2013 Heredity Team
Title: X-inactivation and Gene Dosage
Facilitators
Kathy Miller, Washington University, St. Louis
Victoria Corbin, University of Kansas
Participants
Alyson Zeamer, University of Texas at San Antonio
Brenda Leady, University of Toledo
Donald Auger, South Dakota State University
Douglas Leaman, University of Toledo
Lynn Riley, University of South Dakota
Martha Lundell, University of Texas at San Antonio
National Academies NorthStar Summer Institute for Undergraduate Science Education
Background image: detail from Heredity by Regina Valluzzi
General Context
• Sophomore level genetics course
• Meets in an active learning classroom
• Regularly work in groups
• Routinely use clickers
Specific Context
• Relatively late in the semester
• Have discussed Mendelian genetics and the
basics of gene regulation earlier in semester
• Have an understanding of aneuploidy
Learning Goals
Learning Outcomes
Understand the relevance Explain why neither XX nor XY
of X-inactivation
results in a gene dosage disorder
Suggest why sex chromosome
aneuploidy causes abnormal
phenotypes
Enhanced understanding
of gene dosage
Predict differences in expression
with and without X-inactivation
Be able to interpret and
analyze data
Interpret graphs from the literature
and draw conclusions
Be able to work
collaboratively
Work as a team to generate
hypotheses and predictions
Learning Outcomes
Assessment
Explain why neither XX or XY
results in a gene dosage disorder
Formative: RTL Quiz (individual
and group)
Suggest why sex chromosome
aneuploidy causes abnormal
phenotypes
Formative: Hypotheses;
comparison of data to
predictions
Summative: 1-minute essay
Predict differences in expression
with and without X-inactivation
Formative: Draw predictions
Interpret graphs from the literature Formative: Compare group to
and draw conclusions
peer and published work
Work as a team to generate
hypotheses and predictions
Formative: Compare group to
peer work
Start of Mini Lecture
Dosage Compensation
o Too little or too much gene expression can be detrimental to the
development or health of an organism.
o In organisms with sex chromosomes there is a difference in the
copy number of genes on the sex chromosomes.
o Dosage compensation equalizes gene expression.
http://home.btconnect.com/bordereta/DNA/Human%20DN
A%20Replication-122.htm
X-inactivation was proposed by Mary Lyon in 1961
XX female cells
Barr bodies
Mary Lyon
Adapted from: http://www.studyblue.com/notes/note/n/umkcsod-histology-exam-1-slide-review/deck/3726390
http://oaklawnimages.blogspot.com/2013/04/
a-to-z-blogging-challenge-2013-x.html
http://www.hhmi.org/biointeractive/x-inactivation
Female Mosaicism
Sex-linked anhidrotic ectodermal dysplasia
(absence of sweat glands).
Areas without sweat glands are shown in black.
Figure adapted from:
http://www.ncbi.nlm.nih.gov/books/NBK21977/
Clicker Question
If X inactivation works, should a XXY genotype
cause a problem in humans?
A. Yes
B. No
XXY Syndrome (Klinefelter’s)
o Occurs in ~1:1000 live male births
o Effects include small testes and
reduced fertility
o In adults, characteristics vary
widely and may include no visible
symptoms
o Increased incidence of health
problems that typically affect
females
http://xxytalks.wordpress.com/2013/05/22
/baby-xxy-boys-should-not-be-said-tohave-klinefelters-syndrome/
Teaching tidbit
Why do you see XXY syndrome in
Klinefelter’s patients if X-inactivation
occurs?
In your groups, develop at least 2
hypotheses to address this question.
10 min
Groups report out.
5 min
Guide them back to 2 major
hypotheses
2 Hypotheses:
1: Some causative genes on the X chromosome escape Xinactivation
2: Expression of causative genes on the X chromosome
occurs before X-inactivation early in development
Gene A
Gene B
Gene A
Gene B
Groups report out by showing
data on document projector
10 min
Subject to X-inactivation
NOT subject to X-inactivation
3
relative gene expression
relative gene expression
3
Gene A
2
1
0
Gene B
2
1
0
XX
XY
XXY
XX
XY
XXY
3
relative gene expression
3
relative gene expression
Adult
(post-X inactivation)
Embryo
(pre-X inactivation)
These are the predictions we hope the
students will produce.
Gene A
2
1
Gene B
2
1
0
0
XX
XY
XXY
XX
XY
XXY
Experimental Testing of the Prediction
(Werler et al. 2011)
• Subjects - Adult mice with following phenotypes:
– XY
– XX
– XXY* (model for Klinefelter’s)
• Examined gene expression (RNA) for multiple
genes on the X chromosome in multiple tissues
Results from two different genes in adult mice
In groups, discuss whether these data support either of your
predictions, and how.
Gene 2
Gene 1
** p < 0.01
From Werler et al. 2011
Clicker Question
What can you conclude from these data?
a) Some genes on the X chromosome escape Xinactivation.
b) Some genes on the X chromosome are only expressed
during early development.
Gene 1
Gene 2
** p < 0.01
What additional questions do you have
about X-inactivation?
Topics for next class:
Molecular mechanisms of X-inactivation.
How one X chromosome avoids inactivation.
Counting mechanism(s)?
One minute essay
On your 3 X 5 card, write a few sentences proposing an
explanation for the aneuploid disorders associated with
45, XO and 47, XXY.
End of Teachable Tidbit
Diversity
o Featured a woman scientist
o Diversity of human phenotypes
o Variety of Bloom’s level
o Individual and group class work
o Variety of modalities – written, oral, video
o Inclusive of people with red/green color blindness
Learning Outcomes
Assessment
Explain why neither XX or XY
results in a gene dosage disorder
Formative: RTL Quiz (individual
and group)
Suggest why sex chromosome
aneuploidy causes abnormal
phenotypes
Formative: Hypotheses;
comparison of data to
predictions
Summative: 1-minute essay
Predict differences in expression
with and without X-inactivation
Formative: Draw predictions
Interpret graphs from the literature Formative: Compare group to
and draw conclusions
peer and published work
Work as a team to generate
hypotheses and predictions
Formative: Compare group to
peer work
Feedback
• Was our activity effective?
• Do you feel our goals, outcomes and
assessments are aligned?
2013 Heredity Team
ACKNOWLEDGEMENTS
Robin Wright
Facilitators
Kathy Miller, Washington University, St. Louis
Victoria Corbin, University of Kansas
National Academies NorthStar Summer Institute for Undergraduate Science Education
Ref for data presented in tidbit: Werler et al., 2011. Acta Pediatrica. 100:855-891
Background image: detail from Heredity by Regina Valluzzi