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337 Cards in this Set
- Front
- Back
percentage of HbF in sickled patients is
|
INCREASED
|
|
two reasons HbF is good for SCA patients:
|
1. HbF cells live much longer
2. can't polymerize |
|
how are there 4 alpha-globin genes in each RBC?
|
two from mom, two from dad
- can have two mutated and still be fine, because you only need two a-globin subunits for functional HbA |
|
HbS is a disease in which the B globins subunits of a normal Hb protein are mutated; the A of GAG (glutamic acid) is replaced with
|
T (=> valine)
|
|
can HbS still carry oxygen?
how much? |
yes. It can carry the normal amount, until it becomes deoxygenated/part of a permanently sickled RBC
|
|
"encodes a protein" ~
|
mRNA
|
|
3 reasons for processing RNA:
|
1. to remove unnecessary NT's
2. to produce recognition sites for proteins 3. to alter the coding properties of the RNA |
|
"intron" refers to both:
|
the DNA sequence and the corresponding RNA sequence
|
|
***mature RNA = ***
|
5'cap - exons - PolyA tail
|
|
when does mRNA leave the nucleus?
|
*when it's mature*
(ending with the Poly A tail, specifically) |
|
**where does transcription occur?**
|
in the nucleus
|
|
**what makes the binding site for enzymes that process mRNA?**
|
Phosphorylation of two Serines in the CTD of RNAP II
|
|
what is the 5' cap, exactly?
|
7-methylguanosine
|
|
**what's the first step of mRNA processing?**
|
addition of the 7-methylguanosine cap
|
|
what's the process by which the 5' cap is added?
(2) |
1. one enzyme transfers guanine to the 5' phosphate group
2. second enzyme methylates guanine and several riboses at the 5' end |
|
***what does presence of the 5' cap do for the mRNA?***
(3) |
1. protects against nucleosomes
2. identifies it as pre-RNA 3. creates a binding site for the Cap Binding Protein |
|
what's the most challenging step of RNA processing, and why?
|
RNA splicing, because it has to be very accurate
|
|
****when does RNA splicing occur?****
|
****DURING transcription****
- AS the mRNA is being created from DNA |
|
what provides the signal for splicing?
|
**conserved sequences** at the 5' and 3' ends of Exons, to which U1 and U2 bind
|
|
what is the spliceosome made up of?
|
** 5 snURP's **
|
|
what are snURP's made up of?
|
snURP's = snRNA's + associated proteins
|
|
what are the five snURP's?
|
U1+proteins,
U2+proteins, U4+proteins, U5+proteins, U6+proteins |
|
slicing in yeast and invertebrates has 2 official steps:
|
1. A-branch point attacks an intron's 5' end as that end gets cleaved; => lariat
2. intron 3' cleavage and exon ligation => free lariat for degradation |
|
more thorough explanation of splicing in yeast and invertebrates:
(5) |
1. U1-snRNP binds a splice site
2. U2 binds to branch point 3. the rest of the U-snURP's bind 4. A-branch point attacks intron's 5' end as that end gets cleaved; => lariat 5. intron's 3' cleavage and exon ligation => free lariat for degradatoin |
|
alternative splicing =>
|
different proteins from one gene
|
|
how does the Poly A tail get added?
(6) |
1. 2 signals call 2 proteins
2. they bend the transcript 3. Cleavage Factor binds 4. PAP binds 5. CF is activated, nuclease cuts off the end 6. PolyA Binding Protien II binds to the new end immediately and starts adding A's |
|
PABP II =
|
Poly A Binding Protein II
|
|
what is the Poly A tail essential for?
|
export from the nucleus
|
|
PAP =
|
Poly A Polymerase
|
|
rRNA processing:
|
rRNA's associate with proteins as soon as they're made
|
|
where does assembly of the ribosomal subunits occur?
|
in the nucleolus
|
|
what mlcls facilitate modifications of rRNA?
|
**snoRNA's**
|
|
***what do snoRNA's do?***
(2) |
1. cleave rRNA into subunits
2. serve as binding sites for enzymes that modify ribosomes |
|
how is tRNA processed?
