cott, & Snead, 2000).
The analogy involved building a structure (collagen) using
plastic blocks to represent COL2A1 proteins. Students were
given eight lego blocks (COL2A1 proteins) and asked to stack
them in sets of two. They were told that four stacks of two were
sufficient for the wild-type phenotype (homozygous wild-type,
Figure 1(A)). Students were then asked to break down the
blocks, remove four of them, mimicking a deletion at one allele
(heterozygous, Figure 1(B)). Students were asked to re-stack
the blocks in sets of two. Again, four sets were required for a
normal phenotype, but were not produced illustrating that at
times 50% production is insufficient for a maintenance of reti-
nal attachment (wildtype phenotype).
Mechanism 2: Acquired Function
The acquired function explanation for mutant allele domi-
nance involves the mutant allele encoding a protein that has
acquired something “extra” and is therefore responsible for the
abnormal phenotype. The mutant allele may encode a regulated
protein whose control has been lost or the protein may be able
Figure 1.
Examples of Analogy Visuals. (A)-(B) Haploinsufficiency (homozy-
gous wildtype vs. heterozygous); (C)-(D) Poison product (heterozygous
before vs. after cellular destruction of “poisoned complexes”; (E)-(F)
Acquired function (normal function vs. acquired function).
to perform some alternate function in a different biological
pathway or process. In this case, the phenotype may have noth-
ing to do with the normal function of the protein, but instead
result from destroying or altering a second, unrelated pathway
or process.
The human molecular example of acquired function was
sickle cell anemia variant Antilles. Sickle cell anemia can be
caused by several different mutations in the beta globin gene
(HBB, OMIM #141900, 2012). One mutation in the beta globin
gene, which is dominant, is the HbS Antilles allele (OMIM
#141900.0244, 2012). Wildtype hemoglobin, which is com-
posed of both beta and alpha globin, functions to carry oxygen
in red blood cells. This mutation, a change of valine to isoleu-
cine at amino acid 23 (V23I), results in a modified hemoglobin
molecule that polymerizes into long rods (Herrick, 1910).
These rods deform the normally pliable red blood cell into a
rigid sickle-shaped cell. Abnormal red blood cells then occlude
tiny capillaries and deprive tissue of necessary oxygen resulting
in sickle cell crisis.
The analogy involved creating a structural tangle (Sickle cell
rods) using an object with a different known function (a clothes
hanger). Students were shown a hanger and asked the function
(to hang up clothes, Figure 1(C)). Equal numbers of plastic
hangers (wildtype proteins) and wire hangers (HbS proteins)
were placed in a sack and shaken to simulate low oxygen ten-
sion. This generated a tangle of hangers (Figure 1(D)), mim-
icking the polymerization of the hemoglobin rods that generate
the inflexible, sickle-shaped red blood cell.
Mechanism 3: Poison Product
The explanation for mutant allele dominance by poison
product is probably least intuitive because it involves protein
quaternary structure and probability. Generally, one mutant
protein in a protein complex initiates the cell’s quality control
mechanism and destroys the entire protein complex. This re-
sults in only 25% normal protein complexes being present, thus
leading to a more severe phenotype than simple allele loss.
The human molecular example of poison product was osteo-
genesis imperfecta, type II (OMIM #166210, 2011). Patients
with this inherited disease have very brittle bones and severely
weakened heart valves that must be monitored closely if the
patient survives. This disease is caused by a mutation in the
alpha 1 collagen gene, which produces a protein that is a pri-
mary building block for structural collagen in bones. The col-
Copyright © 2012 SciRes. 885
R. L. SEIPELT-THIEMANN
lagen trimer is composed of two molecules of alpha 1 and one
molecule of alpha 2. In heterozygotes, each trimer can contain
no, one, or two mutant alpha 1 molecules; however, only purely
wildtype trimers are not degraded by the cell. Therefore, only
25% of the original trimers are available to build structural
integrity, resulting in the brittle bones and weak heart valves
observed in the disease (Williams & Prockop, 1983).
