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50 Cards in this Set
- Front
- Back
Genetic Anticipation
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-Severity of genes increases with successive generations
-involves trinucleotide repeats (CAG and CGG being most common) of variable length within their immediate vicinity |
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Genetic Anticipation: What makes it different from normally polymorphic genes in the general population
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-The repeat number is expanded well beyond the expected polymorphisms
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Premutations
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-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 |
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Because of the propensity for the mutation to change from generation to generation, trinucleotide expansions are considered ___ _____.
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Dynamic mutations
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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.
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Threshold effect
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Ways in Which a Trinucleotide Expansion can Cause Abnormalities
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1.Methylation of CpG Dinucleotide
2. Interference with Transcription 3. Toxic RNA 4. Polyglutamine Tract Toxicity |
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What does heavy DNA methylation result in with patients with Fragile X syndrome?
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-Transcription silencing of the FMR1 gene
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Individuals with fragile X syndrome and the same number of repeats may have ______ degree of methylation.
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Vary
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Higher degree of methylation is associated with a _____ severe disease phenotypes.
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More
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Methylation of CpG Dinucleotide: In fragile X syndrome, the trinucleotide repeat sequence ______ is in the 5' UNTRANSLATED REGION of the _____ gene
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-CGG
-FMR1 |
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Interference with Transcription: In Friedreich ataxia, the trinucleotide repeat sequence ______ is an INTRON of the ______. (What does this reeat sequence interfere with?)
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-GAA
-frataxin -transcription splicing of the gene |
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Toxic RNA: In myotonic dystrophy, the trinucleotide repeat sequence _____ is in the 3' UNTRANSLATED REGION of the gene _____. (Why does this happen?)
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-CTG
-DMPK -RNA carrying the expanded repeat sequence CUG interferes with normal RNA handling and metabolism (mechanism still being worked out) |
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Polygluatmine Tract Toxicity: In Huntington disease, the trinucleotide repeat ____ is in the CODING REGION. (What does this result in?)
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-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 |
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Meiotic Drive
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Segregation Distortion
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Disorders that demonstrate meiotic drive
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-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) |
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Lyon Hypothesis
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-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 |
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Barr Body
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Inactive X chromosome can be seen as a dense body attached to the nuclear envelope of cells from a female individual
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Where does X chromosomal inactivation occur at in the early embryo?
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1,000 to 2,000 cell stage in the early embyro (Late blastocyst stage)
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What is the chance for a paternal or maternal X to be inactivated?
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50% of cells will have an active X(p) and 50% of the cells have an active X(m)
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The pattern of X-inactivation is inherited accurately during ______. (Why does this happen?)
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-Mitosis
-Daughter cells will inactivate the same X chromosome as their parent cells |
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All X chromosomes are re-activated during ____.
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Meiosis
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The X counting mechanism must be able to take into consideration the ____ of the cell.
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Ploidy
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X-inactivation is genetically determined and controlled by ____ _____ ____.
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cis-acting elements
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The X-inactivating function maps to what region? What is this called?
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-the long arm of the X-chromosome Xq13.2
-X-inactivation center (XIC) |
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What two genes are in the region of the X-inactivation center (XIC)?
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-XIST
-TSIX -->Genes overlap and are in opposite orientation with each other |
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What does TSIX produce?
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-RNA transcript which is antisense to the XIST RNA
-Gene within X-inactivation center (XIC) |
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_____ 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.
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-XIST
-RNA |
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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:
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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 |
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What occurs following transcription and spreading of XIST RNA?
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-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 |
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What are the names of the 2 small regions of the X chromosome escape inactivation?
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Pseudoautosomal region (PAR)
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Major Pseudoautosomal region (PAR1)
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-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 |
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Minor Pseudoautosomal region (PAR2)
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-Located at the extreme telomeric end of Xq (and Yq)
-Contains 4 genes and recombination in this region is infrequent |
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Somatic Mosaic
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-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
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Non-Random X-inactivation (or skewed X-inactivation)
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A significant deviation form the expected 50% chance of inactivating the X chromosome with the normal allele
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What may happen when skewed X-inactivation results in >>50% of X chromosomes carrying the normal allele being inactivated, what happens?
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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
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4 Explanations for non-random X-inactivation
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-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 |
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Monozygotic twinning
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-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) |
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In a female with a balanced X-autosomal translocation, the X-chromosome with the translocation is always _____.
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Active
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If the X-autosomal translocation interrupts a gene on the X chromosome, the disease will always be manifested in the _____.
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female
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If a mutant allele on an X chromosomes negatively impacts cell survival, cells forom females heterozygous for the allele will always have an ____ ___ ____ ____ ___ chromosome.
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Active normal-allele bearing X chromosome
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Fragile X syndrome
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X-linked disorder caused by mutations in the FMR1 gene which maps the Xq28
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Where does the FMR1 gene map?
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Xq28
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Fragile X syndrome: a stretch of trinucleotide repeats _____ is present within the 5'untranslated region of the gene.
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CGG
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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.
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-60
-200 |
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Fragile X syndrome: Individuals with ____ to ____ repeats have what has been called premutation.
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60 to 200 repeats
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Transmitting Male
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Father who is phenotypically normal when his two daugthers who are phenotypically normal who all have children with fragile X syndrome
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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) |
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Myotonic Dystrophy
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-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) |
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Proteins derive from genes via ____, which itself derives from ____ _____.
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-mRNA
-precursor (pre-)-mRNA |
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Each _____ ____ of a protein derives from an mRNA sequence of 3 nucleotides termed a ____.
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-Amino Acid
-Codon |