(4) |
1. 5' end cleaved
2. anticodon loop (introns of RNA) is spliced out 3. bases modified 4. CCA added to 3' end |
|
what does the CCA at the 3' end of tRNA do?
|
***it binds AA's during translation***
|
|
K-type enzymes are regulated by changing their
|
affinity/ Km
- Vmax stays the same |
|
increase Km =
|
acts slower (because it's a dec. in affinity)
|
|
in V-type enzymes, what changes?
|
Vmax
|
|
which kind of enzymes are subject to competitive inhibition?
|
ALL enzymes are
|
|
when is Hb least stable?
|
during its high-affinity/R conformation
|
|
when are the allosteric enzymes most stable?
|
at LOW activity
|
|
K-type enzymes are regulated by changing their
|
affinity/ Km
- Vmax stays the same |
|
when are the allosteric enzymes LEAST stable?
|
at HIGH activity
|
|
increase Km =
|
acts slower (because it's a dec. in affinity)
|
|
p21ras =
|
SLOW G-protein
- 1 to 2 catalytic events per hour |
|
in V-type enzymes, what changes?
|
Vmax
|
|
p21ras is dependent not on the concentration of GTP, but on
|
how long it takes to hydrolyze GTP
|
|
which kind of enzymes are subject to competitive inhibition?
|
ALL enzymes are
|
|
***allosteric enzymes are subject to:***
(2) |
1. feedback inhibition
2. feed-forward activation |
|
when is Hb least stable?
|
during its high-affinity/R conformation
|
|
when are the allosteric enzymes most stable?
|
at LOW activity
|
|
when are the allosteric enzymes LEAST stable?
|
at HIGH activity
|
|
p21ras =
|
SLOW G-protein
- 1 to 2 catalytic events per hour |
|
p21ras is dependent not on the concentration of GTP, but on
|
how long it takes to hydrolyze GTP
|
|
***allosteric enzymes are subject to:***
(2) |
1. feedback inhibition
2. feed-forward activation |
|
a change in physiological status - disease, pregnancy, starvation - will lead to a change in circulating hormones, which will lead to:
|
change in enzyme expression
|
|
what kind of enzymes are blood-clotting enzymes?
|
V-type
|
|
blood-clotting enzyme operate in a
|
cascade
|
|
thrombin production =
|
[E] x time
- an inc. in either will lead to more thrombin |
|
isozyme =
|
enzyme with a different AA sequence that catalyzes the same reaction
|
|
isozymes are subject to
|
mutations
|
|
mutations in isozymes =>
(2) |
1. novel function
or 2. nothing |
|
not all duplicated genes produce:
|
functional proteins
|
|
not all isozymes are
|
useful/significant
|
|
4 ways to alter enzyme activity:
|
1. gene induction/repression
2. preteolysis (x2) 3. covalent modification 4. binding of regulatory metabolites |
|
ALL enzymes can be inhibited by:
(2) |
1. their product
2. drug analogs |
|
***for allosteric enzymes, activators stabilize which conformation?***
|
the R conformation,
while inhibitors stabilize the T conf. |
|
***where are allosteric enzymes usually found?***
|
**at the committed step of pathways**
|
|
allele =
|
copy of a gene
|
|
how many alleles are there for each gene?
|
two
|
|
AD inheritance definition:
|
you only need one allele mutated in order to display the phenotype/manifest the disease
|
|
AD definition
|
check
|
|
characteristics of AD inheritance:
(5) |
1. males and females affected equally
2. mutant allele is dominant to wild-type 3. vertical inheritance 4. individual risk to each child = 50% 5. transmission is via either male or female |
|
penetrant =
|
has inherited the disease
|
|
at the individual level, penetrance is
|
all or nothing - you either have it or you don't
|
|
at the pop. level, penetrance is
|
a fraction
|
|
***age-related penetrance =
|
individuals who carry the allele don't manifest the disease until later in life
|
|
it's possible for someone to be the first in their family with the AD condition; this is due to:
|
a new mutation
- parents are not affected, don't carry the mutated gene - to confirm, test them |
|
*certain* AD and X-linked diseases have a high rate of new mutations, while certain others
|
have a low rate
|
|
what's a big risk factor for a new mutation?
