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104 Cards in this Set

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What are the major trisomies?
16 (lethal)
13 (Patau), 18 (Edward's), 21 (down syndrome)
XXX, XXY (Klinefelter's), XYY (Supermales)
What is the only monosomy we studied?
Turners syndrome (XO)
What are the three different types of chromosomes
-metacentric
-submetacentric
-acrocentric
Name acrocentric chromosomes?
-13,14,15, 21, 22
ttaggg
telomer end sequence
Why would you do a karotype?
-suspected abnormality
-congenital malformation
-mental retardation
-advanced maternal age (>35)
-family history
-infertility in parents
-sex diffferentiation disorder
-multiple miscarriages
What are types of chromosome abnoprmalities
-inversion
-translocation
-deletion
-monosomy, trisomy, triploidy
What type of nondisjunction is 123
meiosis 1 nondisjunction
uniparental isodisomy
trisomic rescue after a meiosis II event leads to two copies of the same gene from one parent.
Trisomic rescue
-occurs after a nondisjunction event to kick out one of the three chromosomes
uniparental disomy
- trisomic rescue following a meiosis I event - i.e. 123, the 3 gets kicked out and you get 12, this is both from one parent, but they are different genes
wolf-herchorne?
4p deletion
Pericentric
-refers to a duplication or inversion that involves the centromere
paracentric
-referes to a duplication or and inversion that does not involve the centromere (normally on the q arm)
Robertsonian translocation
-normally involves acrosentric chromsomes
-the q arms of two chromosomes comes together and the p arms are lost
-this is normally fine for the subject, but results in high percentages of abnormal offspring
Wilms tumor
-cancer
-deletion 11p15
Beckwith-Wiedmann
+ 11p15
Digeorge/VLS
deletion
-22q11
Cat eye
+22q
centromere
- the primary constriction, looks like a pinch
what is the p arm?
-short arm of the chromosome
-contains lots of satellite DNA (repitions of DNA
-also is where the ribosomal RNA is kept
giesma stain
-staining technique
-stain hits AT rich regions
-CG regions tend to be lighter because (active chromatin turns out lightly because it is loosely packed and subjected to degradation by trypsin
isochromosome
you get a 2p chromosome and a 2q chromosome due to improper splitting - it splits the wrong way during mitosis
acentric
without a centromere
-means that you end up with monosomy; you loose the chromosome because it cannot attach to the mitotic spindle
FISH
-fluorescent insitu hybridization
-has a DNA probe complementary tothat region - wherever it binds it flouoresces
-for instance telomeric probes can tell you were the telomers are and if there is telomeric deletion, etc.
SKY
-Spectral karotyping using different dyes
-used for tumors
what is the most common cause of down syndrome?
-maternal meiosis I error (old mommy)
Fragile X syndrome
-methylation at a portion of the gene silences it
-lots of mental retardation & bad behavior
CGH - comparative genomic hybridization
take the sample DNA and try to hybridize it to the normal DNA, the areas that don't overlap suggest a deletion/insertion, etc...
Prader-Will Syndrome
- 2 copies of MATERNAL 15.11
Angelman Syndrome
- you have two copies of PATERNAL 15.11
post pubertal testicular failure, small testes, azoospermia, gynecomastia, dull socially mall adjusted
Klinefelters
normal sex development, fertile, tall thin habitus, weak slow jail story, antisocial, explosive behavior, reduced IQ
- supermales (XYY)
aneuploidy
# of chromosoems is abnormal - either yo have extra or missing chromosomes
The four steps in Positional cloning
1. Family studies and genetic linkage analysis - co-inheritance of the disease nad genetic markers revelals the approximate chromosomal position of the gene
2. Cloning the chromosomal region fo the disease gene - large DNA clones that encompass the disease gene's position are isolated from genomic DNA libraries
3. Transcript mapping - Candidate genes are mapped to genomic clonzes to hybridize them to mRNA transcripts from the tissues of the affected diseases
4. search for a mutation

-establish the relationship between mutations in the candidate gena dn the disease
Retinoblastoma
pRB - a tumor suppressor gene that is often mutated in cancer
positional cloning
-locating a disease causing gene on a chromosome based on its linkage to genetic markers

