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285 Cards in this Set

  • Front
  • Back
What are ribozymes?
RNA catalysts
Lipmann's Law?
ATP is common currency exchange in all forms of life
Cells maintain an energy charge of about ___?
0.85
ion gradients are primary or secondary transports?

metabolite transport is primary or secondary transport?
primary


secondary
What is the final common pathway in oxidative metabolism?
TCA (Krebs) cycle
Which hydrogen carrier is mostly used in energy-generating catabolism?

Which hydrogen carrier or reductant is mostly used in anabolic processes?
NADH


NADPH
How many genes code for one enzyme or polypeptide?
one
In what direction does mRNA read?
5' --> 3'
How many genes in human DNA?
20,000-25,000
How many base pairs in human DNA?
3 billion
Single Nucleotide Polymorphism (SNP)

pronounced "snip"
a DNA sequence variation occurring when a single nucleotide in the genome differs b/w individuals or b/w paired CHs in an individual

almost all common SNPs have two alleles (ex: AAGT vs AATT)

For a variation to be considered a SNP, it must occur in at least 1% of the population!!!
The DNA of any two people is __% identical
99.9

about 1 in every 1,200 bases, on average, the sequences will differ
What is the purpose of the HAPMAP Project?
to identify the SNPs in the human population, specifically to develop a haplotype map of the human genome to describe the common patterns of human DNA sequence variation.

(~10 million exist; ~8 million have cataloged; ~5 million have been identified)
What is a haplotype?
the pattern of close SNPs being inherited together as a block (region of CH)
What has the HAPMAP project found?
that 300,000 to 500,000 variants can serve as a proxy for the ~10 million common genetic variants in the human genome
What is the 1000 Genome Project?
will sequence the genomes of at least 1000 ppl from around the world; will produce the most detailed map of human genetic variation to support disease studies (10-fold better than HAPMAP)

It will map not only the single-letter differences in ppl's DNA (aka SNPs), but also will produce a high-resolution map of larger differences in genome stxr called stxral variants (which are rearrangements, deletions, or duplications of segments of the human genome)
What are the reasons for genetic testing?
Predictive testing (presymptomatic or predispositional [estimating risk of developing])

Diagnostic Testing

Carrier Testing

Prenatal Testing

Newborn Screening

Preimplantation genetic diagnosis
Why is genetics impt in pharmacogenetics?
b/c each year 100,000 pts die form ADR and over 2 million have serious rxns

ppl metabolize drugs differently due to genetic variance

So in the future, PAs will have to prescribe based on pt's genotype and SNP pattern
How many significant genetic flaws does the average person have?
5-50
What is a synonymous SNP?

non-synonymous?
a SNP in which both forms lead to the same polypeptide sequence (silent mutation)

if a diff polypeptide is produced
Where can a SNP be found?
may fall w/in CDS of gene, non-coding regions, or intergenic regions

thus, SNPs that are not in protein-coding sequences may still have consequences for gene splicing, TXN factor binding, or the sequence of non-coding RNA
What is the purpose of testing an individual's "tag" SNP (aka genotyping)?
reserachers will be able to identify the collection of haplotypes in a person's DNA.

The # of tag SNPs that contain most of the info about patterns of genetic variation is estimated to be about 300,000 to 600,000
Medical genetics
a branch of medicine that deals with the inheritance, Dx, and Tx of diseases caused by single gene mutations, CH abnormalities, and multifactorial predispositions

Genetic counseling and screening are also part of medical genetics
Clinical genetics
is the APPLICATION of genetics to clinical problems in individual families and pts
Molecular medicine
is the CLINICAL APPLICATION of molecular biology to the Dx and Tx of disease
Why is molecular medicine impt?
b/c a new era is emerging, characterized less by treating Sx and more by looking to the most fundamental causes of disease

The present classification system, mostlly based on clinical desc of disease, is being replaced with a more rational classification based on genetic causes and influences. So instead of merely describing diseases using a broad phenotype, we will be able to redefine them by genotype and mechanism. Knowing the mechanisms and susceptible genes involved will direct the dvlpt of drugs
T or F: With genetics, emphasis will shift from Tx to prevention!!!
True
Single gene (Mendelian or monogenic) disorders

List examples:
conditions produced by the effects of one gene or gene pair; usually transmitted in simple patterns as described by Mendel; individually rare but affect ~2% of pop.

AD
AR
X-linked
Mitochondrial
AD
autosomal dominant; transmitted on autosomes (i.e. CH other than X or Y); expressed when only a single copy of the mutant gene is present.

ex: Waardenburg syn.
AR
autosomal recessive; also on autsomes; only express when both copies of a gene are mutant.

ex: Usher syn
X-linked
transmitted on X CH

ex: Alport syn
Mitochondrial disorders
transmitted on the mito DNA via maternal inheritance

ex: aminoglycoside-induced deafness
What are the major types of genetic disease?
Single gene (Mendelain or monogenic); Chromosome abnormalities; Multifactorial traits
CH abnormalities
are deviations from the normal CH # or stxr

ex: Down and Turner syn

FYI: about half of the 5-15% spontaneous abortions rate, thus 2.5-7.5%, are due to CH abnormalities

