Genetics Week 2 Flashcards
What is imprinting?
A naturally occurring epigenetic difference between certain alleles expressed at the paternal and maternal loci of a chromosome set.
In this certain subset of genes, either the maternal set or the paternal set is expressed, but not both. Imbalance of this leads to imprinting disorders.
Both the paternal and maternal copies of the genes must be there for functional expression.
what causes Prader-Willi Syndrome?
An interstitial microdeletion on chromosome 15 at site q11-q13.
PATERNAL CHROMOSOME
Essentially,the genes at position q-12 are gone from #15.
Which has more mental dysfunction: a child with Prader-Willi or a child with Angelman?
Angelman - only moderate retardation with Prader-Willi
Can a person inherit an epigenetic alteration of DNA?
Yes, but anything epigenetic is REVERSIBLE
What are the 3 examples of epigenetics she gave us?
- Methylation - regulation of gene expression, may be dynamic.
- X inactivation - heritable from cell to cell but not passed to offspring
- Genomic Imprinting: Parent of origin effects; transmitted through gametes.
- what happens to the kid is based on which parent they inherit the imprint from.
What protein is lost in Prader-Willi Syndrome?
Paternal chromosome 15,q12 codes a SNRP called
SNRPN –> only copies we have are from Dad.
(Small Nuclear Ribonucleaprotein N)
What protein is lost in Angelman Syndrome? How is this related to the symptoms of the disease?
UBE3A -Ubiquitin Protein Ligase 3
Only the maternal UBE3A is expressed in the brain, but both copies are expressed everywhere else in the body.
This results in the SEVERE MENTAL RETARDATION associated with Angelman.
What do we blame for the micro deletions in Prader-Willi and Angelman syndromes?
Low Copy Repeats causing unequal crossing over.
The common deletion points encompass the critical region for BOTH DISEASES
Describe the Etiology of Prader-Willi Syndrome.
70% paternal micro deletion of chromosome 15
28% maternal uniparental disomy
2% mutation of imprinting center
Describe the Etiology of Angelmann Syndrome?
70% maternal microdeletion
Less than 5% paternal uniparental disomy (RARE)
10% UBE3A point mutations (hereditary)
10% unknown
Women are always more complicated.
What is uniparental disomy?
An individual inherits both chromosomes of one homologous pair from a single parent and NO copy of that chromosome from another parent.
WTF is trisomy rescue?
Initially, a nondisjuction arises in meiosis that leads to trisomy at conception.
The rescue part occurs when a SECOND nondisjuction occurs (this time in MITOSIS) that results in loss of a chromosome in early embryogenesis.
This can result in UNIPARENTAL DISOMY if the lost chromosome was from the parent opposite that of the original meiotic nondisjuction.
What is the chance the paternal chromosome gets lost in normal Trisomy Rescue?
1/3, because there are 3 chromosomes that can get lost.
What has to happen to yield UNIPARENTAL DISOMY?
Tw independent errors. One in meiosis, then trisomy rescue nondisjuction error in MITOSIS during early embryogenesis.
FACT: VERY RARE to see Parental disomy in Angelmann syndrome. More common to see MATERNAL UNIPARENTAL DISOMY in Prader-Willi syndrome.
Yes.
What is the most common form of inherited mental retardation?
Fragile X Syndrome - 1 in 5000 males.
What is the genetic basis of Fragile X?
Trinucleotide Repeat Expansion Disorder.
CGG expansion in the 5’ UNTRANSLATED region of the FMR1 gene. Expansion is accompanied by METHYLATION which shuts off gene expression.
What percentage of males that inherit the fragile X expansion are affected? Females?
100% of males (only 1 X chromosome)
50% of females due to random X inactivation
Is Fragile X syndrome considered a LOF or a GOF mutation?
LOSS OF FUNCTION - FMR1 gene is shit down by expansion and resulting methylation
HOw many CGG repeats must accumulate for a person to express a Fragile X allele?
200-1300 repeats = FRAGILE X
6-54 is NORMAL
55-200 is PERMUTATED ALLELE (threatens dysfunctional expansion in future generations)
Fact: FMR1 is a polymorphic gene. It naturally has variation in copy number. It’s when this copy number gets expanded by CGG repeats that it has disease tendency.
Remember: 6-54 = normal
Yes.
Expansion of premutated (carrier) FMR1 genes to full-blown Fragile X Syndrome only occurs in __________ __________.
Female Meiosis
Expansions of a trinucleotide (CAG) coding for GLUTAMINE is characteristic of what trinucleotide repeat expansion disorder?
Huntingdon’s
What are the differenced between Fragile X and Huntingdon’s?
FRAGILE X:
- LOF
- Noncoding sequence
- CGG repeat
- 200+ repeats = disease
- FMR1 gene
- X-linked
- childhood onset
HUNTINGDONS:
- GOF
- Coding sequence
- CAG = polyglutamine repeats
- 36+ repeats = disease
- Autosomal Dominant
- Adult onset
What causes the neuronal damage associated with Huntingdon’s?
Abnormal proteins aggregate near neurons.
What TNR (Trinucleotide repeat) Expansion causes LOF and decreased gene expression?
Fragile X
What TNR causes expansion of polyglutamine tract, and produced toxic protein aggregates?
Huntingdon’s
What TNR has 3’ expansion of the untranslated region, DISRUPTING SPLICING?
Mytonic Dystrophy
slide 12 of handout
You’re more likely to get Huntingdon’s disease from a paternal or maternal meiosis expansion of the gene?
What about Fragile X?
PATERNAL Meiosis expansion = Huntingdon’s
MATERNAL Meiosis expansion = Fragile X
What does the term “anticipation” mean when applied to Trinucleotide Repeat Expansion Disorders?
A general feature of TNR disorders is progressive expansion of the gene with each successive generation. Copy number increases from generation to generation.
Progressive earlier onset and increased severity as families continue to reproduce.
Affected Huntingdon’s individuals have greater than _____ copy #s. What about Fragile X?
Huntingdons: More than 36
Fragile X: More than 200
“Direct testing” is also called…..
Genotyping for one or more specific mutations.
What are the pros and cone of direct genetic testing? (AKA genotyping)
Pro: Very accurate and specific FOR THE GENES TESTED
Con: Only tests for the specific genes you determine, so it can only test for KNOWN MUTATIONS.
What molecular method is used in direct testing?
What is its limitation?
DNA hybridization with ALLELE-SPECIFIC NUCLEOTIDES
Limitation: Only perfect hybrids will be detected.
WTF is a homoduplex?
2 matching, complimentary sequences of DNA that can hybridize
How do you use direct testing to screen for a Trinucleotide Repeat Disorder?
Direct testing and allele sizing.
- Use gene-specific primers on flanking regions of the trinucleotide repeat region.
- PCR amplification of flanked region
- Elecrophoresis to separate by size.
SIZE OF PCR PRODUCT REFLECTS REPEAT #