|
a large gene
|
|
nonprenetrant carrier =
|
someone who's got the gene, but not the manifestation
|
|
mosaic =
|
tissue or individual that's derived from a single zygote, but comprised of two or more populations of cells with different genotypes
|
|
new mutations occur in dividing cells throughout
|
our lives
|
|
somatic mosaicism =
|
different genotypes in our somatic cells
|
|
***somatic mosaicism is a major mechanism of:***
|
cancer
|
|
a proportion of an individual's cells will carry
|
mutations
(the proportion depends on how early the somatic progenitor cell was mutated) |
|
even twins are mosaic - they have different
|
somatic mutations
|
|
somatic mosaicism accounts for:
|
rare disorders that aren't inherited
|
|
if a mutation occurs in a germ cell, an unaffected parent will have kids with the mutation, even though
|
they might not be affected
|
|
when is germ line mosaicism more serious?
|
the earlier it occurs
|
|
***germline mosaicism =
|
a person has two populations of cells in the gonads (testes or ovaries), one population of cells containing the usual genetic complement whilst the other contains a DNA mutation
If a sperm or an egg produced from the cells in the parent's gonads containing the DNA mutation or chromosome anomaly is used to form a fetus, the child will have the genetic condition ( even though the parent is healthy). A child would not have the condition if formed from the cells in the gonad with the usual genetic pattern. |
|
Gonadal/germline mosaicism is a likely explanation of the rare situations where:
|
a person without a dominant condition can have two children with the same AD condition.
|
|
variable expressivity =
|
degree to which disease is manifest
- siblings can have the same inheritance, but show vastly different symptoms |
|
sex influence =
|
decreased or increased chance of manifestation of the disease, depending on your sex
- males far less likely to manifest breast cancer |
|
sex limitation =
|
NO chance of manifestation
(e.g. males can't get ovarian cancer - no ovaries) |
|
gene regulation involves two players:
|
1. the cis-element - usually DNA
2. the trans-factor - usually protein |
|
positive control =
|
activation of expression
|
|
**where do DNA-binding proteins recognize their target?**
|
***at the MAJOR groove***
- they DON'T separate DNA strands to read the sequence |
|
many DNA-binding porteins bind as
|
dimers
|
|
what are the binding sites of DNA-binding proteins?
|
**palindromes**
|
|
if the genome is the same in every cell, how are different genes expressed in different cells?
|
***covalent modification of the chromosomes***
- i.e. methylation, adenylation |
|
each cell type has a _______ __________ that's expressed early in development
|
master regulator
|
|
what determines if a gene can be expressed in a cell?
|
**packaging**
- heterochromatin => genes inactivated |
|
different cells have different genes in
|
heterochromatin, euchromatin
|
|
***many genes are expressed in ALL cells;*** called:
|
housekeeping genes
- only a fraction of genes are actualy cell-specific |
|
where is DNA methylated so that genes aren't expressed?
|
at CG doublets in a major groove, at both ends of DNA
|
|
what does methylation of CG doublets do to DNA?
|
alters ability of proteins to bind to it => LOCKED out of transcription
|
|
***methylating the lysines of histones =>
|
1. prevention of acetylation
BUT 2. creation of a binding site for proteins that can EITHER repress or activate transcription |
|
acetylation of histone tails =>
|
loss of positive charge of lysines => dissociation from nucleosomes => euchromatin, open to transcription
|
|
acetylation of histones is easily
|
reversible
- high turnover |
|
histone methylation competes with
|
acetylation
- particular gene is activated or deactivated depending on who wins |
|
**DNA methylation is:**
|
**inherited**
|
|
one X chromosome of every woman is inactivated by
|
methylation
- while the other is unmethylated/active |
|
proteins also regulate transcription - TF's have both a
|
DNA-binding domain AND a separate activation/repression domain
|
|
TF's activation domain binds
|
histone acetylases
|
|
TF's repressor domain binds:
(2) |
1. histone deacetylases,
2. methylated DNA (locking it up) |
|
combo control =
|
the number of activating vs. inactivating proteins, at different sites, will determine whether the gene gets transcribed or not
|
|
TF's bind as
|
homo or heterodimers
|
|
how is combo control regulated?
|
1. covalent modification
2. noncovalent, via hormones |
|
Phosphorylation can switch a TF
|
on or off
|
|
the promoter of DNA prevents
|
nucleosomes from binding up DNA
|
|
enhancers of DNA do what?