This affects about 7 in 1000 liveborns
Multifactorial traits (complex)
combined effects of multiple genetic and nongenetic influences; these are the most common genetic disorders; affect ~5% of peds cases and >60% entire pop.

ex: AMD, DM, spina bifida, glaucoma, hypertension
congenital
present since birth
anomaly
something that is irregular; strange, unusual
What is the incidence of genetic disease and other congenital anomalies apparent by age 25?
7.9%
What is the lifetime prob of devlping cancer?
1 in 2 for men

1 in 3 for women

23% of all deaths
Among autosomal and X-linked disorders, what are the prevalences of AD? AR? X-link?
>50%; 33%; 10%
What is the primary goal of medical genetics?
to determine the etiology of a pt's illness
T or F: Inherited gene or CH mutations affect all cells of the body
T
T or F: Inherited gene or CH mutations may manifest in many different organs and systems
T
The cell cycle is repeated each time a cell ____
divides
T or F: The cell cycle is TEMPORARILY SUSPENDED in nondividing cells that are in the G0 state
T
T or F: The cell cycle is PERMANENTLY INTERRUPTED in differentiated cells that do not divide (ex: cardiac muscle cells and neurons)
T
Interphase
INTERval b/w cell divisions; considerably longer than M phase; is the period during which the CELL DOUBLES IN SIZE AND DNA CONTENT; is divided into 3 separate phases (G1, S, and G2)
M phase
mitosis (the period of cell division)
What are the 3 phases of interphase?
G1, S, and G2
G1 phase (gap phase one)
RECUPERATION PHASE and REPLICATION PREP PHASE; occurs after mitosis; period during which the cell grows and proteins are synthesized, thus restoring the daughter cells to normal volume and size; RNA, protein, lipid, carbs (all major macromolecules) are synthesized during this period

lasts from hrs to several days
S phase (synthetic phase)
REPLICATION PHASE; period when DNA is replicated and proteins are synthesized, resulting in DUPLICATION OF THE CH; centrioles are also replicated

lasts 7-12hrs
G2 phase (gap phase two)
DIVISION PREP PHASE; follows S phase and extends to mitosis; cell prepares to divide; the centrioles grow to maturity; ATP is synthesized and stored for mitosis; RNA and proteins needed for mitosis are synthesized

lasts 2-4 hrs
What are the 2 main protein families that control the cell cycle?
cyclin-dependent protein kinases (Cdk) and cyclins. These protein then form Cdk-cyclin complexes
What is the fxn of a Cdk-cyclin complex?
to PO4 specific target proteins, which is directed by the specific cyclin in the complex
What is a cell cycle checkpoint?
where Cdk-cyclin complexes mediate control
Describe the G1 checkpoint, and which proteins mediate control here
occurs at G1-->S phase transition

mediated by Cdk2-cyclins D & E; and also p53 tumor suppressor gene

Specifically, if a cell in G1 phase has undamaged DNA, Cdk2-cyclins D & E allow the cell to enter the S phase.
If a cell in G1 phase has damaged DNA, it is prevented to enter S phase via the action of p53, which prevents replication of transformed or metastatic DNA. p53 also can activate DNA repair proteins, hold the cell in G1 phase until repaired, or initiate apoptosis if repair isn't possible
Describe the G2 checkpoint, and which proteins mediate control here
occurs at G2-->M phase transition

If a cell in G2 phase has undamaged DNA, Cdk1-cyclins A & B allow the cell to enter M phase.
If a cell in G2 phase has damaged DNA, it is prevented from entering the M phase which prevents formation of transformed, metastatic cells
How are cyclins inactivated?

(Hint: how does polyubiquitination degrade cyclins in anaphase of mitosis?)
The enzyme ubiquitin ligase covalently attaches a ubiquitin protein to a lysine residue of the cyclin (called polyubiquitination), which marks the cyclin for rapid degradation by proteosomes

FYI: polyubiquitination marks many enzymes for rapid degradation
How many S phase checkpoints are there?
three (Intra-S; Replication; and S-M)
Why are S phase checkpoints impt?
b/c are even more significant for preventing genetic instability than the G1 and G2 checkpoints
Intra-S phase checkpoint
activated when there are double-stranded breaks that occured indpt of active replication forks
Replication checkpoint of S phase
initiated when the progression of replication forks is stalled by stresses like: depletion of deoxyribonucleotides, chemical inhibition of DNA polymerases, or the collision of replication forks with damaged DNA and/or aberrant DNA stxrs
S-M checkpoint
guarantees that cells do not attempt to divide before their entire genomes are faithfully replicated
Mitosis
follows G2 phase; completes cell cycle; division of nucleus (karyokinesis) and cytoplasm (cytokinesis) results in the production of two identical daughter cells.

