : B blood type Father X O Blood type Mother
Genotype: I
B
i X ii
i i

I
B

I
B
i
B Blood Type
I
B
i
B Blood Type

i
ii
O Blood Type
ii
O Blood Type
RESULT:
 These parents may produce offspring with the following blood type phenotypes: B
and O, each with a 50% chance of occurring in their next child.
 It would be impossible to produce children with either type A or type AB blood.

7. MULTIPLE ALLELES
7
QUESTION NO: 3
A man with AB blood is married to a woman with AB blood. What blood types will their
children be and in what proportion?
SOLUTION:

The man with blood type AB will have the genotype I
A
I
B

Similarly, the woman with blood type AB will have the genotype I
A
I
B
CROSS:
Parents : AB blood type Father X AB Blood type Mother
Genotype: I
A
I
B
X I
A
I
B

I
A
I
B


I
A

I
A
I
A
A Blood Type
I
A
I
B

AB Blood Type

I
B

I
A
I
B

AB Blood Type
I
B
I
B
B Blood Type
RESULT:
 These parents may produce offspring with the following blood type phenotypes in
the given proportions:
50% AB blood type
25% A blood type
25% B blood type
 It would be impossible to produce children with type O blood.



QUESTION NO: 4
A man with type AB blood is married to a woman with type O blood. They have two
natural children, and one adopted child. The children's blood types are: A, B, and O.
Which child was adopted?
SOLUTION:

The man with blood type AB will have the genotype I
A
I
B

The woman with blood type O will have the genotype ii

CROSS:
Parents : AB blood type Father X O Blood type Mother
Genotype: I
A
I
B
X ii
i i

I
A

I
A
i

A Blood Type
I
A
i
A Blood Type

I
B

I
B
i
B Blood Type
I
B
i

B Blood Type
RESULT:
 The cross shows that these parents may produce offspring with the A and B blood
type each with a 50% probability
 It would be impossible to produce children with type O blood.
 So the adopted child is the one with O blood type.

8. MULTIPLE ALLELES
8
QUESTION NO: 5
A man with type A blood (unknown genotype) marries a woman with type O blood. What
blood types are possible among their children?
SOLUTION:

The man with blood type A can be either homozygous (I
A
I
A
) or heterozygous (I
A
i)


The woman with blood type O will have the genotype ii

CROSS 1: If father is homozygous
Parents : A blood type Father X O Blood type Mother
Genotype: I
A
I
A
X ii
i i

I
A

I
A
i

A Blood Type
I
A
i
A Blood Type

I
A

I
A
i
A Blood Type
I
A
i

A Blood Type

CROSS 2: If father is heterozygous
Parents : A blood type Father X O Blood type Mother
Genotype: I
A
i X ii
i i

I
A

I
A
i

A Blood Type
I
A
i
A Blood Type

i
ii
O Blood Type
ii

O Blood Type
RESULT:
 If the father has homozygous genotype for A blood type, all children will be having
blood type A.
 If the father genotype is heterozygous, then when he produce kids with O blood
group woman, the children can have A or O type blood group each blood type
having a 50% probability.



QUESTION NO: 6
If the father of a fetus is Rh positive and the mother is Rh negative, what are the chances
that there will be a mother-fetus incompatibility problem? Assume that the couple has
already had a child and that there has been no medical treatment to prevent this
problem.
a) 100%
b) at least 50%
c) less than 50%
d) 0 %
SOLUTION:
If the father is homozygous dominant (DD) the chances of the fetus being Rh positive and
an incompatibility problem occurring will be 100%. If the father is heterozygous (Dd), the
chances are 50%. There will be no problem if the fetus is Rh negative.

9. MULTIPLE ALLELES
9
Task :
1. locate – local Blood bank
2. who is your potential donor?
3. How many blood groups in total? 29