(2) |
1. bind TF's
2. loop around to the promoter |
|
promoter's factors interact with enhancer's factors - the TF's bound to each will keep
|
histones off
|
|
except in RBC's, globin genes are packed in
|
heterochromatin
|
|
****what catalyzes splicing? ****
|
***RNA***
|
|
***exon definition: even though splicing occurs across introns, ***
|
EXONS are initially recognized
**U1 has to bind first, and also be present at both sites of exon splicing** for yeast/invertebrates: U1, then U2 for vertebrates: U1, then U2 and U2AF |
|
in vertebrates, exons are spliced only if:
|
splicing snURP's bind to BOTH SIDES of the exon.
- the splicing complex is assembled across EXONS, rather than introns |
|
in vertebrate splicing, what does the binding of U2 and U2AF depend on?
|
**the binding of U1** to the same exon
|
|
in yeast/invertebrates, splicing occurs across
|
their *much shorter introns*
|
|
what's the start codon? what AA does it correspond to?
|
AUG;
methionine - ALWAYS begins initiation |
|
what are the 3 steps of translation?
|
1. initiation
2. elongation 3. termination |
|
in initiation, the ribosome does what?
|
binds
|
|
what are the 3 stop codons?
|
1. UAG
2. UGA 3. UAA |
|
codon =
|
group of 3 NT's on mRNA
|
|
tRNA possesses an
|
*anticodon*
|
|
which two AA's are the only ones that are encoded by only one codon?
|
Met, Tryptophan (Trp,W)
|
|
each codon encodes
|
one AA
|
|
one AA can have more than one
|
codon that encodes it
|
|
how is accuracy achieved during translation?
(4) |
1. starting at the right place
2. charging the tRNA properly 3. stopping translation where it should 4. fixing errors |
|
to "charge" tRNA =
|
to attach an AA to it
|
|
***which enzymes charge tRNA?***
|
aminoacyl-tRNA synthetases
|
|
how many aminoacyl-tRNA synthetases exist in the cell?
|
**20**
- one for each AA - a synthetase will recognize every codon for its AA |
|
***transfer of AA to tRNA is ATP-
|
DEPENDENT
|
|
***how does aminoacyl-tRNA synthetase recognize the correct tRNA?***
(2) |
1. its *structure* - hugs it tight
2. its anticodon |
|
special feature of aminoacyl-tRNA synthetase =
|
proofreading
|
|
what are the ribosomal subunits?
|
40S, 60S
|
|
when are the ribosomal subunits together?
|
only when they're BOUND to mRNA
- otherwise they're dissociated |
|
3 sites of the ribosomal complex =
|
1. E
2. P - where chain grows 3. A - where tRNA with next AA comes in |
|
***what's the only tRNA that binds to the P site?***
|
***tRNAi, which binds methionine***
|
|
***eIF2 will NOT bind to tRNAi if it's:
|
**bound to GDP**
|
|
what is the preinitiation complex?
|
tRNAi + small subunit (40S)
|
|
what locks the preinitiation complex to the start site?
|
hydrolysis of eIF2-GTP to eIF2-GDP
|
|
how is the 60S subunit locked to 40S and the preinitiation complex?
|
via GTP hydrolysis
|
|
what protein brings in subsequent AA's during translation?
|
eF1alpha
|
|
how are correct AA's locked into the ribosome during translation?
|
via GTP hydrolysis
|
|
what enzyme catalyzes peptide bond to connect the incoming AA to the chain and severs the link between tRNA in the P site and the chain that it holds on to (so that tRNA can leave E site alone)?
|
peptidyl transferase ON 60S - RNA HAS CATALYTIC PROPERTIES
|
|
what happens when the stop codon reaches the A site?
|
termination factors recognize the stop codon => bind to it => GTP is hydrolyzed => conformational change => cleavage of AA chain from tRNA in P site => ribosomal subunits dissociate
|
|
changing a NT in the DNA =>
|
difference in the AA => difference in the protein
|
|
frame shifts usually cause a:
|
**premature stop codon**
|
|
Nonsense-Mediated Decay =
|
a fail-safe that eliminates improperly-spliced mRNA's
- triggered by stop codon UPSTREAM of EJC |
|
EJC =
|
Exon Junction Complex
|
|
an EJC is found at:
|
each site where two exons are spliced together
|
|
normally, a stop codon in mRNA is found in the
|
last exon of a gene
=> **there should be no EJC's BEHIND a stop codon** |
|
if a mutation makes a premature stop codon, there will be
|
EJC's 3' to that stop codon
|
|
during translation, if a ribosome comes upon a stop codon that has EJC's downstream of it, it triggers
|
NMD
|
|
NMD =>
|
mRNA degraded via SURF/SMG7 complex
|
|
when is mRNA circular?
