Week 2 Flashcards
What is the term for increased propensity for mutations, including DNA base changes and structural alterations, in the genomic DNA?
Genomic instability
Describe the differences between Exogenous and Endogenous genetic damage.
Exogenous: involved influences from our physical environment (e.g. UV light, ionizing radiation, or carcinogens)
Endogenous: involve unintended consequence for metabolic processes (e.g. oxidation, nitrosylation, or hydolysis of DNA strands, errors in DNA replication.)
What does UV light do to DNA?
Pyrimidine bases can absorb UV light to form abnormal covalent bond called Pyrimidine dimers. These dimers distort the structure of a DNA helix, because they bond with each other rather than their counterparts.
What effects do pyrimidine dimers have?
DNA lesions that create structural defects, such as pyrimidine dimers, interfere with nuclear processes such as transcription and replication.
What are two ways endogenous sources of DNA lesions can damage individual nucleotides?
Through methylation and oxidation
True/False: ROS (reactive oxygen species) can be created from endogenous sources (i.e. many enzyme-catalyzed reactions, the mitochondrial electron transport chain, Fenton reactions, etc.)
True
How are ROS created?
When O2 accepts an extra electron, it becomes a superoxide anion O2-, an ROS.
Because ROS’s are so reactive to DNA, what sort of damage can they do?
Altering the structure of individual nucleotides, introducing covalent bonds between strands, or severing phosphodiesterase bonds leading to strand breaks.
How can pyrimidine dimers be created and why are they significant?
UV light create pyrimidine dimers. If left uncorrected, they will interfere with DNA replication and transcription.
Somatic mutations are mutations affecting tissue that is not passed on to offspring. Name an example disease that is a somatic mutation.
McCune-Albright syndrome, disease affecting bone, skin, and several endocrine tissues.
Germline mutations affect tissue uniquely designed to produce sex cells. They are inherited. Would the mutation that exhibits cafe au lait spots on skin be considered a germline mutation?
Yes, Mutation in the NF-1 gene, results in a patient with neurofibromatosis type 1, where the patient will have changes in skin pigmentation.
What is the name of the type of repair where cells can attempt to repair damaged nucleotide bases without breaking the phosphodiester bonds that hold nucleotides together?
Direct repair
What is the name of the enzyme that can break pyrimidine dimers in photo reactivation?
Photolyase enzyme
Do human possess Photolyase?
No, only plants
When do humans use direct repair mechanism?
What is the enzyme used?
To address spontaneous methylation.
Enzyme: O6-methylguanine methyltransferase (MGMT) detects and removes methyl groups.
What sort of repair will occur if the damage is just on one strand of the helix?
Use the complementary strand as a template for repair.
What repair occurs if the damage affects only a single nucleotide?
Base excision repair! (BER)
3 type of base excision repair: 1) _____ 2) _____ 3) _____
1) Introduction of uracil into DNA during replication
2) Deamination
3) Depurination (where a nucleotide loses it base entirely)
How is the process of BER, initiated? Enzyme used?
DNA Glycosylase, recognizes the damaged nucleotide and removes its base, creating an AP (apurine/apyrimidine) site.
What if the DNA lesion involves more than one nucleotide?
Nucleotide excision repair (NER) “Remove and replace” mechanism. Instead of a single base, a stretch of nucleotides containing the lesion is removed during NER.
Which phase of the cell cycle does NER primarily occur in?
G1 Phase
What type of damage does NER repair, that photolyase does in plants?
Pyrimidine dimers
How does NER differ from BER?
NER can recognize a broader range of single-strand lesions and removes an oligonucleotide instead of excising a single nucleotide.
What about when incorrect bases are incorporated into newly synthesized strands, what protein recognizes this mistake?
“Mut” class proteins recognize the mismatch and recruit endonuclease. From there, mismatch repair follows a similar strategy as NER.
What cell cycle does mismatch repair occur in?
