Chromosomes and Karyotypes : Mutation & Variation
How can two physically healthy parents produce a child with Down syndrome and a second
child with Klinefelter syndrome?
Introduction/Background Information
Birth defects and disease arise in a variety of ways, including (a) the mutation of a single gene due to
changes in DNA, (b) changes in chromosome structure due to incomplete crossover during meiosis (c)
changes in chromosome number due to nondisjunction in meiosis, and (d) errors in embryonic
development due to maternal and environmental factors, such as drug and alcohol use, infection, and
exposure to carcinogenic, mutagenic, or teratogenic substances, which may damage DNA. These are
discussed below.
Gene Mutations
Some inherited diseases are single gene recessive disorders that occur only when an individual inherits
two malfunctioning copies (mutant alleles) of the relevant gene—one carried on the father’s sperm and the
other carried on the mother’s egg. In many cases, children with recessive disorders have normal parents.
Individuals with single gene mutations have normal karyotypes.
For example, sickle cell disease is a recessive disorder that affects the red blood cells. Red blood cells use
a protein called hemoglobin to transport oxygen from the lungs to the rest of the body. Normally, red blood
cells are round and flexible so they can travel freely through the narrow blood vessels. Patients with sickle
cell disease have a point mutation, specifically a substitution, at position 6 in the HBB gene on
chromosome 11 that codes for the hemoglobin protein, causing the hydrophilic amino acid glutamic acid to
be replaced with the hydrophobic amino acid valine. This substitution results in irregularly shaped (sickle
shaped) blood cells, which get stuck in blood vessels and are unable to transport oxygen effectively,
causing pain and damage to the organs.
Each parent has two copies of chromosome 11, one that contains the
mutation for sickle cell disease and the other that is normal. In this
case, the egg and sperm cell can carry the “S” or “s” allele on
chromosome 11. The Punnett square on the right predicts the outcome
of sexual reproduction between these parents. The child (ss), that has
sickle cell disease, inherited a copy of the mutated allele from each
parent. Hence, the egg and sperm must have carried “s” on
chromosome 11.
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Changes in Chromosome Structure
Crossing over in meiosis involves the 'swapping' of genetic material between homologous chromosomes.
During equal crossing over, the homologous sequences of the two DNA molecules align, and crossing over
produces no net change in the number of nucleotides in either molecule. If homologous chromosomes
misalign, there is unequal exchange of genetic material that may result in insertions (extra genetic material)
or deletions (missing genetic material). Individuals with insertions or deletions will have abnormal
karyotypes.
In this case, Chromosome 4A has a
deletion, and chromosome 4B has an
insertion.
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Changes in Chromosome Number
A chromosome mutation that causes individuals to have an abnormal number of chromosomes (too few or
too many) is termed aneuploidy. Aneuploid cells may occur due to nondisjunction errors, in which
homologous chromosomes or sister chromatids fail to separate during meiosis. Nondisjunction is the failure
of homologous chromosomes (meiosis I) or sister chromatids (meiosis II) to separate during anaphase.
Nondisjunction produces gametes with either extra or missing chromosomes. (See diagrams below)
If these gametes (n+1 or n-1) unite to form a zygote, the child will have an abnormal karyotype because
he/she will have missing or additional chromosomes.
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Environmental Factors
About 10 percent of birth defects are caused by environmental factors such as maternal infection, maternal
drug and alcohol use, exposure to radiation (ex. X-rays, UV rays, and gamma rays) and exposure to
mutagenic (change the genetic information of an organism, usually by changing DNA), carcinogenic
(associated with causing or promoting cancer in humans and animals), or teratogenic (cause damage to
developing baby while mother suffers no ill-effects) substances. These environmental factors can cause
death, severe birth defects, or might have no effect at all on the developing baby depending on when
during pregnancy the exposure occurs.
Once the egg is fertilized (conception), it takes about six to nine days for implantation (anchoring into the
uterus) to occur. Once the fertilized egg is connected to the uterus, a common blood supply exists between
the mother and the embryo. In other words, if something is in the mother's blood, it can now cross over to
the developing baby. The developing baby goes through two major stages of development after conception.
The first, or embryonic stage, occurs during the first 10 weeks after conception. Most of the major body
systems and organs form during this time. The second, or fetal stage, is the remainder of the pregnancy.