|
during translation
|
|
***during translation, there are multiple:***
|
ribosomes translating the same mRNA
|
|
proteins at the 5' and 3' ends of mRNA __________ _____ each other to increase efficiency
|
interact with
|
|
****what regulates GTP hydrolysis?****
|
Guanine Exchange Factors
|
|
there is a specific GEF for
|
a specific G-protein
|
|
inhibiting GEF's =>
|
dec. in translation,
and vice versa |
|
what decreases GEF activity?
|
Phosphorylation
|
|
premature stop codons due to point mutation are responsible for:
|
10% of cystic fibrosis, 15% of DMD
|
|
the Locus Control Region (LCR) does what?
(2) |
1. makes delta and B-globin regions into euchromatin
2. increases expression of those genes |
|
the LCR is ______ of both delta and Beta-globin genes
|
*upstream*
|
|
causes of B-thalassemia include POINT mutations in:
(3) |
1. transcription
2. splicing 3. poly-Adenylation (3' end processing) |
|
ways to affect levels of mRNA:
(3) |
1. rate of transcription
2. processing 3. mRNA half-life |
|
2 ways of regulation protein levels:
|
1. rate of translation
2. protein half-life |
|
levels of mRNA or protein are increased or decreased by changing:
|
different regulations *simultaneously*
|
|
**what 2 things do you need in order for mRNA to be translated?**
|
1. 5' cap
2. Poly A tail |
|
3 steps of mRNA degradation:
|
1. remove Poly-A tail***
2. cap chopped off 3. mRNA chewed up by nucleases |
|
***when is degradation of mRNA initiated?***
|
**DURING translation**
|
|
which sequences control mRNA half-life?
|
**sequences in the 3' UTR**
- tell cell when to degrade mRNA |
|
**which mlcls regulate mRNA degradation?**
|
microRNA's - 21 NT's
|
|
what makes miRNA's?
|
Dicer
|
|
where do miRNA's bind?
|
mRNA's 3' UTR, leading them to RISC
|
|
if miRNA's match perfectly with mRNA =>
|
mRNA is cleaved
|
|
if miRNA's match imperfectly with mRNA = >
|
stall translation
|
|
miRNA's are critical during:
|
development
|
|
miRNA's resulted in:
|
the RNA interference technique - can now knock out any mRNA you don't want
|
|
not all miRNA binding results in degradation; can also result in:
|
STORAGE
- later reverted to translatable form |
|
a set of miRNA is OVERexpressed in
|
lymphomas and other cancers
- these mutated miRNA's caused DOWNregulation of tumor suppressors |
|
are the sex chromosomes interchangeable?
|
no - Y is much shorter
|
|
there are many genes on X,
|
few on Y
|
|
males =
|
**heterogametic**
|
|
"X-linked" usually refers to
|
X-linked *recessive*
|
|
****5 characteristics of X-linked recessive mutations:****
|
1. disease appears much more in males
2. disease is much more severe in males 3. NO male to male transmission 4. ALL daughters of an affected male are carriers 5. female carriers are unaffected (generally) |
|
XCI =
|
X chromosome inactivation
|
|
what does XCI mitigate?
