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6/20/09
Human Blood Group Genetics (Mainly ABO)
There are several independent blood group phenotypes that you may have run across; each one is
determined by a separate gene.
• MN
The MN system of blood typing is briefly described in Sec. 4.1.1 (Incomplete Dominance and
Codominance, p. 68) as an example of the phenomenon of CODOMINANCE. Also see Basic
Exercise #1 (p. 87) and Question and Problems #4.1 (p. 89).
The MN system is used again as an example to present the basic concepts of population
genetics in the following sections:
24.1.1
24.1.2
24.1.3
See also:
ESTIMATING ALLELE FREQUENCIES
p. 710
RELATING GENOTYPE FREQUENCIES TO ALLELE FREQUENCIES: THE HARDYWEINBERG PRINCIPLE
p. 711
APPLICATIONS OF THE HARDY-WEINBERG PRINCIPLE
p. 711
Basic Exercises #1, 2, and 3 (p. 726)
Testing Your Knowledge #1 (p. 727)
Questions and Problems 24.1, 24.2, 24.3, 24.4, 24.4, 24.6 and 24.12 (p. 728).
• Rh
This well-known blood group system is not discussed in the text. It is important clinically as the basis for
maternal/fetal incompatibility and hemolytic disease of the newborn (erythroblastosis fetalis).
• Duffy
The Duffy system is introduced, somewhat gratuitously, as an example of a GENETIC POLYMORPHISM
in human populations.
See Sec. 25.2.1 VARIATION IN PHENOTYPES
p. 733
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• ABO
The text uses the ABO system as an example of MULTIPLE ALLELES. It also exemplifies codominance.
Sec. 4.1.2
Multiple Alleles
p. 69
Also see Questions and Problems #4.5, 4.6, 4.7, and 4.9 (p. 90).
Karl Landsteiner published the results of his studies on the ABO blood group in 1909. He was awarded
the Nobel prize in 1930.
Relevance:
blood transfusion compatibility
fetal/maternal incompatibility
forensics: paternity discrimination etc.
An individual's ABO Blood Type PHENOTYPE is entirely determined by their GENOTYPE for a single
gene on chromosome #9. For this gene there are of 3 types of ALLELES present in the human
population. The usual allele designations are: IA, IB, i. The dominance relationships among them is: IA =
IB > i .
Blood Type
Phenotype
A
Antigens Present
Antibodies Present
Genotype/s
A
anti-B
B
B
antiA
IA IA,
IA i
IB IB ,
IB i
AB
A&B
none
IA IB
O
H
anti-A & anti-B
ii
universal
recipient
universal
donor
The unique and most intriguing thing about anti-A and anti-B antibodies is that they are naturally present,
prior to transfusion.
A famous early forensic application was the Charlie Chaplin paternity suit (1943).
Mother = Type A
C. Chaplin = Type O
F1 = Type B
The average allele frequencies worldwide:
IA = 0.22
IB = 0.16
i = 0.62
What do these allele frequencies tell us about human origins and human evolution?
A
B
The Institute for Creation Research proposes that Adam's genotype was I i, and that Eve was I i.
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Does natural selection act on the frequency of the ABO alleles, or are they NEUTRAL?
There are suggestive, but controversial correlations between ABO blood types and the incidence of some
infectious diseases. The strongest is the association between blood group O and duodenal ulcer. (Type O
individuals experience approximately twice the risk of infection by for Helicobacter pylori, the bacterium
responsible. H. pylori uses the H antigen exposed on gastric epithelial cells as receptor for attachment.)
There is also significant geographic variation in allele frequency. For example, O-type alleles are very
frequent in Native American populations, and less frequent in Europeans.
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Molecular and Biochemical aspects of the ABO Anitgens
The A, B, and H antigens appear on other cell types including epithelial cells, and may also be present in
body fluids such as saliva. However, we usually discuss them in terms of RBC's because of their primary
relevance in determining compatibility in blood transfusion. Also, RBC’s are the most accessible human
cells for scientific study.
The A, B, and H antigens are chains of 6-carbon sugars anchored in the cell membrane and extending
6
outwards. There are approximately 10 antigen chains extending from the surface of each RBC!
The H Antigen is produced from a precursor chain by an enzyme product from an allele of gene H.
Individuals homozygous for a rare, NULL ALLELE of this gene (hh) do not produce the H Antigen. hh
individuals appear to be Type O regardless of their genotype for the ABO gene. This is an example of a
type of gene interaction called EPISTASIS (See Sec. 4.2.5 EPISTASIS p. 77). The absence of the H
Antigen in hh individuals traditionally has been referred to as the “BOMBAY PHENOTYPE".
A
B
I and I alleles code for two versions of an enzyme with slightly different substrate specificities.
i alleles are null alleles; they do not code for any active enzyme at all.
O
O
O
RBC
O
n
H
CH2OH
CH2OH
O
HO
O
O
OH
OH
O
O
O
OH
GALACTOSE
H ANTIGEN
IA
ACETYLGALACTOSAMINE
B
I
O
O
O
O
OH
OH
n
O
N-C-CH3
H
O
O
HO
O
O
O
O
O
n
O
A ANTIGEN
n
O
B ANTIGEN
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DNA Sequencing of the ABO gene
The ABO gene has 7 EXONS. i.e. The coding sequence is interrupted by 6 INTRONS. (See Sec. 11.5 p.
299.)
Sequencing ABO alleles from many individuals worldwide has demonstrated the existence of at least 200
different alleles, most of them quite rare.
For example, 13 different alleles were found in a 1996 study of 262 Japanese individuals. The common
alleles are indicated with stars.
Notice that i alleles are NONSENSE MUTANTS created by DELETION of a specific GC base pair in exon
#6 (indicated by "ΔG"). The FRAMESHIFTING that results from this deletion (ΔG261) causes premature
termination of translation. (see p. 338).
Notice that there are several examples of SILENT SUSTITUTIONS, as well as several examples of
NEUTRAL MISSENSE SUBSTITUTIONS.
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NAME: __________________________________________
Get together with other students if you can and take your best shot at working out the answers to the
following questions. Turn them in on Wed. Attach extra pages if needed.
1. The Institute for Creation Research proposes that in the mating of Adam with Eve, the genotypes
A
B
could have been I i X I i. Propose an alternate set of genotypes for Adam and Eve that would have
led to the same allele frequencies.
A
B
2. Imagine an isolated human population in which the frequency of I , I , and i type alleles is 1/3 each. If
mating among individuals is random, what would be the frequencies of the ABO Blood Type
phenotypes?
3. In the allele sequences shown on the previous page, all A allele gene products have Leucine at
position 266, and all B allele products have Methionine at position 266. This difference in the
sequence of the protein is correlated with a single base pair difference of CG796 ↔ AT796.
Using the genetic code table on p. 332, determine which of the 6 synonymous Leucine codons is
used at this position in the A alleles.
4. (This one is tough! Don't be CROSS with me OVER it!)
A woman with Type B has a child with Type A fathered by a Type O man. How could this happen
without multiple mutations?
HINT: You will need to look very carefully at the allele sequences in the diagram on the previous
page.
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