The analogy involved building structures (collagen trimers)
using wooden blocks (alpha 1 collagen) and other miscellane-
ous materials (alpha 2 collagen, Figure 1(E)). Students were
given eight small wooden blocks among other items such as
crayons and rubberbands. Half of the blocks were marked with
an “X” to denote one allele’s “worth” of mutant alpha 1 colla-
gen molecules. Students were asked to build four identical
structures without looking at the “X” status of the blocks. Stu-
dents were then asked to destroy all structures containing a
mutant alpha 1 molecule (Figure 1(F)). On average one mole-
cule of the four remained in each group, illustrating how pro-
duction of 50% mutant alpha 1 collagen molecules could result
in only 25% normal collagen trimers which results in the ex-
tremely weakened bones and heart valves observed in osteo-
genesis imperfecta patients.
Mechanism 4: Increased Enzyme Activity
The increased enzyme activity explanation for mutant allele
dominance was that the enzyme encoded by the mutant allele is
more active than the wildtype enzyme and generates too much
product in a biochemical reaction or pathway. Build up of the
product or shunting the product to a different pathway gener-
ates the phenotype.
The human molecular example of increased enzyme activity
was hereditary gout. Hereditary gout can be caused by a muta-
tion in the PRPS (phosphoribosylpyrophosphate synthetase
gene (OMIM #300661, 2012). The metabolic/biochemical
pathway functions as a certain rate and when PRPS activity
increases, the pathway becomes overloaded so that product is
shunted to another pathway whose final product is uric acid
(Becker, Meyer, & Seegmiller, 1973). Uric acid crystallizes in
the fluid-filled spaces of the joints producing the severe joint
pain characterizing gout.
The analogy for increased enzyme activity was illustrated
using a film clip freely available on the internet. Students were
shown a video clip from the “I Love Lucy” show in which Lucy
works in a candy factory (Oppenheimer, Pugh, Carroll, & Asher,
1952). A reliably available clip of this scene can be found at
http://www.youtube.com/watch?v=0YGF5R9i53A (Busciglio,
2010). At normal speed, the candy (the product), is acted upon
by people (enzymes) to produce a box of wrapped candy (the
final product). However, when the pathway speed is increased,
via an upstream overactive enzyme, Lucy is unable to wrap
candy pieces and place them back on the conveyor belt. She
starts pulling candy off the conveyor belt without wrapping it
(buildup of intermediate product), and finally, puts candy in her
hat and shirt (shunting the product to an alternate path). This
film clip humorously illustrates how alleles for overactive en-
zymes, such as PRPS in hereditary gout, can produce unneces-
sary products that generate a phenotype even though a normal
allele is also present with the mutant allele.
Mechanism 5: Inappropriate Expression
The explanation for mutant allele dominance via inappropri-
ate expression involves altered control of gene expression ra-
ther than production of a mutant protein. A functional protein is
expressed, but in the wrong tissue or at the wrong time during
development. The presence of the protein and its functionality
produces the mutant phenotype.
The human molecular example of inappropriate expression
was chronic myeloid leukemia. Chronic myeloid leukemia is
caused by a fusion of chromosomes 9 and 22 that puts the ABL
oncogene under the control of a BCR locus (OMIM #608232,
2012). This inappropriate expression of a growth-promoting
protein drives proliferation of immune cells generating cancer
(De Klein, Van Kessel, Grosveld, Bartram, Hagemeijer, Bootsma,
Spurr, Heisterkamp, Groffen, & Stephenson, 1982).
The analogy for inappropriate expression involved the use of
texting-type language in a more formal situation (Table 1).
Students were directed to an internet site listing the “texting”
version of many common phrases, such as TTYL denotes “talk
to you later” and “2moro” for tomorrow. See NetLingo for
numerous examples at http://www.netlingo.com/acronyms.php.
It was agreed that this type of shorthand is generally acceptable
while texting, but then students were asked whether it was ap-
propriate to use these for 50% of the language (one mutant
“texting” allele and one wildtype allele) in a formal paper, such
as those assigned in English classes, or on essay questions in
exams. This example illustrates how appropriate timing, whether
it is expression of proliferation-promoting genes or use of for-
mal language, is critical for a good outcome (normal phenotype
or a decent grade).
Extending the Experience
Present a genetic disease with a known molecular cause and
ask students to make a hypothesis as to whether the mutant
allele is dominant or recessive and if dominant, then iden-
tify to which mechanism it is most similar.
Have students categorize known dominant genetic diseases
based by mechanism based on molecular information.
Have students develop their own analogy for each mecha-
nism using different genetic diseases.
Results
The main objective of this study was to present analogies
involving the complex and counter-intuitive mechanisms of
mutant allele dominance to the molecular biology education
Table 1.
