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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