- the gene that is sufficient for a specific trait or disease and for which an inheritance pattern can be determinded can be located ona chromoseome and isolated by exploiting its linkage to known genetic markers
BRCA1
the breast cancer gene
What are the two types of cancer genes
1. oncogenes - promote unrestrained cell proliferation
2. tumor suppressor genes - negatively regulate cell growth, are often mutated in tumor growth
inheritance of breast cancer gene is ...
- inherited as a dominant genetic trait
-results in a predisoposition or susceptibility to cancer
How does BRCA1 act as a recessive allele?
-loss of both copies is required for cancer
genetic marker
-distinguish parental and maternal contributions to chromosomes to the offspring
-distinct alleles of the se polymorphisms that cna be traced through families are used as genetic markers
What are RFLPs used for in positional cloning?
- used with BRCA-1 to determine if you have the genetic marker that would indicated you have the disease
-result from the differences in the DNA sequecnes of a chromosome region that alter the band pattern generated by digestion with restiction enzymes
how do we clone the chromosomal region of the disease gene?
- genomic DNA gragments that contain the candidate gene are isolated froma l ibrary of overlapping clones that collectively encompass the chromosomal region
-library is preconstructred from NORMAL human genomic DNA
-hybridize probes to genomic libbrary to identify clones
what kind of DNA can you use to clone the chromosomal region of the DNA?
-normal human DNA
How does loss of BRCA1 lead to cancer
-BRCA1 is involved in DNA repair, loss of BRCA1 doesn't directly lead to cancer, but the cell starts to accumulate other mutations, if the mutation is in an important gene like p53, then this can lead to disregulation of the cell cycle and unregulated cancer growth
candidate genes
-genes that we think are the BRCA gene due to their expresison in the tissue (active), there proximity to a genetic marker, and also their location (potentially).
transcript mapping
-fragment s of genomic clones identified in step 2 are used as probes to ID expressed genes in the region of tissue that you're looking at
what is the strucutre of the nuclear envelope?
-TWO lipid bi-layers
-the outside bilayer is connecte to the ER
what is the role of the laminins in the nucleus
-keeps the chromatin in place (anchor)
-is a point of attahment for NP
-is important for Tx
-gives rigidity to the cell
what holds the nucleoli in place in the nucleus
-probably proteins
-also, fibers extending into the nucleus can hold the nucleoli in place
how do nuclear pores regulate traffic into and out of the nucelus?
- gives signals to the nucleus about when to turn genes on and off
-controls the movement of patricular molecules through the nucleus
NP complex
Nuclear pore complex
-regulates transport of molecules
-8 fold symmenry
-"basket" on the inside of the nuclear membrane
POM121
proteins that hold the NP in contact with the lipid bilayer
gp210
proteins that hold the NP in contact with the lipid bilayer
proteins that hold the NP in contact with the lipid bilayer
gp210
POM121
Emerin
-protein found near/in the NP/nuclear membrane
-defect in emerin leads to Emery-Dreifuss muscular dystropy
-Emerin-baf is required for HIV infection, but is also required for other cellular processes
LAP2
a protein found in the nuclear membrane required for infection with retroviruses (non-HIV)
LBR
a protein found in the nuclear membrane
Lamin B receptor - important for diseases
-hetoxygous LBR mutations causes Peger-Huet abnomaly in granulocytes
-homozygous LBR mutations cause Greenberg skeletal dysplasia
Peger-Huet abnomaly
-hetoxygous LBR mutations causes Peger-Huet abnomaly in granulocytes
Ran-GTP/GDP
complex is responsibe for setting up the cytoplasmic-nuclear gradient

involved in transporting cargo across the nuclear membrane through the nuclear pores.
NLS
- nuclear localization signal found on proteins causes the cargo to be directed to the inside of the nucleus with the help of importin and Ran-GTP.
explain how importation works
importin binds cargo with NLS signals, brings it thorugh the nuclear pore, Ran-GTP binds importin causing a conformational change and causing it to drop it's cargo in the inside
explain how exporation works
Ran-GTP binds exportin, which binds the cargo, they travel across the nuclear membrane; in the cytoplasm, hydrolsyis of the GTP causes the release of the cargo from emportin
Ran-GTPase activating protein
on the cytoplasmic side, helps cause the hydrolysis of GTP to GDP (with the help fo RAN BP1 (Ran binding protein)
RanBP1
a binding protein found on the cytoplasmic side that helps convert Ran GTP --> Ran GDP
RCC1
exchanges GDP for GTP. activates Ran as RanGTP
why is nuclear regulation important?
- to partition factors for timed interactions or regulated interactions
-speed of export can change splicing patterns and change expression of proteins
what major molecule is responsible for the nuclear encelope coming apart during mitosis?
-the NE is pulled apart by DYNEIN anchored ot the NE as its pulled along microtubles, it stretches until it breaks
baf
protein that works with emerin to bind the chromatin to the lamin
autosomal dominant and recessive forms of EDMD
-Disease associated with Lamin A
-Limb-gridle muscular dystrophy
-Disease associated with Lamin A
-dilated cardiomyopathy
-Disease associated with Lamin A
dunnigan-type familial partial lipodystrophy
-Disease associated with Lamin A
-charcot-Marie tooth disorder type 2
-Disease associated with Lamin A
Hutchison-Gilford progeria syndrome
-Disease associated with Lamin A
atypical werner syndrome
Disease associated with Lamin A
purpose of the cell cycle
to produce genetically identical daughter cells
Which two cells cycle phases have the same amount of DNA?
mitotic cells and cells in G2
cells that have completed mitosis have what two options?
-continue through G1 phase and enter s phase
-exit the cell cycle and enter Go
restriction point
a reugulatory point late in G1 phase - after pasing htis point, cells are committed sto entering s phase, the point of no return
passage through the restriction point is dependent on?
-presence of growth factors
-integrin mediated adhesion to the extracellular matrix
what are the characteristics of a G1 phase cell?
-prepare for entry into s phase by assembling pre-replication complexes which remain inactive until the initiation of DNA synthesis
-synthesize ribosomal RNA and proteins to support synthetic activity required for doubling of cell mass during the cell ccle
checkpoints - what are they and what are the three types?
-DNA damage checkpoints arrest cells in G1 phase