S phase
What are the two repair mechanisms a cell will try when both strands of DNA are severed?
1) Homologous recombination (HR): uses a homologous chromosome as a template to process the severed strands.
2) Nonhomologous end joining (NHEJ): mechanism that uses a special ligase complex to directly fuse the ends of two DNA fragments.
Why is HR preferred over NHEJ?
Because NHEJ connects any two severed strands it can find (i.e the strands don’t have to be homologous) it is error prone and can result in mutations.
How do HR and NHEJ differ?
What phases do they occur in?
NHEJ is error-prone; HR restores nucleotide sequence by using a template. HR primarily occurs during S and G2 phases; NHEJ can occur in any phase.
What is the enzyme that unzips the DNA during DNA replication?
DNA Helicase
What additional phase will the DNA go through if it is damaged?
Go Phase
Can DNA Polymerase fix its own mistakes?
Yes it can act as an exonuclease, to remove and replace.
What enzyme removes the damaged base in Base Excision Repair?
Glycosylases
How many chromosomes are included in a person’s genotype?
46 chromosomes
What term describes a specific location on a chromosome?
A locus (Loci: plural)
Can a variation in alleles result in a disease?
If so, what it is considered now?
Most allelic variation is NOT related to disease. However, if it does, the allele is considered a pathogenic variant.
Explain Wildtype alleles.
Alleles that encode genes that do not cause disease and result in an otherwise healthy individual.
Homozygote vs. Heterozygote: If each chromosome in a pair has:
Homozygote: the same allele
Heterozygote: different alleles.
What term is used to describe the physical expression of one’s genes?
A phenotype
True/False: If only one allele is necessary to produce the phenotype encoded by the allele, then the condition is dominant.
True
Males are _____ for genes on the X chromosome.
Hemizygous - Individuals with only one allele for a trait.
How many mutant alleles are necessary to result in a male that displays the phenotype of an X-linked disorder?
One, regardless of whether or not the disorder is recessive or dominant.
True/False: Individuals can be carriers of an autosomal dominant disorder.
False! Any person who has one dominant allele of an autosomal dominant condition will express the disordered phenotype.
Why are males not the carriers of X-linked disorders?
They only have one X chromosome and do not have another to compensate with a wild type allele.
Is there male-male transmission in an autosomal dominant pedigree?
Yes, an affected male can transmit an autosomal dominant disorder to male and female offspring alike.
What kind of disorder does Tay-Sachs come from?
Autosomal recessive disorder (Tay-Sachs: mutated hexosaminidase A leading to build-up of gangliosides within lysosomes.)
Do pedigrees of autosomal recessive disorders typically show affected individuals in every generation?
No, a key feature of autosomal recessive pedigrees is that they often do not show affected members in every generation.
Explain what Heterozygote advantage is in terms of Sickle Cell disease and malaria.
People who are heterozygous with one HbA allele and one HbS allele will rarely have symptoms of sickle cell disease, and they have a natural protection against the most severe symptoms of malaria.
In an X-linked dominant pedigree, how often will affected males produce affected females?
100% of the time
In an X-linked recessive pedigree, how often will affected males produce affected males?
Never; males do not transmit X-linked disorders to their sons.
Which of Mendel’s laws states that an organism’s gametes (sperm or egg cells) randomly receive one of their two alleles?
Law of Segregation
Mendel’s Law of independent assortment: Inheritance of one gene does not affect the ______ of inheriting any other gene.
Probability
The exception of the law of independent assortment is ______.
Linkage
In terms of crossing over chromosomes, what is Linkage?
The tendency for genes that near one another to cross over together and thus be inherited together during meiosis
Are genes that are closer together or father part more likely to be inherited together?
Closer, due to linkage
An exception to the law of Dominance: ______, the proportion of individuals with a certain genotype that express the associated phenotype. Give an example.
