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50 Cards in this Set

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  • Back
Genetic Anticipation
-Severity of genes increases with successive generations
-involves trinucleotide repeats (CAG and CGG being most common) of variable length within their immediate vicinity
Genetic Anticipation: What makes it different from normally polymorphic genes in the general population
-The repeat number is expanded well beyond the expected polymorphisms
Premutations
-Individuals with an intermediate repeat number (genetic anticipation)
-At high risk for having affected children because of meiotic instability of the repeats results in their further expansion to full mutations in germ layers
Because of the propensity for the mutation to change from generation to generation, trinucleotide expansions are considered ___ _____.
Dynamic mutations
Disorders caused by trinucleotide expansions also demonstrate ___ ___, int that hte range of repeat number for normal individuals, premutations carrier and affected individuals can often be clearly defined.
Threshold effect
Ways in Which a Trinucleotide Expansion can Cause Abnormalities
1.Methylation of CpG Dinucleotide
2. Interference with Transcription
3. Toxic RNA
4. Polyglutamine Tract Toxicity
What does heavy DNA methylation result in with patients with Fragile X syndrome?
-Transcription silencing of the FMR1 gene
Individuals with fragile X syndrome and the same number of repeats may have ______ degree of methylation.
Vary
Higher degree of methylation is associated with a _____ severe disease phenotypes.
More
Methylation of CpG Dinucleotide: In fragile X syndrome, the trinucleotide repeat sequence ______ is in the 5' UNTRANSLATED REGION of the _____ gene
-CGG
-FMR1
Interference with Transcription: In Friedreich ataxia, the trinucleotide repeat sequence ______ is an INTRON of the ______. (What does this reeat sequence interfere with?)
-GAA
-frataxin
-transcription splicing of the gene
Toxic RNA: In myotonic dystrophy, the trinucleotide repeat sequence _____ is in the 3' UNTRANSLATED REGION of the gene _____. (Why does this happen?)
-CTG
-DMPK
-RNA carrying the expanded repeat sequence CUG interferes with normal RNA handling and metabolism (mechanism still being worked out)
Polygluatmine Tract Toxicity: In Huntington disease, the trinucleotide repeat ____ is in the CODING REGION. (What does this result in?)
-CAG
-The triplet expansion results in a lengthened polyglutamine tract in the Huntington protein. In affected neurons, protein precipitates can be observed and neuronal death follows
Meiotic Drive
Segregation Distortion
Disorders that demonstrate meiotic drive
-Myotonic dystrophy
-Fragile X Syndrome
-Males with Huntington disease
(genetic anticipation only occurs in the female germline in females for myotonic dystrophy and fragile X syndrome, and only in males with Huntington)
Lyon Hypothesis
-States that in any given cell, there is only one active chromosome
-This allows for dosage compensation between male and female
-Inactive X=Barr Body
Barr Body
Inactive X chromosome can be seen as a dense body attached to the nuclear envelope of cells from a female individual
Where does X chromosomal inactivation occur at in the early embryo?
1,000 to 2,000 cell stage in the early embyro (Late blastocyst stage)
What is the chance for a paternal or maternal X to be inactivated?
50% of cells will have an active X(p) and 50% of the cells have an active X(m)
The pattern of X-inactivation is inherited accurately during ______. (Why does this happen?)
-Mitosis
-Daughter cells will inactivate the same X chromosome as their parent cells
All X chromosomes are re-activated during ____.
Meiosis
The X counting mechanism must be able to take into consideration the ____ of the cell.
Ploidy
X-inactivation is genetically determined and controlled by ____ _____ ____.
cis-acting elements
The X-inactivating function maps to what region? What is this called?
-the long arm of the X-chromosome Xq13.2
-X-inactivation center (XIC)
What two genes are in the region of the X-inactivation center (XIC)?
-XIST
-TSIX
-->Genes overlap and are in opposite orientation with each other
What does TSIX produce?
-RNA transcript which is antisense to the XIST RNA
-Gene within X-inactivation center (XIC)
_____ inactivates the chromosome that it resides in by producing an ____ that spreads from the site of its transcription in a bidrectional manner, eventually coating almost the entire X chromosome.