Consists of FIVE major stages (PMAT)

lasts 1-3hrs
Karyokinesis
division of the nucleus
Cytokinesis
division of the cytoplasm
What are the 5 major stages of mitosis?
PMAT (Prophase, metaphase, anaphase, telophase)
Prophase
-begins when the CH condense and form well-defined CHs

-here, the nucleolus and nuclear envelope begin to disappear

-Centrioles migrate to opposite poles of the cell and give rise to spindle fibers and ASTRAL RAYS of the mitotic spindle

Kinetochores develop at the centromere region and fxn as MTOCs
MTOC
microtubule-organizing center; centrosomes is the principal MTOC of the cell
T or F: CH consist of two parallel sister chromatids (future daughter CHs) attached at the centromere
T
What do kinetochores do?
fxn as MTOC at the centromere region
(Prometaphase)
begins when the nuclear envelope disappears giving the microtubules access to the CHs

The kinetochores complete their dvlpt and attach to specific spindle microtubules, thus forming kinetochore microtubules; spindle microtubules that don't attach to kinetochores are called polar microtubules
Polar microtubules
spindle microtubules that don't attach to kinetochore during prometaphase
Metaphase
CHs align at the metaphase plate

FYI: at this stage, cells can be isolated for karyotype analysis
Anaphase
begins as the chormatids separate (at centromere) and the daughter CHs move to opposite poles

spindle elongates

In the later stages of anaphase, a CLEAVAGE FURROW BEGINS TO FORM around cell due to contractile ring
Contractile ring
band of actin filaments that contract in anaphase to generate a cleavage furrow
Telophase
CH decondenses to form chromatin

nuclear envelope is reestablished

nucleolus reappears

kinetochore microtubules disappear, facilitating cytokinesis and formation of 2 identical daughter cells
What are the 2 mitosis checkpoints?
one near the beginning of mitosis called apoptosis checkpoint, where survivins override signals telling the cell to die

one later in mitosis called spindle assembly checkpoint that overseas construction of the spindle and the binding of CHs to it
Meiosis
a special form of cell division in which the CH # IS REDUCED from diploid (2n) to haploid (n)

occurs in developing germ cells in prep for sexual reproduction; subsequent fertilization results in diploid zygotes

The DNA content of the original diploid cell is DOUBLED in the S phase prep to meiosis, followed by 2 successive cell divisions that give rise to 4 haploid cells

Recomb occurs via cross-over and random assortment
How many CHs are there?
46 (23 pairs)
What are the 5 stages of Prophase 1 in meiosis?
leptotene, zygotene, pachytene, diplotene, and diakinesis
What happens in the 5-staged Prophase 1 of meiosis?
Chromatid condenses into visible CHs, each containing 2 chromatid joined at the centromere; CROSSING OVER occurs b/w maternal and paternal CH arms; the nucleolus and the nuclear envelope disappear
When does crossing over occur in meiosis?
during Prophase 1
Where does crossing over occur?
at the chiasmata, which increases genetic diversity
T or F: Homologous maternal and paternal CHs pair via the SYNAPTONEMAL COMPLEX, forming a TETRAD
T
About how many recomb events occur per each set of homologous CHs?
2 (two)
T or F: Crossing over in Prophase 1 in meiosis occurs only b/w maternal and paternal CHs (non-sister chromatid) and does not occur b/w sister chromatid
T
T or F: Anaphase 1 in meiosis is similar to anaphase in mitosis except that each CH consists of 2 chromatids that remain held together
T
T or F: Telophase 1 is similar to telophase in mitosis in that the nuclear envelope is reestablished and two daughter cells are formed via cytokinesis
T
What is another name for Meiosis 1?
Reductional division
What is another name for Meiosis 2?
Equatorial division
When does Meiosis 2 occur?
soon after meiosis 1, after a brief interphase with NO DNA REPLICATION
T or F: Meiosis 2 is similar to mitosis
T
T or F: Meiosis 2 occurs more rapidly than mitosis
T
What is the approx. length of CHs?
~50 million to 250 million bps
What is the composition of a DNA chain?
deoxyribose sugar, a phosphate, and a pyrimidine or a purine base
What makes up the "sides" of the DNA ladder?
the deoxyribose residues linked by phosphates
What makes up the "rungs" of the DNA ladder?
the pyrimidine and purine bases
About how many bps per DNA helix turn?
10
Why does the DNA double helix have a stiff, extended shape?
b/c of the elctrostatic repulsion of the successive phosphate groups
T or F: Alternative stxrs for the DNA exist

What are they if true?
T

the usual Watson-Crick double helix is known as the B-form

A-form (similar to B but more compact; not found in living cells but is formed from the B-form in dehydrated cells

Z-form (which Zig-Zags in a left-handed helix that is more stretched out than other forms; small segments of Z-form DNA found in eukaryotic CHs)
How can you denature DNA strands without breakage of the phosphodiester bonds?
by heat, high pH, decreasing [salt], or exposing to a variety of chemical agents

How does low salt work? The backbones of DNA have a strong negative charge. The presence of cations (positive ions) in the solution helps to shield the negative charges of the two strands from each other. Low salt means no shielding cations, which can allow the negative charges on each strand's backbone to force them to separate.