Penetrance:
Ex: Familial breast cancer caused by BRCA1 gene mutation. It’s autosomal dominant, however not everyone with a BRCA1 mutation develops breast cancer.
Another exception of law of Dominance: What is expressivity?
The extent to which individuals express a phenotype.
When a homozygous red snapdragon (RR) is bred with a homozygous white (WW) one, heterozygous offspring (WR) will be pink. What is the name of the dominance shown here?
Incomplete dominance
When somebody is heterozygous with both A and B alleles, both genes are expressed. So one gene is not dominant to the other, and these people will have red blood cells with both A and B antigens. What sort of dominance is shown here?
Codominance
What is a mutation that occurs after fertilization? This generates cells that are different in genetic composition from other cells in the body, and as the embryo grows, so do to cells that are different (multiply)
Mosaicism
True/False: Germline mosaicism occurs after development of primordial germ cells.
False, it occurs before or during development of primordial germ cells.
Does Germline or somatic mosaicism affect the mosaic individual’s offspring?
Germline
Does allelic or locus heterogeneity involve genes at different locations?
Locus heterogeneity.
What is the mitochondrial matrix?
Name of the lumen surrounded by the inner mitochondrial membrane.
How many genes comprise Mitchondrial DNA (mtDNA)?
37 genes
True/False: mtDNA also use Histones.
False
True/False: Mitchondria lacks certain DNA repair mechanisms, and so is more likely to damage by reactive oxygen species. (ROS)
True
Mitochondria divide by prokaryotic _______.
Binary fission
How does mtDNA differ from nuclear DNA?
mtDNA is circular, does contain histones, and has a higher mutation rate than nuclear DNA.
True/False: Mitochondrial inheritance is also termed maternal inheritance.
True
Heteroplasmy vs. Homoplasmy in terms of collection of mitochondria is what?
Heteroplasmy: some cells may receive some mitochondria with normal mtDNA as well as some mitochondria with mutated mtDNA.
Homoplasmy: cells that receive a uniform collection of mitochondria containing either all normal mtDNA or all mutant mtDNA.
Explain the threshold model of disease for mitochondrial diseases.
Mitochondrial disease becomes clinically apparent only once the number of affected mitochondria reaches a certain level. It takes into account, the 1) severity 2) Relative abundance of mutation 3) and reliance of an organ system on mitochondrial ATP.
True/False: Mitochondrial mutations primarily affect tissues with high energy demands.
True
What does the Hardy-Weinburg equation allow you to find?
The genotypes and allele frequencies of a population.
What is the Hardy-Weinburg equation?
p2 + 2pq + q2 = 1
Term describing the frequency of alleles changes in a given population purely due to random chance.
Genetic drift
Is genetic drift due to actions of individuals or random chance?
Random chance
Term describing the result of genetic variation among populations due to the migration of individuals from other populations.
Gene flow
Term referring to the desire for individuals to mate with others who are similar to them.
Assortative mating
What are the two general types of assortative mating?
Phenotypic and socioeconomic
What is the difference between the cell populations affected by germline and somatic abnormalities?
Germline abnormalities occur before fertilization, so all cells in a fetus will be affected. Somatic abnormalities arise from a somatic cell (not a sperm or egg precursor) and only affect a subset of the cells in the body.
What are Chromosomal translocations?
Rearrangements between segments of nonhomologous (chromosomes are entirely different) chromosomes.
A chromosomal translocation can be balanced or unbalanced. What is the difference between the two?
Balanced: the exchange between each chromosome is equal with no genetic information lost, genes are still functional.
Unbalanced: the exchange is unequal, and there is some extra or missing genetic material from the exchange.
The types of translocations are: 1) ______ 2) ______ and 3) _______.
1) Reciprocal 2) Nonreciprocal 3) Robertsonian
The type of translocation where two chromosome segments exchange places.
Reciprocal translocation
The type of translocation where a segment of one chromosome transfers or moves to another without “reciprocation” by a segment from the other chromosome.