-XIST
-RNA
The mechanism of how X-inactivation is initially triggered is poorly understood, but recent evidence suggests that 2 XIC may first pair with each other, whereupon the following events occur:
1. Decrease in the expression of the TSIX gene from the X chromosome that will be inactivated
2. A temporary chromatin-mediated silencing of the XIST gene by a surge of its expression on the chromosome that will be inactivated
What occurs following transcription and spreading of XIST RNA?
-The X chromosome becomes inactivated following the same pathways of histone modification
-XIST RNA can recruit other DNA- and histone-modifying proteins that lead to the processive heterochromatization of the entire X chromosome
*****As a result, all genes within the heterochromatin region are inactivated
What are the names of the 2 small regions of the X chromosome escape inactivation?
Pseudoautosomal region (PAR)
Major Pseudoautosomal region (PAR1)
-Located at the extreme telomeric end of Xp (and Yp)
-2.6Mb in length and contains 13 genes
-Recombination between the X and Y chromosomes occurs commonly within this region
Minor Pseudoautosomal region (PAR2)
-Located at the extreme telomeric end of Xq (and Yq)
-Contains 4 genes and recombination in this region is infrequent
Somatic Mosaic
-When a female is heterozygous at a locus on the X chromosome, each of her cells will only express one of the two alleles, but not both
Non-Random X-inactivation (or skewed X-inactivation)
A significant deviation form the expected 50% chance of inactivating the X chromosome with the normal allele
What may happen when skewed X-inactivation results in >>50% of X chromosomes carrying the normal allele being inactivated, what happens?
The patient may become symptomatic due to significant decrease in normal gene function, much like a male with the X-linked recessive mutation=an occasional female may be seen that shows symptoms of an X-linked recessive trait, such as hemophilia A
4 Explanations for non-random X-inactivation
-Chance
-Monozygotic twinning
-X-chromosome with translocation is active in a female with a balanced X-autosomal translocation
4. If a mutant allele on an X chromosome negatively impacts cell survival, cells from females heterozygous for the allele will always have an active normal-allele bearing X chromosome
Monozygotic twinning
-Disease manifesting twin=inactivated most of the normal chromosome
-Non-disease manifesting twin=has inactivated most of the mutation-carrying X chromosome
(Could have been the consequence of cell surface differences caused by X-inactivation resulting in division of the early embryo)
In a female with a balanced X-autosomal translocation, the X-chromosome with the translocation is always _____.
Active
If the X-autosomal translocation interrupts a gene on the X chromosome, the disease will always be manifested in the _____.
female
If a mutant allele on an X chromosomes negatively impacts cell survival, cells forom females heterozygous for the allele will always have an ____ ___ ____ ____ ___ chromosome.
Active normal-allele bearing X chromosome
Fragile X syndrome
X-linked disorder caused by mutations in the FMR1 gene which maps the Xq28
Where does the FMR1 gene map?
Xq28
Fragile X syndrome: a stretch of trinucleotide repeats _____ is present within the 5'untranslated region of the gene.
CGG
Fragile X syndrome: Normal individual can have up to ___ repeats. However, individuals with over ____ repeats will have mild to moderate (if female) or severe (if male) mental retardation.
-60
-200
Fragile X syndrome: Individuals with ____ to ____ repeats have what has been called premutation.
60 to 200 repeats
Transmitting Male
Father who is phenotypically normal when his two daugthers who are phenotypically normal who all have children with fragile X syndrome
Sherman Paradox
---> How was this conundrum resolved?
-In 1985, Stephanie Sherman noted that while daughters transmitting males often have children with fragile X syndrome, their mothers almost never do
-FMR1 (repeat unstable in women=only female premutation carriers will have children with fragile X syndrome)
Myotonic Dystrophy
-Autosomal dominant condition characterized by myotonia and muscle wasting
-Clinical manifestation in infancy is only seen when the disease is inherited from the mother (Huntington=expansion occurs in the male germline)
Proteins derive from genes via ____, which itself derives from ____ _____.
-mRNA
-precursor (pre-)-mRNA
Each _____ ____ of a protein derives from an mRNA sequence of 3 nucleotides termed a ____.
-Amino Acid
-Codon