High pH disrupts the hydrogen-bonding between the strands. These are the Adenine/Thymine and Guanine/Cytosine bonds that are responsible for holding the strands together. Disrupting them will allow the strands to drift apart.
Know the difference b/w renaturation and hybridization
Hybridisation generally refers to annealing two strands of nucleic acid that haven't been together before, but can also mean a certain procedure in which you use oligos or short DNA fragments to localize a complimentary DNA sequence. Re-naturing means to get two strands back together, which have been together before and have been denatured (generally by heat).
What is G0 phase?
a resting phase of interphase b/w G1 and S phase
T or F: DNA replication is semiconservative, bidirectional, and occurs at multiple origins/replication forks (eukaryotic)
T
What ATP-dependent enzymes unwind the DNA double helix during DNA synthesis?
helicases
In order to prevent extreme supercoiling of the parental helix, what enzymes are used to break and rejoin the DNA chain in DNA synthesis?
topoisomerases
T or F: DNA polymerases catalyze DNA synthesis
T
What are the 5 eukaryotic DNA polymerases?
α, β, δ, ε, and γ
What are the roles of each DNA polymerases below:
α, β, δ, ε, and γ
α and δ - involved in nuclear DNA replication

β and ε - used in repair of nuclear DNA

γ - is active in mitochondria
T or F: DNA polymerases copy the DNA template in a 3' to 5' direction and assemble the newly synthesized DNA in the 5' to 3' direction
T
What are the precursors for DNA synthesis?
deoxyribonucleoside triphosphates (dATP, dGTP, dCTP, dTTP)
What is pyrophosphate?
PPi (P2O74−)
What makes the DNA synthesis polymeration reaction irreversible?
when the remaining two phosphates (pyrophosphate) of the nucleotide triphosphate are hydrolyzed rapidly to yield 2 inorganic phosphates and cleavage from the monophosphate attached to the 3'OH of the DNA ladder
T or F: The DNA pols require an RNA primer since they can't initiate synthesis themselves
T
About how long is an RNA primer?
~10 nucleotides and is made by copying the parental strand using the enzyme PRIMASE
T or F: The leading strand is continuously made and is made TOWARD the replication fork
T
T or F: The lagging strand is made via discontinuous copying AWAY form the replication fork, and generates short fragments about 200 nucleotides called Okazaki frags
T
About how long are Okazaki fragments?
200 nucleotides
T or F: RNA primers are removed by nucleases and the resulting gaps are filled in by complementary deoxyribonuc using a DNA pol, then loose ends of the Okazaki frags are joined by DNA ligase which catalyzes the formation of phosphodiester bonds b/w 2 frag strands
T
T or F: Editing a base error in DNA synthesis is done via a 3' to 5' exonuclease activity of DNA pol
T
What are the four types of mutations, and which is the MOST COMMON type (need to know!!!!)?
Base substituition (most common); deletion, insertion, and triplet repeat expansion
T or F: DNA repair uses the undamaged sister strand as a template, as well as exonucleases, endonucleases, a DNA pol, and a ligase, thus accomlishing repair of a damaged DNA segment
T
Base excision repair
involves the use of specific DNA glycosylases to remove abnormal bases
Nucleotide excision repair
requires the removal of several nucleotides, not just a single bp; this type of repair requires ~10 diff proteins that scan the DNA, recognize a lesion, and remove a part of the damaged strand. DNA pol and ligase then fill the gap
Postreplication mismatch repair
DOESN'T recognize DAMAGE to DNA, but does recognize MISMATCHES (bases that do not match template), thus removes base mismatches and small insertions/deletions that result from errors in DNA replication
Direct repair
base modifications can be repaired directly w/o excision repair
CLINICAL CORRELATE of DNA repair:

Hereditary nonpolyposis colon cancer (HNPCC)
a common inherited colon cancer that is AD; involves a defect in genes normally fxning in DNA mismatch repair, thus this defect results in an accumulation of uncorrected mutations in DNA synthesis that eventually leads to cancer progression
CLINICAL CORRELATE of DNA repair:

xeroderma pigmentosum (XP)
a group of diseases with an AR inheritance pattern; results from defects in nucleotide excision repair system
About what percent of DNA in human genome is actually transcribed into RNA and then translated into protein?
2%
What kind of DNA are components of genes?
exons, intron, non-coding/junk regions
Where does TXN occur?
nucleus and mitochondria
What kind of pol is used in TXN?
RNA pol, which does not need RNA primers b/c it can initiate synthesis on its own
What are the precursors for RNA chains?

DNA chains?
ribonucleotide triphosphates (ATP, CTP, GTP, TTP)

deoxyribonuc triphosphates (dATP, dCTP, dGTP, dTTP)
What is the fxn of RNA pol 1?
to produce rRNA; it is found in the nucleolus; is RESISTANT to inhibition by the mushroom toxin (alpha-amanitin)
What is the fxn of RNA pol 2?
to produce mRNA and small nuclear ribonucleic proteins (snRNPs); found in the nucleoplasm; is STRONGLY inhibited by alpha-amanitin
What is the fxn of RNA pol 3?
to produce tRNA and 5S rRNA; also found in the nucleoplasm; inhibited by HIGH [] of alpha-amanitin
What is the fxn of mito RNA pol?
to transcribe RNA from the mito DNA; is inhibited by antibiotic (abx) rifampicin BUT NOT BY alpha-amanitin
What are the regulatory elements of eukaryotic genes?
promoters, silencers, enhancers
What is the fxn of promoter regions?
to bind TXN factors (i.e. proteins that bind RNA pol2); is necessary for correct orientation of RNA pol 2 on start site; contain a number of consensus sequences
What are the 3 types of consensus sequences and where are they found?
TATATAA box - located 25-30bp upstream from the start site; found in most protein-coding genes transcribed by RNA pol 2