Nonreciprocal translocation
Whether it be reciprocal or nonreciprocal translocation, what is often the end result?
One of the genes induces up regulation or overactivation of its newly neighboring gene.
What kind of translocation is the Philadelphia chromosome t(9,22)(q34,q11) translocation?
Reciprocal translocation
What is the correct notation for the translocation between chromosomes 8 and chromosomes 14? What is the name of the disease associated with this translocation?
t(8,14)
Burkitt lymphoma
Name two clinically important chromosomal deletion conditions.
1) Cri-du-chat syndrome
2) Williams syndrome
True/False: In the third type of chromosomal rearrangement, inversion generally do not present with any clinically significant abnormalities.
True
Which part of the cell cycle does Nonhomologous end joining mostly occur?
Since it does not require an intact homologous second strand, the pathway will happen during the G0 or G1 phases of the cell cycle.
When is Karyotyping actually done?
It’s a snapshot of chromosomes during mitosis because that’s when the chromosomes are the most condensed and most visible.
Two type of trisomies: 1) _____ and 2) _______
1) X/Y 2) Autosomal
True/False: A Robertsonian translocation can lead to trisomies in offspring.
True
A Robertsonian translocation occurs between two _____ chromosomes.
Arcocentric (meaning one very short p arm relative to a q arm)
What would the notation look like for a Robertsonian translocation?
t(13,21)
What kind of chromosomes are commonly involved in Robertsonian translocations?
Acrocentric chromosomes
What are the three most common trisomy syndromes that compatible with life?
Down Syndrome (Trisomy 21), Edwards Syndrome (trisomy 18), and Patau Syndrome (Trisomy 13)
With Down Syndrome, where does the majority of nondisjunction occur?
In Meiosis I.
Down Syndrome, Edwards syndrome, and Patau syndrome can all present with abnormal findings involving the hands. What are they?
Down Syndrome = single palmar crease
Edwards syndrome = overlapping fingers
Patau syndrome = polydactyly
In general, there are 3 purposes of the immune system, the 3 categories:
1) ______
2) ______
3) ______
1) Defense against pathogens
2) Defense against malfunctioning cells
3) Clean up of old tissue to facilitate growth.
Out of the two branches of the immune system, which branch characterized by slower but more targeted responses? (Also known for holding a grudge ;)
The adaptive immune system
What are the two arms of the immune system?
The innate and adaptive immune systems
Which organ produces the key portion of the innate immune system?
The liver
What is the first layer of defense for the innate immune system?
Physical barriers, such as the skin and epithelial layers.
The adaptive immune system can further be divided into two branches: 1) _____ and 2) ______
1) Humoral and 2) Cellular
Which of the two branches of adaptive immunity, do B cells initiate?
Humoral immunity
Which of the two branches of adaptive immunity do T cells initiate?
Cell-mediated immunity
True/False: The hallmark of T cells is that is signals cellular production of antibodies.
False, it signals cellular apoptosis.
Which cell types are included in the cell-mediated adaptive immune response?
Helper T cells, cytotoxic T cells, regulatory T cells, and memory T cells
Which cell types are included in the Humoral immune response?
B cells, Plasma cells, Antibodies
The cellular adaptive immune system contains ___ cells that modulate the immune system, ____ cells that directly attack cells, and ______ T cells that downregulate the immune response of CD4+ and CD8+ cells.
CD4+, CD8+, regulatory
_____ of the innate immune system destroy pathogens using cytoplasmic granules or oxidative burst.
Neutrophils
Immunologic memory is a feature of the (adaptive/innate) ____ immune system.
Adaptive
CD8+ T cells only kill the body’s own cells that present antigens on ____ molecule on the cell’s surface.
MHC type I
_____ cells destroy pathogens and break up its proteins into short amino acid chains to present to T-helper cells.
Dendritic cells
Monocytes migrate into tissues and differentiate into _____ which remain in tissues and aren’t found in the blood.