|
the gene dosage problem
|
|
***in XCI, EITHER the maternal OR the paternal
|
X chromosome is inactivated, RANDOMLY, in each cell
|
|
genes of an inactivated X are
|
silent
|
|
barr body =
|
the inactivated X
|
|
**the inactivated X (either maternal or paternal) is inherited by ALL
|
progeny of a cell that inactivated initially
- the inactivated X is heritable from one cell division to the next |
|
females =
|
functional mosaics
- all of their cells are NOT phenotypically identical |
|
***half the cells of a female express ____________, while the other half express ___________***
|
maternal X;
paternal X |
|
5 steps of X inactivation:
|
1. Counting - X to autosome ratio
2. Choice - which X remains active 3. Initiation - *begins at XIC locus* 4. Spread 5. Maintenance - inactive X in heterochromatin, passed through cell divisions |
|
some genes escape X inactivation,
|
get expressed
|
|
TSIX inhibits XIST; XIST wins if
|
TSIX is downregulated,
TSIX wins when it's upregulated |
|
in X-linked diseases, female carriers will have an average of
|
half of their cells expressing normal X, half expressing the mutated X
|
|
female carriers CAN have manifestations of the disease - alters meaning of
|
X-linked recessive
|
|
skewed XCI =
|
more or less than the 50/50 ratio of maternal X inactivated vs. paternal X inactivated
|
|
in skewed XCI, the mutated X can be expressed more (60/40, 70/30) =>
|
symptoms
|
|
****3 characteristics of X-linked dominant****
|
1. daughters of affected males ALWAYS inherit the mutant gene AND THUS the disease - need only one X'
2. sons of affected males NEVER inherit the disease 3. affected females transmit the disease to 50% of their offspring |
|
X-linked dominant is called that because:
|
if you have one affected X, you have the disease
- it's rare |
|
in X-linked dominant, affected males pass the disease on ONLY to their
|
daughters
|
|
***X-dominant conditions are seen only in females, b/c males:
|
don't survive.
so females have relatively less severe symptoms (although they are severe in the absolute sense) |
|
Y-linked disorders are nigh-
|
nonexistent
|
|
mutations of the SRY gene on the Y chromosome =>
|
female phenotype in a chromosomal male
|
|
mit. inheritance exhibits ______________________ inheritance
|
***Non-Mendelian***
|
|
two other names for mitonchondrial inheritance:
|
1. maternal
2. cytoplasmic inheritance |
|
mit. have their own:
|
**genome**
|
|
which is bigger, the nuclear genome or the mit. genome?
|
the nuclear; mit. genome is MUCH SMALLER
|
|
genes of the mit. genome =>
|
proteins involved in energy production via oxidative Phosphorylation
|
|
each cell contains ________ of mitochondria
|
hundreds
|
|
***which 2 cell types DON'T contain mit.?***
|
1. RBC's
2. sperm |
|
how many copies of its genome does EACH mit. have?
|
**5 - 10**
|
|
during mitosis, how are a cell's mit. partitioned?
|
***RANDOMLY***
|
|
all of a person's mit. come from
|
his mother
|
|
mit. disorders involve 3 HIGH-ENERGY tissues:`
|
1. brain
2. muscles 3. endocrine |
|
***hallmarks of mit. inheritance:***
(4) |
1. nearly ALL of a female's children will be affected
2. but reduced penetrance is seen 3. NONE of a male's children will be affected 4. *HIGHLY-VARIABLE expressivity (due to randomness of partitioning) |
|
****MOST disease that affect the mit. do NOT demonstrate:****
|
mit. inheritance
- mit. genome only codes for 13 proteins - **the vast majority of proteins in the mit. come from the nuclear genome** - mutations in these nuclear genes demonstrate regular inheritance - mostly AR |
|
**which genome, the nuclear or the mitochondrial, has a higher mutation rate?**
|
the mit. genome
|
|
many polymorphisms exist between individuals and
|
among populations
|
|
when is the only time that chromosomes form?
|
during mitosis
|
|
what are the bands and sub-bands on chromosomes?
|
different proteins and packaging patterns
|
|
p = petite =
|
short arm
|
|
where does band numbering of a chromosome start?