This fetal period is a time of growth of the organs and of the fetus in general.
The developing baby is most vulnerable to injury during the embryo stage when organs are developing.
Indeed, infections, drugs, and exposure to mutagenic, carcinogenic, and teratogenic substances and
radiation cause most of their damage when exposure occurs two to 10 weeks after conception.
The following are examples of birth defects caused by environmental factors:

Rubella, or German measles, is an example of an infection that causes birth defects if a woman
has the infection during early pregnancy. The type of birth defect that results depends on the stage
of development when the infection occurs. Rubella causes cataracts if infection occurs during the
sixth week of pregnancy, deafness if the infection occurs during the ninth week, and heart defects if
the infection occurs between the fifth and 10th week of pregnancy.
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Radiation during the first three months of pregnancy can cause birth defects such as microcephaly
(small head), spina bifida (a hole in the back that marks the premature end of the spinal nerves),
blindness, or cleft palate.
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Various medicines and recreational drugs can cause birth defects, which are most severe when
used during the first three months of pregnancy. Thalidomide, an anti-nausea medicine prescribed
during the 1960s, caused birth defects called phocomelia (absence of most of the arm with the
hands extending flipper-like from the shoulders).
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Alcohol consumption causes birth defects such as learning disabilities, mental retardation,
irritability, hyperactivity, poor coordination, and abnormalities of facial features.
Individuals exposed to teratogens will have normal karyotypes.
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The Problem. Christopher and Jill Miller have been married for 15 years and they have two children.
Their first child, Emily was born with Down syndrome. Children with Down syndrome have developmental
delays, intellectual disability, a characteristic facial appearance (upward slant to eyes), small stature, and
weak muscle tone. In addition, these children have an increased risk of heart defects, digestive problems
such as gastroesophageal reflux, and hearing loss.
Their second child, Andy was born with Klinefelter syndrome. Klinefelter syndrome affects male physical
and cognitive development. Affected individuals may have learning disabilities, delayed speech and
language development, and introverted personalities. They typically have small testes that do not produce
as much testosterone as usual, which can lead to delayed or incomplete puberty, breast enlargement
(gynecomastia), reduced facial and body hair, and an inability to have biological children (infertility).
Although the Millers were in their early forties when they had Emily, both of them were in excellent health.
They both eat a well-balanced diet, exercise on a regular basis, and they do not smoke or drink. Mrs. Miller
followed the advice of her obstetrician and took pre-natal vitamins and avoided taking over the counter and
prescription medications during her pregnancies. Mrs. Miller did not have any illnesses or infections during
either of her pregnancies.
Thus, the Millers want to know why Emily was born with Down syndrome and Andy was born with
Klinefelter syndrome. In this investigation, you will explore how children can inherit Down syndrome and
Klinefelter syndrome.
There are three possible explanations. Your job is to determine which of these explanations is the most
plausible.
1. Down syndrome and Klinefelter syndrome are both recessive genetic disorders. Mr. and
Mrs. Miller each carried a recessive allele for these syndromes and they each passed it
down to their children.
2. Down syndrome and Klinefelter syndrome are both caused by a chromosomal abnormality.
Either the sperm from Mr. Miller or the egg from Mrs. Miller had a damaged, missing, or
additional chromosome.
3. Down syndrome and Klinefelter syndrome are both caused by maternal behaviors and
exposure to teratogens, such as drinking, smoking, poor diet, infection, or exposure to
environmental toxins.
Your Task. Determine which one of these explanations is most valid or acceptable.
You must use the evidence provided
(a) to support the explanation you choose
(b) to refute the explanations you excluded
The guiding question for this investigation is: How can two physically healthy parents produce a child
with Down syndrome and a second child with Klinefelter syndrome?
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Materials. You may use any of the following materials during your investigation:
 Karyotyping Information sheet
 Karyotype placement grids
 A karyotype from Mrs. Miller
 A chromosome smear from Mr. Miller
 A chromosome smear from Emily (born with Down syndrome)
 A chromosome smear from Andy (born with Klinefelter syndrome)
 A Miller family pedigree
Getting Started. Unlike diseases that are transmitted from person to
person, such as the flu or strep throat, people are born with Down
syndrome and Klinefelter syndrome. These syndromes, as a result, may
have a genetic basis. Once might determine if a syndrome has a genetic
basis by reviewing a family pedigree and/or producing a karyotype to look
for chromosomal abnormalities.