-purpose is to prevent a cell from replicating damaged DNA

-replication checkpoint
-S-M checkpoint
-Intra-S checkpoint
restriction point vs. replication checkpoint
-restriction point - there must be GF, enough nutrients & integrin mediated adhesion to get back the checkpoint - the point of noreturn for S phase entry

-replication checkpoint - in s phase cells, if there is an error at the replication fork, everything will be slowed and or halted until the damage can be repaired
characteristics of Go arrest
-cell has the same DNA content as a G1 phase cell
-cell has not passed the restriction poitn
-cells are not synthesizing proteins required for DNA synthesis
-cell is metabolically active
-cell type specific proteins may be expressed
conditions that result in Go arrest include
-absence of growth factors
-absence of amino acids (nutritional deprivation)
-cell cell contact
What is the difference between anaphase A and anaphase B?
anaphase A - shortening of the kinetochore MTs , movement of daughter chromosomes to poles

anaphase B - a sliding force is generated between overlap MTs from opposite poles to push the poles apart
spindle checkpoint
- cells will not initiate anaphase untill al the chromosomes have attached to the spindle
G2 functions
- get ready for mitosis
-synthesize all the machinery and proteins for M
three different types of MTs
astrial MTs
kinetochore MTs
overlapping MTs
MPF
Mphase promoting factor
-is made of CDC2/CDK1 + cyclin B
-very important !!!

Activation of CDC2/cyclin B causes the cell to go into mitosis (proteins involved : wee1 (inhib), Cdk activating kinase (activating), CDC25 phosphatase (activating)
wee1
-inhibits cdk1/cyclin B activity by phosphorylating the ATP binding site on the cdk1/cyclin B complex
-INHIBITS
Cdk activating kinase
- phosphorylates cdk1/cyclin B at another spot to activate it - won't be active until the wee1 phosphate is removed though!
CDC25 phosphatase
-activates cdk1/cyclin B complex
-causes cell to go into mitotic phase
-removes inhibitory phosphates added by the wee1
ATM
- actiavted due to ionization radiation DNA damage
-in the G1 checkpoint, phosphorylates p53, increase p53, increase p21, p21 inhibits cdk2/cyclin E
-transcription of E2F regulated genes does not occur.
-cell does not pass the restriction point
cdk1
what cyclin does it bind
where in the cell cycle is it important?
-binds cyclin B or (cyclin A)
-G2/M transtion
-initiates mitosis
cdk2
what cyclin does it bind
where in the cell cycle is it important?
-binds cyclin A for S phase progression
-binds cyclin E for G1-s transition
cdk4
what cyclin does it bind
where in the cell cycle is it important?
-cyclin D 1,2,3
G1 progression
cdk6
what cyclin does it bind
where in the cell cycle is it important?
-cyclin D 1,2,3
G1 progression
which cyclins in associations with cdks regulate progression past the restriction point?
-cdk4/cyclin D
-cdk2/cyclin E
-cdk4/cyclin D
-cdk2/cyclin E
-regulate progression past the restriciton point
-responsible for pRB phosphorylation, pRB will then dissociate E2f, which is a Tx factor that promotes cell growth
pRB
-tumor supressor gene involved in getting past the restriction point (G1)
-normally bound to E2f, suppresses growth
ATR -
UV tends to activate
-phosphorylates Chk1 - involved in phosphorylation of CDC25, prevents activation of MPF
- if activated won't get passed G2 checkpoint