Activity 2: Meiosis and Nondisjunction

Activity Week 2
Student name & RedID:
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Fathe
r
Mother
Exercise 1.
1
3
What is the most likely cause of triploidy?
Why?
Fetus
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Fathe
r
Mother
Exercise 2.
Locus: D7S820
Can you draw the same conclusions from
these data that you could from Exercise 1?
Why?
Fetus
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Exercise 3.1, normal chromosome segregation
Locus: D2S1338
Mother
1
1
4
4
Meiosis I
Meiosis II
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Exercise 3.2, non-disjunction at Meiosis I
Locus: D2S1338
Mother
1
1
4
4
Meiosis I
Meiosis II
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Exercise 3.3, non-disjunction at Meiosis II
Locus: D2S1338
3.4: At which meiotic division did
the mother undergo nondisjunction?
Answer: ____________
Mother
1
1
4
4
Meiosis I
Meiosis II
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Exercise 4.1, crossover during maternal meiosis
Locus: D8S1179
*
*
*
(These might be useful)
*
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Exercise 4.2, non-disjunction after a crossover
Locus: D8S1179
Mother
*
*
*
(These might be useful)
*
Meiosis I
Meiosis II
Copyright 2021 Richard Cripps, Nermeeta Dhillon and Kanya Long
Biology 351 Genetics
Fall 2023
Biol 351, Week 2 Activity: Meiosis and Non-Disjunction
Learning objectives for this activity section:
1. Understand and interpret findings from a primary research article.
2. Diagnose aneuploidy events in meiosis, and predict outcomes.
Before class:
The purpose of the exercises below is to introduce you to reading a scientific paper, understanding
some advanced concepts of meiosis, and to understand how we can diagnose errors that occur
during meiosis.
Before attending activity section, read the paper by Huang et al, (2004) Three consecutive
triploidy pregnancies in a woman: genetic predisposition? European Journal of Human
Genetics, 12: 985-986. The paper is fairly straightforward, but don’t worry if you don’t follow all
of it – we’ll discuss it as a group!
To find and print the paper:
The url for the paper is: http://www.nature.com/ejhg/journal/v12/n12/abs/5201274a.html
Once you go to this webpage, click on the “Download pdf” link on the right, to get a printable copy.
If you are on campus, you should be able to access the pdf directly from the link above. If you are
not on campus, you can access the pdf through Remote Library Access:
https://library.sdsu.edu/computers-technology/remote-access
Read this paper and bring a copy with you to the Discussion section.
In brief, this paper describes a situation where a woman undergoes three miscarriages. The data
in the paper itself focus upon an analysis of the fetus from her third miscarriage. The researchers
determine that the fetus is triploid.
Before class:
As you read through the article, answer the following questions. Questions 2-4 are the kinds of
questions we think about when looking at all papers. Some of the questions may not be relevant
for this paper.
1. Define the following terms:
Triploidy:
Karyotype:
Microsatellite analysis:
If you see a word you don’t know, look it up. This is what scientists do!
Copyright 2023 Richard Cripps, Alexis Guzman, Tamsen Dunn and Jenna Armstrong
Copyright 2023 Richard Cripps, Alexis Guzman, Tamsen Dunn and Jenna Armstrong Page 1
Biology 351
Fall 2023
2. Abstract/Summary
What is the main question or problem the researchers are investigating?
What is the hypothesis (the “If…then…” prediction)?
What is the model (what organism or system are they using as an example)?
What types of experiments do you expect they need to do?
What kind of results would confirm their hypothesis? What kind of results would refute (prove
wrong) their hypothesis?
3. Results
How does each experiment test a part of the hypothesis?
Did the researchers repeat the experiments (look for error bars in graphs, statistics, multiple
examples, etc.)?
4. Discussion
Did the authors support their hypothesis?
Are there other experiments you would have recommended?
Are there other reasons why the authors could have gotten the results they got?
What are the questions they still need to answer?
What do you think their next paper will be about?
Exercise 1
Look at locus D5S818, on chromosome 5 (row five of the table). In this region, both of the mother’s
homologous chromosomes have the same length, so she is designated a 1 1 (not eleven). For
the father at the same locus, his chromosomes have a slightly different length to each other, and
also different to the mother. So he is designated 2 3. Now, look at the analysis of the fetus. Since
the fetus has three chromosome sets, it will have three numbers.
1. In the attached powerpoint file, slide 2 will be labeled Exercise 1. To the diagram on this slide
of chromosome 5 in the parents, complete the annotation of the mother and father’s
chromosomes, to indicate the microsatellite data.
Note: on this first diagram, we have drawn the chromosomes prior to duplication for meiosis, so
there is only one sister chromatid per homolog.
Copyright 2023 Richard Cripps, Alexis Guzman, Tamsen Dunn and Jenna Armstrong
Copyright 2023 Richard Cripps, Alexis Guzman, Tamsen Dunn and Jenna Armstrong Page 2
Biology 351
Fall 2023
2. Next, draw chromosomes and complete the microsatellite data for the fetus, using information
from Table 1 of the article.