A lab technician can create a karyotype by collecting a sample of cells
from an individual. The sample of cells is then stained by a dye that
makes the chromosomes easier to see (see Figure 1). Next, the
chromosomes are photographed using a microscope camera. The
pictures of the chromosomes are then organized onto a grid by size,
Figure 1. Chromosome Smear
shape, and banding pattern. Medical professionals can then use the
(Human Male)
karyotype to look for abnormalities. Chromosomal abnormalities include
such things as a missing chromosome or the presence of too many chromosomes. A chromosomal
abnormality can also be found on a single chromosome. A chromosome, for example, might be shorter or
longer than it should due to the insertion or deletion of genetic material.
In order to create a karyotype for Mr. Miller and the two children, you will need to actually sort images of
chromosomes taken from their cells according to length, pair any matching sets of chromosomes, and then
place them onto a grid. The final product is a karyotype (a picture of an individual’s chromosomes). You
teacher will provide you will a karyotype from Mrs. Miller (a normal female). You should create a
karyotype for Mr. Miller before creating a karyotype for each child.
Your teacher will also provide you with the Miller family’s pedigree to analyze.
Investigation Proposal Required:
___ Yes
x No
Connections to Crosscutting Concepts and the Nature of Science and Scientific Inquiry. As you work
through your investigation, be sure to think about:
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The importance of identifying patterns;
How scientists attempt to uncover causal mechanisms;
How structure is related to function in living things;
How the work of scientists is influenced by social and cultural values; and,
The different methods that scientists can use to answer a research question.
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Argumentation Session: Once your group has finished
collecting and analyzing your data, prepare a whiteboard that
you can use to share your initial argument. Your whiteboard
should include all the information shown Figure 2.
To share your argument with others, we will be using a
Round-Robin format. This means that one member of your
group will stay at your lab station to share your groups’
argument while the other members of your group go to the
other lab stations one at a time in order to listen to and
critique the arguments developed by your classmates.
The Research Question:
Our Claim:
Our Evidence:
Our Justification of
the Evidence:
Figure 2. Information needed on a Whiteboard
The goal of the argumentation session is not to convince others that your argument is the best one; rather
the goal is to identify errors or instances of faulty reasoning in the arguments so these mistakes can be
fixed. You will therefore need to evaluate the content of the claim, the quality of the evidence used to
support the claim, and the strength of the justification of the evidence included in each argument that you
see. In order to critique an argument, you will need more information than what is included on the
whiteboard. You might, therefore, need to ask the presenter one or more follow up questions such as:
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Is that the only way to interpret the results of your analysis? How do you know that your
interpretation of your analysis is appropriate?
Why did your group decide to present your evidence in that manner?
Why did your group abandon the other alternative explanations? What evidence excluded them?
How confident are you that you claim is valid? What could you do to increase your confidence?
Once the argumentation session is complete, you will have a chance to meet with your group and revise
your original argument. Your group might need to gather more data or design a way to test one or more
alternative claims as part of this process. Remember, your goal at this stage of the investigation is to
develop the most valid or acceptable answer to the research question!
Investigation Report
As the Millers’ genetic counselor, you will need to prepare an investigation report for Mr. and Mrs. Miller
(using the template provided) that consists of the following:
1. Analysis of the evidence (background text, maternal and paternal histories, constructed
karyotypes, and pedigree)
2. Your claim (which explanation was the most plausible) of the origin(s) of Emily and Andy’s
conditions
3. Refutation of counterclaims (which explanations you excluded and why)
4. Recommendations for the Millers should they desire to have more children (ex. Are their conditions
inheritable or non-inheritable?)
LDC Writing Prompt: As a summative assessment of students’ understanding of cell division, molecular
genetics, and Mendelian genetics, students should respond to the following LDC writing prompt.
After researching informational text, completing an ADI scientific investigation, and participating in
JIT teaching, write an essay that discusses how gene and chromosomal mutations arise and
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evaluate how they may or may not affect the organism and its offspring. Be sure to support your
position with evidence from your research.
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The Miller Family’s Pedigree
Key to Pedigree Shading
Black—affected by Down Syndrome
Grey—affected by Klinefelter Syndrome
Mrs. Miller’s Karyotype
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