Genet 302 lec 45 & 46
What is triploidy in humans?
Having 3 complete sets of chromosomes for a total of 69 chromosomes
What is a common cause of human triploidy in this lecture?
Double fertilization of one egg by 2 sperm
What karyotype example was given for triploidy?
69,XXY
Why is triploidy nonviable because of gene imbalance?
All autosomes are present in 3 copies instead of 2, disrupting normal dosage balance
Do 69,XXY, 69,XYY, and 69,XXX embryos have the same autosomal gene dosage problem?
Yes
Why can triploidy also be nonviable because of genomic imprinting?
The extra chromosome set can create an abnormal balance of maternal and paternal imprints
In the lecture’s imprinting example for triploidy, what happens when there are 2 paternal sets and 1 maternal set?
The embryo is large and the placenta is too large
What is the overall cause and consequence of triploidy in humans?
It is commonly caused by double fertilization and is nonviable because of both whole-genome gene imbalance and abnormal imprinting balance
What is mLOY?
Mosaic loss of the Y chromosome
In what cells was mLOY emphasized in this lecture?
White blood cells made in bone marrow
Why is it called mosaic loss of Y?
Because only some cells lose the Y chromosome while others remain XY
What 45,X condition in females was compared with loss of Y?
Turner syndrome
What was the general health effect of 45,X females in this lecture?
Relatively mild health problems
How does mLOY change with age in men?
It increases with age
Does age-related chromosome loss also happen for the X chromosome in women?
Yes
Does age-related loss also increase for autosomes in this lecture?
No
What possible mitotic causes of mLOY were emphasized?
Nondisjunction, anaphase lag, late DNA replication, and telomere loss leading to degradation
How can mitotic nondisjunction cause mLOY?
Sister chromatids segregate improperly, producing one cell with YY and one with no Y
How can anaphase lag cause mLOY?
The Y chromosome fails to enter the daughter nucleus and is lost
What environmental factor increases risk of mLOY?
Smoking
Why does mLOY matter medically?
It is associated with cancer, heart disease, Alzheimer disease, and increased COVID-19 lethality
What key causal question was tested in the mouse study?
Whether mLOY causes heart disease
How was the mouse model of mLOY created in principle?
Bone marrow cells were edited to lose the Y chromosome and then transplanted into a recipient mouse
How was CRISPR used to get rid of a mouse chromosome without repair?
Cas9 plus guide RNA targeted the Y centromere so the Y chromosome was lost
What was targeted by the CRISPR guide RNA to remove the Y chromosome?
The Y centromere
What was used as the negative control in the chromosome-loss experiment?
Cells treated with a CRISPR setup targeting nothing
Why are negative controls essential in experiments like this?
They show whether the observed effect is due specifically to the treatment rather than the procedure itself
How was the recipient mouse prepared before bone marrow transplantation?
Its existing bone marrow was destroyed with X rays
What was transplanted into recipient mice?
Control bone marrow cells or LOY bone marrow cells
What does FISH show when verifying mLOY cells?
Control cells are XY while mLOY cells are XO
How can karyogram analysis identify mLOY?
By showing loss of the Y chromosome from the chromosome spread
How can mRNA quantification identify mLOY?
Y-linked transcripts are greatly reduced or absent
What overall result showed the mouse model had many LOY cells?
Most blood cells in experimental mice were LOY compared with control mice
What effect did mLOY have on mouse survival?
It decreased longevity
When were heart problems in mLOY mice especially obvious?
After minor surgery used to provoke a cardiac response
What heart tissue change was increased in mLOY mice?
Fibrosis, with excessive collagen deposition
What conclusion was emphasized from the mouse study?
mLOY does cause heart disease
What mechanism was proposed for mLOY causing heart disease?
Defective white blood cells enter the heart and promote excessive collagen synthesis