3. Based upon what you have drawn, explain whether the data suggests that the extra
chromosome 5 arose from the mother or the father. What is the most likely cause of triploidy in
this instance? Type your answer on the powerpoint slide.
Exercise 2
We are now going to repeat this analysis for another locus, D7S820.
On slide 3 (labeled Exercise 2), draw a similar diagram to what you have done above, but this
time using the D7S820 data.
Based upon this information, can you draw the same conclusions that you drew for D5S818?
Type your answer and explain your reasoning on the powerpoint slide.
Exercise 3.
In Exercise 1, you will have identified the parent who contributed the extra chromosome set, and
how this most likely happened. In Exercise 3, we will look at a microsatellite marker, to determine
if the non-disjunction occurred at meiosis I or meiosis II.
For this exercise, concentrate upon locus D2S1338.
1. Using slide 4 (labeled Exercise 3.1), draw how the mother’s chromosomes would segregate
during normal meiotic divisions (i.e. with no non-disjunction).
Note: in this diagram, it is necessary to show the mother’s chromosomes at metaphase I, so there
are two sister chromatids per homolog.
2. Draw how the mother’s chromosomes would segregate if there was non-disjunction (improper
segregation of the chromosomes at Meiosis I.
3. Draw how the mother’s chromosomes would segregate if there was non-disjunction (improper
segregation of the chromosomes at Meiosis II.
4. Based upon your answers to 3.2 and 3.3 above, use the data in the paper for locus D2S1338
to determine if the maternal non-disjunction occurred at Meiosis I or Meiosis II.
Exercise 4
Copyright 2023 Richard Cripps, Alexis Guzman, Tamsen Dunn and Jenna Armstrong Page 3
Biology 351
Fall 2023
Recombination by crossing over occurs in prophase I in meiosis. After crossing over, the two
sister chromatids of one chromosome may contain different alleles at a given region of a
chromosome, as a result of the recombination.
Look at locus D8S1179 on chromosome 8. This locus is near the tip of the long arm of
chromosome 8.
1. On slide 6, labeled Exercise 4.1, draw how the mother’s chromosomes would look at
Metaphase I, if crossing over had occurred in a location between the centromere of chromosome
8 and the locus being tested. We have colour-coded the homologs to make sure your answer is
clear, and added text boxes containing asterisks for you to enter the alleles.
3. Using your answer to 4.1 as a starting point, use slide 7 (Exercise 4.2) to draw how nondisjunction of this cell at meiosis I could give a result that mimics a non-disjunction at meiosis
Bonus question (not worth any points): Point out the typographical error in the paper (It’s pretty
obvious).
Copyright 2023 Richard Cripps, Alexis Guzman, Tamsen Dunn and Jenna Armstrong Page 4
Biology 351
Fall 2023
Copyright 2023 Richard Cripps, Alexis Guzman, Tamsen Dunn and Jenna Armstrong Page 5
European Journal of Human Genetics (2004) 12, 985–986
& 2004 Nature Publishing Group All rights reserved 1018-4813/04 $30.00
www.nature.com/ejhg
LETTER
Three consecutive triploidy pregnancies in a woman:
genetic predisposition?
European Journal of Human Genetics (2004) 12, 985 – 986. doi:10.1038/sj.ejhg.5201274
Published online 6 October 2004
We read with interest ‘Recurrent triploidy of maternal
origin’ by Brancati et al1 published earlier in this journal.
We report in detail of a similar family.
A 35-year-old woman was referred for genetic counseling
due to recurrent pregnancy loss. The patient’s paternal
grandmother had eight miscarriages and two liveborns.
This grandmother’s sister was unable to have children,
although no reason was ever determined. The remaining
family history was unremarkable. The patient had a total of
three detectable pregnancies. She had her first pregnancy
at age 31. Ultrasound examination detected multiple
abnormalities; including bilateral club feet, agenesis of
the cerebrum, heart and spinal anomalies. This pregnancy
was terminated at 16 weeks of gestation and chromosome
analysis revealed a 69,XXX karyotype. The two subsequent
pregnancies occurred when she was 34 and 35 years of age,
respectively. The second pregnancy was miscarried at 8
weeks gestation and the last pregnancy was lost at 8 – 9
weeks gestation. No histological examination was performed. Chromosome analysis revealed that both embryos
were triploid with 69,XXY karyotype. Chromosome analysis on the patient and her spouse showed that they both
had normal karyotypes.
Table 1
Markers
TPOX
D2S1338
D3S1358
FGA
D5S818
CSF1PO
D7S820
D8S1179
TH01
vWA
D13S317
D16S539
D18S51
D19S433
D21S11
Microsatellite analysis was performed on parental blood
specimen and on the cells from the last embryo. A total of
15 markers on 13 different chromosomes from a commercially available kit (AmpFLSTRs Identifilers PCR Amplification Kit, Applied Biosystems, Foster City, CA, USA) were
used for genotyping (Table 1). Six markers revealed that the
embryo inherited two maternal alleles and one paternal
allele, indicating that the triploidy is maternal in origin
(digyny). The time and mode of the triploidy formation
cannot be accurately determined. Although most of the
fully informative markers revealed a maternal meiosis I
error, maternal meiosis II error was inferred from the other
markers (see Table 1). This was due to the occurrence of
recombination in these chromosomes. The most proximal
marker, D7S820, was not informative.
