Genet 302 lec 27 & 28
What are the main genetic causes of Down syndrome covered in lecture 27?
Full trisomy 21, unbalanced Robertsonian translocation involving chromosome 21, unbalanced isochromosome 21, duplication of part of chromosome 21, and somatic mosaic trisomy 21
What is the most common genetic cause of Down syndrome?
Full trisomy 21
What karyotype is typical for full trisomy 21?
47,XX,+21 or 47,XY,+21
About what proportion of people with Down syndrome have full trisomy 21?
About 95%
What is the main parental-age effect for Down syndrome?
A maternal age effect
Is there a paternal age effect emphasized for Down syndrome in this lecture?
No, the lecture emphasized maternal age, not paternal age
Why does maternal age increase the risk of trisomy 21?
Because oocytes pause in prophase I for years, and age-related cohesin deterioration can increase chromosome nondisjunction
What does cohesin do in meiosis?
It helps hold homologs together and helps hold sister chromatids together
What is the cohesin deterioration model for Down syndrome?
Over time cohesin weakens in arrested oocytes, increasing abnormal chromosome attachments and nondisjunction during meiosis
What is the recurrence risk for a couple after a child with standard trisomy 21?
About 1% to 10%, depending mainly on maternal age
What is a reciprocal translocation?
An exchange of chromosome segments between 2 nonhomologous chromosomes
What is a balanced translocation genotype?
The correct amount of genetic material is present, just rearranged
What is an unbalanced translocation genotype?
There is extra or missing genetic material
What is a Robertsonian translocation?
Fusion of the long arms of 2 acrocentric chromosomes, with the short-arm fragment lost
Why can the short-arm fragment be lost in a Robertsonian translocation?
It may lack a centromere, is hard for microtubules to attach to, and contains only some rRNA genes
What proportion of people with Down syndrome have an unbalanced Robertsonian translocation?
About 4%
What example Robertsonian Down syndrome karyotype was emphasized?
46,XX,rob(14;21),+21
Why can a balanced Robertsonian translocation carrier have children with Down syndrome?
Because meiosis can produce unbalanced gametes with extra chromosome 21 material
What recurrence risk was emphasized in general for Robertsonian-translocation Down syndrome?
About 10%
What is an isochromosome?
A chromosome made of 2 identical arms
What proportion of people with Down syndrome have an unbalanced isochromosome 21?
About 1%
Why is recurrence risk especially high for Down syndrome caused by an isochromosome 21 parent?
Because the parent can repeatedly pass on the abnormal chromosome, making the risk extremely high, often treated as near 100%
What is a duplication cause of Down syndrome?
Extra copy of only part of chromosome 21
Why is duplication 21 important conceptually?
It shows that Down syndrome can result from extra dosage of key chromosome 21 regions, not necessarily the entire chromosome
What is somatic mosaic trisomy 21? what is its common origin vs the other two possible origin.
A mixture of normal and trisomy 21 cell lines in the same person. common origin: ND in 46, XX at the two cell stage. other origins: ND in 47, XX, +21 or fusion of 46, XX and 47, XX, +21
What proportion of people with Down syndrome have somatic mosaic trisomy 21?
Less than 1%
What karyotype format was shown for mosaic Down syndrome?
46,XX/47,XX,+21
What are key detrimental phenotypes of Down syndrome emphasized in lecture 27?
Mild to moderate intellectual disability, reduced fertility, congenital heart problems, earlier onset Alzheimer disease, and increased vulnerability to severe COVID-19
What phenotype term applies to the heart defects in Down syndrome because only about half of people have them?
Incomplete penetrance
What phenotype term applies to the heart defects in Down syndrome because severity varies from mild to severe?
Broad expressivity
What beneficial or less detrimental traits were mentioned in lecture 27?
Lower blood pressure and increased social skills
Why is trisomy 21 the most common live-born autosomal trisomy?
It is more compatible with survival to birth than other autosomal trisomies discussed
What is Ts16?
A mouse trisomic for chromosome 16
Why was Ts16 not a good mouse model for Down syndrome?
Because trisomic mouse chromosome 16 includes too much extra material compared with human trisomy 21
What was the goal in generating Ts65Dn mice?
To make a mouse trisomic for the region of mouse chromosome 16 that is equivalent to human chromosome 21
How is Ts65Dn generated?
By creating a translocation involving mouse chromosomes 16 and 17 that yields an extra small chromosome carrying the Down-syndrome-relevant segment
What is the unusual extra chromosome in Ts65Dn called?
17^16
Why is Ts65Dn considered a better model than Ts16?
Because it carries extra copies of a more limited chromosome segment more equivalent to the critical human chromosome 21 region
Are Ts65Dn males and females equally fertile?
No, males are sterile and females have low fertility
How is the Ts65Dn strain propagated?
Ts65Dn females are crossed with Black-6 males
What offspring ratio is expected from Ts65Dn females crossed to Black-6 males?
About half euploid controls and half trisomic experimental offspring
What phenotypes in Ts65Dn mice parallel Down syndrome in people?
Smaller size, learning deficits, Alzheimer-related APP overexpression, and heart defects
What test was used to assess learning in Ts65Dn mice?
The Morris water maze
How do Ts65Dn mice perform in the Morris water maze compared with controls?
They are slower at finding the platform and perform worse
What Alzheimer-related gene was emphasized in Ts65Dn mice?
APP
What was observed about App in Ts65Dn mice?
They had more App mRNA and more APP protein
What important Alzheimer result in Ts65Dn mice argued against the simplest plaque-only model?
APP expression was elevated but amyloid plaques were absent up to 21 months
Which Alzheimer model did the lecture say the mouse results supported?
The alternative model. too many App proteins cause neuron damage but also protective aggregates
What is Tg(Dyrk1a)?
A transgenic mouse with 3 copies of Dyrk1a
How was Tg(Dyrk1a) made?
By pronuclear injection
Why is Tg(Dyrk1a) useful for modelling Down syndrome?
It tests the effect of overexpressing one key chromosome-21-related gene rather than an entire large trisomic region
What major similarity do Ts65Dn and Tg(Dyrk1a) mice share?
Both model Down syndrome by increasing dosage of Down-syndrome-relevant genes and both show learning defects
What is the key difference between Ts65Dn and Tg(Dyrk1a) mice?
Ts65Dn has extra copies of many genes in a trisomic segment, while Tg(Dyrk1a) has extra copies of only one gene
Why is the statement “all genes on chromosome 21 are overexpressed and that causes Down syndrome” overly simplistic?
Because the lecture argues that many major phenotypes can be explained largely by dosage imbalance of a few key genes rather than every gene equally contributing
Which key genes were highlighted in the summary as examples of this “few key genes” idea?
APP for Alzheimer disease, RCAN1 for heart defects, and DYRK1A for CNS problems
If Ts65Dn mice are crossed to reduce Dyrk1a copy number from 3 copies back to 2, what happens to water-maze performance?
It improves compared with standard Ts65Dn mice
What big idea should you remember from lecture 28 about Down syndrome models?
A broad trisomic model like Ts65Dn is useful, but single-gene models like Tg(Dyrk1a) show that specific overexpressed genes can drive specific Down syndrome phenotypes
how is Ts66Yah made from Ts65Dn
got ride of MMU17 using CRISPR-NHEJ
what current research are they doing for DS and what results did it give
algernon is a potential DYRK1A inhibtor, when treated on trisomy mice there was an increase in nuclei in s phase and showed a higher alternation percentage in a y maze
if we were to develop a ds drug who would we give it to
newborns and children with ds but also women carrying a fetus with ds
people with ds are less likely to get what disease
colon cancer