Selected texting acronyms and their meaningsa.
Text speak /Acronym Meaning
addy address
b4 before
nesec any second
ntim not that it matters
ooo out of office
ptp pardon the pun
slm see last mail
Note: aPlease see NetLingo at http://www.netlingo.com/acronyms.php/.
Copyright © 2012 SciRes.
886
R. L. SEIPELT-THIEMANN
Copyright © 2012 SciRes. 887
community for their own use. However, as noted in previous
research (Venville & Treagust, 1997; Orgill & Bodner, 2004),
analogies can be at best helpful, but at least, confusing and/or
harmful to the learning experience. To address this issue, the
analogies were evaluated by upper division undergraduates and
master’s students for two cycles of the course (two years). In-
terest, engagement, understanding and confusion were assessed
on a Likert scale (1 - 5) by students prior to the analogy (Figure
2(A)) and the change in interest, engagement, understanding,
and confusion was self-reported following the analogies (Fig-
ures 2(B) and 3). Pre-analogy interest for all analogies ranged
from a mean of 3.23 to 3.57 out of 5. For engagement, the
(A) (B)
Figure 2.
Student Assessment. Mean values of interest, engagement, understanding, and confusion relating to allele dominance (A) Prior
to analogies. Scoring was 1 - 5 with 1 being least and 5 being most and (B) Change following analogies. Scoring was 1 to +1
with 1 indicating decrease, 0 indicating no change, and +1 indicating an increase. n = 36.
(A) (B)
(C) (D)
Figure 3.
Overview of student-reported change following analogies. Student decreases, no changes, and increases are represented as stacked columns showing
the proportion or percentage of total students having increased, decreased, and no change in (A) Interest; (B) Engagement; (C) Understanding; and (D)
Confusion. n = 36.
R. L. SEIPELT-THIEMANN
average pre-analogy scores ranged from 3.0 to 3.32. The under-
standing pre-analogy mean scores had a range of 2.82 to 3.62.
Self-reported confusion prior to analogy for all analogies
ranged from 1.85 to 2.43.
General observations and trends, rather than statistical anal-
yses, are reported here, first because there is little statistical
power in small observation samples, and second, it is of interest
to observe how individual students within the pool reflected on
their own learning and analogy use. To highlight this, the data
for change in interest, engagement, understanding, and confu-
sion are presented as stacked columns where each student’s
response within the pool is visible (Figure 3). Following the
analogy, students reported little to no decreases in interest,
engagement, or understanding and little to no increases in con-
fusion (Figures 3(A)-(D)). Approximately half of all students
noted an increase in interest and engagement for all analogies
(Figures 3(A) and (B)), while most students reported an in-
crease in understanding for three of the five analogies (Figure
3(C)). The self-reported change in confusion differed the most
of all measurements, with the analogy for inappropriate expres-
sion being ranked as least helpful and the analogy for increased
activity being rated as most helpful (data not shown).
Discussion
Science students and teachers commonly use analogies inside
and outside the classroom to bridge the gap between an idea
they understand and a similar new idea or concept. In particular,
analogies for genetics, molecular biology, and biochemistry
concepts, which are highly abstract, can benefit students’ un-
derstanding. The purpose of this project was to construct and
evaluate analogies of molecular mechanisms to help gain a
greater understanding of mutant allele dominance in human
genetic disease. Five analogies for five distinct molecular
mechanisms were tested with upper-level undergraduates and
masters-level students in two cycles of a human genetics course
(n = 36). All were positively reviewed by the majority of stu-
dents. Extending the experiences with other examples and
thought-provoking problems, as noted in the section above, in
addition to having students identify areas in which the analogy
breaks down, will be helpful to those students who may not
have benefited from the initial analogy. These analogies may be
particularly useful for those instructors who are moving to-
wards a curriculum that is centered on genetic and phenotypic
variation, molecular consequences, and genomics, as proposed
for different educational audiences by Dougherty (2009) and
Redfield (2012), as they help visually illustrate molecular con-
nections among genes, heterozygosity, biochemistry, genotype,
and phenotype in the human.
Acknowledgements and Supplementary Material
RLST thanks Dr. Michael Rutledge and Ms. Chatoria Kent
for their helpful comments. RSLT will gladly share the intro-
ductory powerpoint slides. Please contact her by email at re-
becca.seipelt@mtsu.edu.
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