Triploidy is one of the most common chromosome
abnormalities in humans, occurring in approximately
1 – 2% of all conceptuses and accounts for about 10% of
all spontaneous abortions.2 The primary mechanisms
leading to triploidy include dispermy and maternal
(digynic triploidy) or paternal (diandric triploidy) meiotic
errors.3 – 5 Despite the high frequency and numerous
studies, the etiology of triploidy remains unknown.
Micrasatellite analysis of the 3rd triploid pregnancy
Chromosome locations
2p23-pter
2q35-37.1
3p21
4q28
5q21-31
5q33.3-34
7q11.21-22
8q24.1-24.2
11p15.5
12p12-pter
13q22-31
16q24-qter
18q21.33
19q12-13.1
21q21
Mat: Maternal, MI: Meiosis I error, MII: Meiosis II error.
Mother
Genotypes
Father
Fetus
Interpretation
13
14
12
12
11
12
22
13
33
12
13
12
24
23
12
23
23
33
11
23
11
12
23
12
11
23
12
13
14
23
123
124
123
112
113
111
122
233
233
122
133
222
234
234
223
If Mat, MI
Mat MI
Mat MI
If Mat, MI
Mat
If Mat, MII
Not informative
If Mat, MII
Mat
If Mat, MII
If Mat, MI
If Mat, MII
Mat,MI
Mat, MI
If Mat,MII
Letter
986
Therefore, investigation of families with recurrent triploidy
may provide helpful information regarding the intrinsic
genetic predisposition to the triploidy. Two other studies
have reported on the parental origin of recurrent triploidy.
Brancati et al1 reported maternal origin in two of the three
triploid pregnancies in one family. Pergament et al6
reported another family in which maternal origin was
determined in the last of three triploid pregnancies. In the
family presented here, the last triploid pregnancy was also
determined to be maternal (digynic) in origin. In addition,
the mother had a family history of multiple miscarriages
and infertility. These studies suggest a possible maternal
genetic factor contributing to the recurrent triploid
pregnancies. Interestingly, genetic factors affecting female
meiosis have previously been reported. Based on the
findings from a consanguineous family with six molar
pregnancies, Judson et al7 suggest that a recessive gene may
cause imprinting failure of female germ line, resulting in
the formation of hydatidiform moles. By using a combination of linkage search through the genome and homozygosity analysis, Moglabey et al8 mapped a maternal locus
responsible for recurrent hydatidiform moles to chromosome 19q13.3 – 13.4. In summary, the maternal origin of all
reported recurrent triploid pregnancies, combined with
maternal family history of multiple reproduction difficulties in this family, strongly support the previous studies
and suggest an underlying genetic predisposition to errors
in oogenesis, which may lead to digynic triploidy pregnancies and/or other reproduction difficulties.
European Journal of Human Genetics
Bing Huang1,2, Larry Prensky3, Maya Thangavelu1,2,
Denise Main3 and Shengbiao Wang4
1
Genzyme Genetics, Orange, CA, USA;
2
University of California Irvine;
3
California Pacific Medical Center, San Francisco, USA;
4
Department of Obstetrics and Gynecology, Harbor-UCLA
Medical Center, Torrance, CA, USA
References
1 Brancati F, Mingarelli R, Dallapiccola B: Recurrent triploidy of
maternal origin. Eur J Hum Genet 2003; 11: 972 – 974.
2 Hassold T, Chen N, Funkhouser J et al: A cytogenetic study of 1000
spontaneous abortions. Ann Hum Genet 1980; 44: 151 – 178.
3 McFadden DE, Kwong LC, Yam IY, Langlois S: Parental origin of
triploidy in human fetuses: evidence for genomic imprinting. Hum
Genet 1993; 92: 465 – 469.
4 Baumer A, Balmer D, Binkert F, Schinzel A: Parental origin and
mechanisms of formation of triploidy: a study of 25 cases. Eur J
Hum Genet 2000; 8: 911 – 917.
5 Zaragoza MV, Surti U, Redline RW, Millie E, Chakravarti A, Hassold
TJ: Parental origin and phenotype of triploidy in spontaneous
abortions: predominance of diandry and association with the
partial hydatidiform mole. Am J Hum Genet 2000; 66: 1807 – 1820.
6 Pergament E, Confino E, Zhang JX, Roscetti L, Xien Chen P,
Wellman D: Recurrent triploidy of maternal origin. Prenat Diagn
2000; 20: 561 – 563.
7 Judson H, Hayward BE, Sheridan E, Bronthron DT: A global
disorder of imprinting in the human female germ line. Nature
2002; 416: 539 – 542.
8 Moglabey YB, Kircheisen R, Seoud M, El Mogharbel N, Van den
Veyver I, Slim R: Genetic mapping of a maternal locus responsible
for familial hydatidiform moles. Hum Mol Genet 1999; 8: 667 – 671.

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