CAAT box - ~70bp upstream from initiation site

GC-rich regions (GC boxes) - 40-100bp upstream
Know the diff b/w general and specific TXN factors
General - necessary for all genes

Specific - some, but not all, esp. responsible for control of cell growth and differentiation, tissue-specific gene expression, and the action of some lipid-soluble hormones (steroid hormones)
T or F: Enhancers and silencers are binding sites for regulatory proteins that can be either upstream or downstream
T
How many stages occur in TXN? And what are they?
4; Binding (when pol 2 binds at TXN bubble where short section unwinds), Initiation (involves the formation of first phosphodiester bond), Elongation, Termination
What is a TXN bubble?
the stxr containing the DNA, nascent RNA chain, and the RNA pol; it moves along the DNA chain ~50 nucleotides/sec
Which DNA strand is the template strand, i.e which is read by the RNA pol?
the antisense strand
How does RNA pol catalyze RNA synthesis?
by forming phosphodiester bonds b/w the selected ribonuc in the 5' to 3' direction
When does processing occur?
after TXN
What is the large, unprocessed, PRIMARY TRANSCRIPT made using RNA pol2 called?
heterogenous nuclear RNA (hnRNA)
What are the components of post-TXNal processing?
adding a 7-methylguanine (m7G) CAP to 5' end to protect RNA from nuclease digestion and helps align the mRNA during TLN; adding a 20-200 nuc polyA tail to 3' end to increase stability; splicing
What is the purpose of adding a 5' m7G cap?
to protect the RNA from nuclease digestion and to help align the mRNA during TLN
What is the purpose of adding a 3' polyA tail?
to increase stability
What is the purpose of splicing?
to produce a mature mRNA strand (and other RNAs) via connection of exons and removal of introns
Introns begin with the sequence __ __ and end with __ __, thus these are the splicing points
GU; AG
What is the fxn of snRNPs?
assist in cleavage and splicing process
T or F: hnRNAs contain from 0 to 50 or more exons that must be spliced to form a fxnal mRNA
T
T or F: After processing, the mRNA is transported from the nucleus to the cytoplasm
T
TLN occurs where?
on ribosomes in the cytoplasm with the aid of the RER
What are the two types of ribosomes?
free and RER ribosomes
Free ribosomes produce proteins that do what?
remain in the cell
RER ribosomes produce what kind of proteins?
integral memb. proteins; lysosomal proteins; and secretory proteins
What is the maximum number of different codon sequences that can be generated?
64 (4^3)
What does the statement "the genetic code is NEARLY universal" mean?
that the same codon specifies the same aa in all viruses, bacteria, and higher organisms; the exception is the mitochondria where a few differences occur (ex: UGA codes for tryptophan not termination)
What does degenerate mean?
redundant; an aa may have more than one codon that codes for it
T or F: The code is nonoverlapping in that the code is read continuously from start to stop
T
T or F: Mutations can be germline or somatic
T
Point mutations in TXN (base substitutions) are of two types. What are they?
transition vs tranversion

Transition - denotes a sub of a purine for a purine, or a pyrimidine for a pyrimdine

Tranversion - denotes the sub of a pyrimidine for a purine, or vice versa

FYI: the majority of pt mutations (2/3) are transitions
What are the 5 outcomes of pt mutations?
silent, missense, nonsense, regulatory, or RNA processing
What is a silent mutation?
when a base change specifies the SAME aa; no phenotypic change
What is a missense mutation?
when a base change specifies a DIFFERENT aa; can be either conservative or nonconservative missense mtuation: conservative - mutation results in no or mild effect on protein; nonconservative - mutation results in change of protein fxn
What is a nonsense mutation?
when the base change creates a STOP codon, and thus produces a premature termination of the growing polypeptide chain; leads to nonfxnal proteins that are unstable and readily degraded
What is a regulatory (TXN) mutation?
when the base change occurs in a regulatory sequence (promoter, silencer, enhancer, etc); thus level of TXN and mRNA production is altered (either inc or dec)
What is a RNA processing mutation?
when the base change affects the processing of the primary RNA transcript (hnRNA) - either the 5' cap, the 3' polyA tail, or splicing
T or F: Insertion and deletion mutations involve ONE OR MORE bases of the DNA
T
What is a trinucleotide repeat mutation?
involves an increase in the size of 3-nucl repeat sequences (~200 to 1000 times)

Disease ex: fragile X syndrome; Huntington disease; myotonic dystrophy
What are the 3 fxnal effects of mutations?
loss of fxn; gain of fxn; dominant negative
What is loss of fxn mutation?
fxn of gene product is reduced or completely absent
T or F: If a patient fxns more or less normally with a loss of fxn mutation in only one of the gene's 2 alleles, then the phenotype will be RECESSIVE
T