|
at the centromere
- higher as you move toward the ends |
|
karyotype =
|
picture of all 46 chromosomes
- goes largest to smallest |
|
the karyotype can be obtained from:
|
***ANY cell that can divide in culture***
- usually WBC's or skin cells |
|
normal karyotype =
|
46XX or 46XY
|
|
3 ways to identify a chromosome:
|
1. banding pattern
2. size 3. centromere position |
|
metacentric =
|
chromosome has equal arm length / centromere almost exactly in the middle
|
|
acrocentric =
|
very unequal arms
- tiny p |
|
telocentric =
|
no p arm (not found in humans)
|
|
chromosomal disorders affect 1 out of every
|
150 births**
- common |
|
3 cardinal manifestations of chromosomal disorders:
|
1. MR
2. congenital malformations 3. failure to thrive (grow normally) |
|
reproductive difficulties ~
|
abnormal chromosome(s) in one of the parents
|
|
3 examples of a Numerical chromosome disorder:
|
1. trisomy
2. monosomy 3. triploidy |
|
4 examples of Structural chromosomal disorders:
|
1. inversion
2. translocation 3. deletion 4. duplication |
|
***both autosomal and sex chromosomes can have:
(2) |
numerical and structural chromosomal disorders
|
|
a karyotype CAN'T pick up
|
**small** mutations
|
|
the karyotype only works for problems that are > or = to
|
5 Mb
|
|
Mega =
|
millions
|
|
FISH detects:
|
presence or absence of *specific* sequences
|
|
microarray =
|
millions of probes hybridize the entire sequence
|
|
microarray is best for finding out
|
which genes are there and which aren't
|
|
microarray: green =
red = |
green = gain of DNA
red = loss of DNA |
|
***microarray CANNOT detect:***
|
BALANCED structural rearrangements
- but can detect unbalanced transpositions |
|
3 kinds of Numeric chromosome abnormalities:
|
1. aneuploidy
2. monosomy 3. trisomy |
|
triploid = 3n =
|
69XXX, 69XXy, 69XYY
- multiple sperm fertilize one egg - early miscarriage |
|
tetraploidy = 4n =
|
failure of zygotic cleavage
- earliest miscarriage - don't even know you're pregnant |
|
***monosomy = ***
|
missing one of a pair of chromosomes
|
|
monosomy is NOT compatible with life if:
|
it occurs in the autosomes
- Turner's syndrome if 45X - lethal in earliest stage if 45Y |
|
***"partial monosomy" refers to
|
a deletion of part of a chromosome
- e.g. partial monosomy 1p = deletion in p arm of chromosome 1 |
|
trisomy =
|
chromosome pair has EXTRA copy
- occurs due to nondisjunction |
|
**only 3 kinds of autosomal trisomies survive to birth:**
|
trisomy 21
18 and 13 |
|
***sex chromosome trisomies are***
|
**common**
|
|
trisomy 21 =
|
Down's syndrome
- short stature heart defects, high incidence of Alzheimer's in 40's |
|
what's the most common cause of mental retardation?
|
trisomy 21
|
|
**risk of having a child with Down's increases with
|
increase in maternal age
|
|
trisomy 18 ~
|
clenched fist, rocker feet
severe failure to thrive - typically don't survive past 1 year |
|
trisomy 13 ~
|
cleft palate, heart defects
- rarely survive |
|
sex chromosome aneuploidy occurs in 1 out of every:
|
500 births
- **mild symptoms** |
|
***chromosomal structural rearrangements occur in 1 out of every:
|
375 births
|
|
structural rearrangement =
|
**chromosomal breakage followed by aberrant reconstruction**
- not put back the way it was when it was broken |
|
structural rearrangements are either:
(2) |
1. balanced
OR 2. unbalanced |
|
balanced structural rearrangement =>
|
equal amount of material, just rearranged
|
|
***people with BALANCED structural rearrangements are phenotypically
|
normal
- ***but they will have trouble reproducing, and their offspring will have unbalanced structural rearrangements*** |
|
unbalanced structural rearrangement =>
|
gain or loss of genetic material => phenotypically abnormal
|
|
inversion =
|
segment breaks, gets inverted 180 degrees
|
|
paracentric inversion =
|
NOT involving the centromere
- vs. pericentric |
|
common inversion = inversion on chromosome 9, which occurs once in every
|
100 people
|
|
3 kinds of BALANCED structural rearrangements:
|
1. inversion
2. reciprocal translocation 3. Robertsonian translocation (can be UNbalanced too) - all will lead to problems reproducing/offspring with unbalanced rearrangements |
|
reciprocal translocation =
|
exchange between NON-HOMOLOGOUS chromosomes
|
|
Robertsonian translocation =
|
loss of p arm due to fusion
|
|
Robertsonian translocation occurs ONLY with:
|
acrocentric chromosomes
|
|
acrocentric chromosomes' p arms contain
|
redundancies
=> ribosomal proteins can made by one of the others |
|
Robertsonian translocation is not a big deal - no ______________