Ex: cystic fibrosis; sickle cell anemia
T or F: If a patient DOES NOT fxn normally with a loss of fxn mutation in only one of the alleles, then the phenotype will be DOMINANT
T:

Ex: poryphyrias
What is haploinsufficiency?
occurs when a diploid organism only has a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy of the gene does not produce enough of a gene product (typically a protein) to bring about a w+ condition, leading to an abnormal or diseased state; therefore is an example of INCOMPLETE or PARTIAL dominance; needs both alleles to be fxnal in order to express the w+
What is a gain of fxn mutation?
a mutation that leads to a gene product that has a new or abnormal fxn;

IMPT: these mutations usually result in AD inheritance patterns

EX: Huntington disease
Huntington Disease
Trinucleotide repeat mutation; AD inheritance pattern
What is a dominant negative mutation?
a mutation where the altered gene product interferes with the product of the normal allele; the phenotype in dominant negative mutations is either dominant or semi-dominant

Ex: osteogenesis imperfecta
What is the fxn of aminoacyl-tRNA synthetase?
catalyzes the activation and attachment of aa to their appropriate tRNAs
T or F: At least one enzyme and one tRNA exists for each of the 20 aa
T
Know this rxn for activation of aa:

aa + tRNA + ATP + H20 --> aminoacyl-tRNA +AMP + PPi
This is the activation step that is coupled to the hydrolysis of ATP and the formation of pyrophosphate, which drives the rxn forward and irreversible
What is the anticodon of the tRNA?
it consists of 3 bases that are antiparallel and complementary to the 3-nuc codon on the mRNA, thus is the site that binds to complementary codon of the mRNA
Describe the initiation complex of TLN
assembly of: met-tRNA; mRNA; 40S & 60S ribosomal subunits; initiation factors; ATP; GTP

FYI: ATP and GTP are hydrolyzed during initiation

ALSO: the 60S binds to the 40S subunit to form an 80S initiation complex
What are the 3 stages of TLN?
Initiation, elongation, termination
tRNA attaches to 2 sites on the ribosome. What are they?
P (peptidyl) site, where peptidyl-tRNA (tRNA with peptide chain) is attached

A (aminoacyl or acceptor) site, where aminoacyl-tRNA (tRNA with aa) is attached via the help of elongation factors and GTP
Where does Met-tRNA start?
in the P site
T or F: the formation of a peptide bond b/w Met in the P-site and the next amino acid in the A site is catalyzed by peptidyl transferase that is a part of the 60S ribosomal subunit
T
T or F: The peptidyl-tRNA in the P site becomes deacteylated, and thus dissociates from the complex. The newly formed peptidyl-tRNA in the A site, then moves to the P site and the ribosome moves over 3 nuc on the mRNA
T
Upon TLN termination, the 80S ribo subunit dissociates back into the __ and __ ribo subunits
40S; 60S
List the post-TLNal modifciations of proteins
Phosphorylation; glycosylation (carb chains added in the ER and Golgi); Hydroxylation; Disulfide bridges; Lysyl-lysyl bridges; Acetylation; methylation; and Trimming (cleavage of signal sequence/zymogen)
What are the 4 levels of Protein Synthesis regulation in eukaryotes?
At the gene level (loss, amplification, methylation, translocation)

At the level of TXN (histone role; TF; enhancers; inducers)

During processing and transport of mRNA (RNAi, miRNA, RNA editing, mRNA degradation, Differential splicing)

At the level of TLN (during initiation and elongation)
What is RNAi?
natural mech of silencing gene expression

In short, an enzyme called DICER is used to degrade the DS RNA into small segments of ~20 nucs. These segments then combine with an enzyme called RISC which uses the small segment to seek out and destroy mRNA with a sequence compl to the small segments

FYI: used for knock down expression and then see phenotypic changes that occur
What are miRNAs?
microRNAs that are 18-24 nuc long; found in introns of coding genes and in the introns and exons of noncoding transcripts

FYI: involved in differentiation, dvlpt, apoptosis

A single miRNA can target 100-200 different mRNAs, thus 30% of all genes may be under miRNA regulation

So far 500 miRNAs have been characterized
What is differential splicing?
when sequences are treated as introns by one cell but as exons in another
How does rifampicin inhibit TXN in prokaryotic RNA synthesis?
it binds tightly to bact RNA pol and acts as a bacteriostatic, not bacteriocidal
How does actinomycin D inhibit TXN in prokaryotic RNA synthesis?
by binding tightly to the DNA double helix
Name five inhibitors of TLN
Chloramphenicol - inhibits peptidyl transferase activity of 50S in prok

Cycloheximide - inhibits peptidyl transferase activity of 60S in euk

Erthryomycin - binds and blocks 50S in prok

Puromycin - binds to A site and block peptide elongation in both euk and prok

Streptomycin - binds to 30S and prevents TLN initiation
Know that there are many types of nonprotein encoding segments of the human genome
MORE on p38 in notes
T or F: Mito contain their own DNA (mt-DNA) in the form of 2-10 copies of DS DNA,, measuring ~16 kb in lenght
T
T or F: Mt-DNA differs from nuclear DNA in the following ways:

-Circular, rather than linear
-Mostly unique-sequence DNA rather than repetitive DNA
-transmitted by mothers
-TGA is used to code for Tryptophan, not a stop
-Codes for 13 proteins, 2 rRNAs. and 22 tRNAs
T
T or F: MtDNA mutations can lead to certain diseases of affecting the CNS and muscle
T
T or F: only mothers can transmit mt-DNA mutations, thus only daughters of an infected mother would transmit in subsequent generations
T
T or F: Each CH contains a single molec of DS DNA
T
Chromatin
DNA-protein complex
What are the 5 histones?
H1, H2A, H2B, H3, H4
Nucleosome
consists of a tightly bound package of 8 histones (2 each of H2A, H2B, H3, H4), with a DNA helix wound TWICE around

binds 146bps

packed tightly together by H1 to form a 30nm wide fiber, which then further loops via help of non-histone proteins
The p arm is short or long?
short (petite)
T or F: The 23 CHs are divided into 7 groups, arranged by size and position
T
Acrocentric
If the p (short) arm is so short that is hard to observe, but still present, then the chromosome is acrocentric
Submetacentric
If arms' lengths are unequal, the chromosome is said to be submetacentric
Telomeres
maintain stability and integrity of CH; protect from DNA degradation, end-to-end fusion, rearrangment, and chromosomal loss

Also serves as the molecular clock
Telomerase
a RT enzyme that synthesizes telomeric DNA and is normally inactive in most somatic cells; appears to be activated in ~90% of human cancers, thus it may be a useful tumor marker or Tx
What is X inactivation?
in a female somatic cell, most of the genes on one X CH is inactivated (inactive X CH). The other one is called active X CH; this process is random and not well understood (may be due to TXN inhibition, or methylation to maintain inactivation, or Xist and Tsix UTRs)

FYI: once x inactivn occurs in an embryonic cell, the same X CH remains inactivated in all of the progeny of that cell

Females are mosaics (half of cells have inactive Xpat CH or Xmat CH)

Involves most, but not all genes on the X CH
What is a Barr body?
is an inactive X CH that may be visible in an interphase cell as a condensed mass of chromatin
T or F: The inactive X CH replicates later in the S phase than the active X CH and autosomes
T
T or F: If a female has X-linked Recessive mutation (a carrier), she may express mutant phenotype if most of her cells happen to inactivate normal X CH
T
What is trisomy?
The presence of 3 rather than 2 CH copies; this is much less severe if occurs in sex CHs (X CHs) than if occurred in autosomal CH
What are the 2 types of epigenetic control mentioned in class?
X CH inactivation & genomic imprinting
What is genomic imprinting?
differential expression depending on whether mom or dad gave you gene; affects only a few genes
A deletion of the proximal arm of CH15 on the CH from father results in ___
Prader-Willi syndrome (PWS)
A deletion on CH15 but inherited by mom results in ___
Angelman syndrome
T or F: Uniparental disomy can result, thus if child inherits 2 copies of CH15 from mom and none from dad, then PWS can result; if 2 from dad and none from mom, then Angelman can result
T
What is the definition of euploidy?
means that the CH # per cell is an integral multiple of the haploid number, N=23

For example, a human cell has 46 chromosomes, which is an integer multiple of the monoploid number, 23. A human with abnormal, but integral, multiples of this full set (e.g. 69 chromosomes) would also be considered as euploid.
What is the karyotype formula of men? women?
men = 46, XY

women = 46, XX
What is diploidy?
the normal euploidic condition of 2N = 46 CHs
What are the methods of CH analysis?
Conventional CH analysis; FISH; Comparative genomic hybridization
What are the kinds of CH anomalies?
Numerical, Stxral, Mixoploid
What are some examples of numerical anomalies?
aneuploidy & polyploidy
What is aneuploidy and how does it occur?
when CH # is not a integral multiple of N (ex: trisomy - 3 copies of one CH)

usually due to non-disjuntion in meiosis and usually occurs in the mother, thus child gets one CH from dad and both CHs from mom

This usually is incompatible with survival
What is polyploidy?
is euploidic, but there is an addition of complete haploid sets of CH (ex: triploidy = 3N = 69)
Describe Down syndrome, trisomy 21

(karyotype formula 47, XX, +21
or 47, XY, +21)
INFANT has characteristic face (flat nasal bridge; Brushfield spots, protruding tongue, small ears, mental retardation, life expectancy of 50yrs)
What are Stxral CH anomalies?
like it sounds

ex: deletions, duplications, rings, translocation, inversions
T or F: Single gene alterations are aka Mendelian mutations, which display simple patterns of inheritance
T
Allele
alt forms of a gene at a given locus

most common allele at a locus is labeled w+
Locus
is the specific physical location of a gene on a CH. Since human CHs are paired, we have 2 alleles at each locus (except for the sex CHs)
Phenotype
genetic + environmental
pleiotropy
where a single allele expresses several diff phenotype features (ex: Marfan syndrome)
Phenocopy
environmentally caused trait that resembles Mendelian inheritance
epistasis
when one GENE masks or affects the phenotype of another GENE
If alleles at single locus are identical, this is called:
homozygous
If alleles at single locus are different (thus one normal and one mutant), this is called:
heterozygous
T or F: Heterozygotes are carriers
T
T or F: When loss of half of normal protein causes disease, the situation is referred to as HAPLOINSUFFICIENCY
T