|
phenotype
|
|
**advanced paternal age =>
|
increased risk of reciprocal translocations
- 2x for every 10-year increase in age |
|
carriers of balanced translocations experience frequent
|
miscarriages
|
|
deletions on chromosomes ~
|
losing MANY genes
|
|
genes affected by deletions are usually those that experience
|
haplo- INnsufficiency
- loss of one of those genes due to deletion => bad phenotype automatically |
|
***deletions are LETHAL if at or near:***
|
the telomeres
|
|
duplication => mild phenotype (unless it's cancerous); the body is less tolerant of
|
loss than it is of gain
|
|
LARGE deletions/duplications =
|
>400 kb's
- major cause of mental disability |
|
"screening" ~
|
determining increased or decreased RISK
- NOT a diagnosis |
|
maternal serum screening detects:
|
markers that detect aneuploidy, spina bifida
|
|
diagnositc testing requires:
|
a sample of fetal DNA
|
|
2 examples of diagnostic testing:
|
1. amniocentesis
2. chorionic villus sampling |
|
amniocentesis is performed between weeks:
|
wks 15 - 20
- inc. risk of miscarriage by 0.5%, but operator dependent |
|
amniotic fluid contains
|
fetal cells
|
|
chorionic villus sampling takes villi from
|
the blastocyst
|
|
chorionic villus sampling can be done between weeks:
|
10 - 12
- increases risk by 1%, but also operator dependent |
|
chorionic villus sampling does NOT give info about:
|
spina bifida
|
|
amniocentesis detects:
|
spina bifida
|
|
the philadelphia chromosome =
|
a specific **translocation** observed in CML (leukemia)
=> increased tyrosine kinases => tumors |
|
the philly translocation can be specifically targeted and treated by:
|
Imatinib/Gleevec
|
|
HER2 = a_______________ that's overexpressed in BC
|
a growth factor;
is specifically targeted by herceptin |
|
**genes for tightly-regulated TF's are usually:**
|
haplo-INsufficient
|
|
excess gene dosage =>
|
overexpression
|
|
many genes act as dimers, or higher; a mutant protein will interfere with
|
a normal one binding => haploinsufficiency
(mutant = dominant negative) |
|
****cancer predisposition is:****
|
a phenotype***
|
|
epigenetics =
|
**heritable** changes that occur without changing the DNA sequence
- via modification to chromatin and/or DNA |
|
3 examples of epigenetic modification:
|
1. DNA methylaiton - covalent
2. histone modification - covalent 3. nucleosome remodeling |
|
***nucleosome remodeling is:***
(2) |
1. NONcovalent
2. ATP-dependent |
|
**what methylates DNA?**
|
DNMT's
(to cytosines of CG's) |
|
methylation is highly dynamic during:
|
gametogenesis and early embryonic development
|
|
different cells have different
|
methylation patterns
|
|
**methylation provides a platform for:
|
other proteins (activators OR repressors) to bind
|
|
hypermethylation ~
|
tumor suppressor-silencing in cancer
=> aberrant growth |
|
TF's can either
|
activate OR repress
|
|
chromatin remodeling =
|
transient change in nucleosome positions
|
|
chromatin remodeling =>
|
increased TF binding => repression or activation of expression
|
|
nuclear lamins organize chromosomes and keep them from being a jumble =>
|
gene expression,
nuclear pores |
|
mutation in LMNA / lamin AC =>
|
premature aging
|
|
stem cells aren't used
|
clinically
|
|
when a gene is imprinted, it's
|
inactivated
|
|
imprinting: methylation patterns of genes that come from the other gender are
|
erased, and the genes are re-expressed as if the came from only one gender
|
|
imprinting passes on a copy that came from the mother AND father, but **looks** like
|
it came from only from the mother OR the father
|
|
imprinting = erasing methylation patterns and making all copies of the gene look like
|
they came from one OR the other, NOT both
|
|
a child affected with a condition due to imprinting can be
|
either male or female
|
|
with certain imprinting conditions, disease manifestation depends on
|
which PARENT passed it down
|
|
3 main mechanisms of imprinting:
|
1. epimutations that alter normal imprinting patterns
2. uniparental disomy 3. deletion/mutation disrupting the allele that should be active |
|
epimutations that alter normal imprinting patterns =
|
1. non-imprinted gene gets silenced
OR 2. gene that should be imprinted gets expressed |
|
uniparental disomy =
|
inheriting BOTH copies of a chromosome from THE SAME PARENT
=> both are silenced |
|
deletion/mutation disrupting the imprinting pattern =
|
allele that should be active is taken out of commission, while the other one is already silenced by imprinting
- or mutation causes aberrant behavior in the good gene |