b/c normal fxn may require more than 50% protein production
Haploinsufficiency vs Dom Neg
Know this
Dom Neg effect
when an abnormal protein interferes with the protein fxn of the normal allele
T or F: Dom and recess are phenotypic descriptions
T
What is a compound heterozygote?
like the name implies: 2 diff mutant alleles (compound) at one/SAME locus
what is a double heterozygote?
like the name implies: 2 diff mutant alleles at DIFFERENT loci
What are the criteria for AD traits?
-Vertical inheritance pattern (from generation to generation w/o skipping)
-Every affected child will have affected parent (direct transmission thru 3 generations is diagnostic of AD trait)
-both sexes are affected equally
-Father to son transmission is seen
-Expressed in heterozygote, but more severe in homozygote
What is the % chance each child will be affected by AD trait from Hetero mom and Homo dad?
50%
What is reduced penetrance? nonpenetrance?
reduced penetrance - refers to the expression of the mutant phenotype (all-or-nothing phenomenon); if less than 100%, then RP exists; ex: if only 85 of 100 heter express mutant phenotype, then 85% penetrance

nonpenetrance - when mutant allele is inherited but not expressed
What is variable expressivity?
refers to how or to what degree a particular allele is expressed; common in Dom disorders
What is codominance and what is a clinical example (hint: blood)
when a heterozygote displays the phenotypes of both homozygotes simultaneouosly (i.e. both alleles are expressed equally in heterozygote)

Ex: person homo for I(A) allele has type A blood; person home for I(B) allele has type B blood; person HETERO for I(A) and I(B) allele has type AB blood
what is incomplete dominance (aka semi dominance)?

Give an example
when hetero is INTERMEDATE to both homozygous genotypes

ex: carrying sickle-cell anemia allele:
T or F: AD disorders tend to involve genes that code for STRUCTURAL proteins and also tend to remain in populations if the Sx don't emerge until after the person has reproduced
T
What is anticipation?
when phenotypic changes get worse and quicker
Describe myotonic dystrophy
-AD disorder
-incomplete penetrance
-anticipation occurs
Describe Marfan syndrome
-AD disorder
-variable expressivity
-affects Connective Tissue (esp in skeletal system, cardiovascular, and occular)
AR inheritance
suspected in consanguineous (genetically related) parents

-horizontal inheritance pattern (i.e. disorder is found in a single grp of bros and sisters; not found in multiple generations)

-both sexes are affected in equal numbers

-affected individuals are almost always the offspring of normal heterozygotes (not homo)

-tend to be more severe and earlier onset than AD
T or F: Carriers are assumed to be unaffected
T
T or F: Most AR traits involve enzyme deficiency
T
T or F: X-link recessive is usually only observed in men b/c they are hemizygous
T
X-link Recessive
-suspected when several male relatives in the female line of a family are affected

-may or may not be expressed in females b/c of lyonization (aka X inactivation)

-there is no male-to-male transmission

-affected daughters are produced only by matings of hetero females with affected males
X-link Dominant
NO MALE-TO-MALE TRANSMISSION
Mitochondrial inheritance
-almost all mito DNA is maternally inherited

-pedigree should show that all children of an affected mother are also affected; all children of an affected father are normal

-variable expressivity

-mito diseases are commonly myopathies, neurologic syndromes, cardiomyopathies, and optic neuropathies
What is homoplasmy?


heteroplasmy?
homo-all mito have mutated mtDNA; so severe that embryonic dvlpt is prevented

hetero-both mutant and normal mtDNA are found in the mito; very severe; not manifested until adulthood
In probability, to calculate prob of getting outcome A AND B, you need to multiply
In probability, to calculate prob of getting outcome A OR B, you need to add
T or F: The Hardy-Weinberg Law measures allele and genotype frequencies in a population
T
T or F: A population is a local group belonging to the same species, within which mating can occur
T
T or F: The Hardy-Weinberg Law can be used to measure the freq of AD or AR alleles in a population
T
T or F: The Hardy-Weinberg Law can be used to estimate the freq of heterozygotes (carriers) in a pop
T
T or F: For X-linked recessive traits, the Hardy-Weinberg freq in females are the same as those for autosomal loci

However, in men, the freq of the genotypes will be the same as the freq of the alleles in the pop
T
T or F: Multifactorial (complex) disorders are the most common types of disorders
T
T or F: Polygenic = trait generated by combined action of many genes

Multifactorial = polygenic + ENVT
T
T or F: Most phenotypic differences among individuals are due to multifactorial inheritance (ex: height, color, intelligence)
T
Concordance rates in twins

Disconcordance
if both twins have disorder

if one twin has disorder, and the other doesn't
Concordance rates in monozygotic twins would essentially be ____%
100
How to calculate the theoretical risk of 1st degree relatives in multifactorial inheritance?
= square root of population incidence

FYI: the lower the pop incidence, the greater the relative risk for 1st degree relatives
What does this mean?
□==O
consanguineous
T or F: Most polymorphisms produce no clinical phenotype, and are useful as genetic markers
T