Macrophages
Clonal deletion is when most of the clonally expanded cells of the ____ immune system die off after the infection is over.
Adaptive immune system
The _______ cells develop into cells of the innate immune system like neutrophils, eosinophils, mast cells, macrophages, etc.
Myeloid progenitor cells
_________ cells are large lymphocytes that target cells infected with viruses and cancer cells.
Natural Killer cells
Where does the immune response begin in the body?
Bone marrow –> produce lots of neutrophils –> phagocytosis
Is it acidic inside the Phagolysozome?
Yes, from acidic granules
Antigen Presentation are done by which immune cells?
Dendritic cells, macrophages, Monocytes
Are all lymphocytes able to travel in and out of tissue and bloodstream?
Yes
Antibodies are generated in the (white/red) pulp of the spleen.
White
Most of the lymph is drained into the ______ which returns the lymph into circulation via the junction between the left jugular and subclavian vein.
Thoracic duct
Lymph from the right arm, chest, and side of the head is drained into the (lymphatic vessel): ______
Right lymphatic duct
What do lymphatic vessels do?
Collect interstitial fluid and return it to the blood.
Does the lymphatic system utilize pumps to push the lymph through?
No, rather they use the pushing of the arteries and muscle movements.
Fatty acids are packaged into _____ in the small intestine, and since they are quite large, they go into lymphatic vessels called _____.
Chylomicrons, Lacteals
Can Dendritic cells be found in the lymph nodes?
Yes, where can meet collected pathogens.
The two main microbial factors that trigger inflammation are: 1) ______ and 2)_______.
1) Virulence factors
2) Pathogen associated molecular patterns (PAMPs)
The endogenous equivalent to PAMPs is _______.
DAMPs: damage associated molecular patterns
The 2 types of immune cells that typically initiate inflammation are 1)____ and 2)_____.
1) Macrophage
2) Mast cells
How are these patterns (PAMPs and DAMPs) recognized?
By Pattern Recognition Receptors (PRRs)
How do Neutrophils find the site of infection and inflammation?
Adhesion proteins, attraction to Chemokines and microbial products at the site.
What is Angiogenesis triggered by?
Growth factors released by macrophages
______ are the first leukocytes recruited during the acute inflammatory process.
Neutrophils
In the classic pathway, complement proteins are activated in the presence of ______.
Antibodies bound to pathogens.
The T-cell Receptor (TCR) comprises two transmembrane proteins 1)___ and 2)___ chains, and they are linked together by a _______.
1) alpha and 2) beta chains
Disulfide bridge.
What other receptors aids the TCR in sending a signal downstream?
CD3 receptors
The generation of antigen receptors in T cells occurs through a unique mechanism of _______.
Genetic recombination
True/False: MHC genes from each parents are codominantly expressed.
True
What accounts for the variability of MHC molecules among individuals?
There is great degree of variability in the alleles (gene variations) of the MHC genes among individuals inside a population.
MHC I molecules vs. MHC II molecules. Which presents itself on “professional” antigen-presenting cells, including dendritic cells?
MHC II molecules
Which type of T cell do each (MHC I and II) present to?
MHC I = CD8+ cytotoxic T cells
MHC II = CD4+ helper T cells
Which MHC molecule type would present viral antigens, and which co-receptor would be immediately involved in the immune response?
Because these are intracellular pathogens, MHC I molecules would present these antigens to CD8 T cells, which express the CD8 co-receptor.
MHC II molecules are a family of molecules found only on _________ such as dendritic cells, mononuclear phagocytes, and B cells.
Antigen-presenting cells
Antigen peptides are processed in the _______ before being loaded onto MHC I.
Rough endoplasmic reticulum
MHC I molecules present endogenously synthesized antigens (eg. viral or cytosolic proteins) to ____ T cells.
CD8+
MHC I molecules are associated with the _____ protein.
Beta-2-microglobulin
MHC II molecule are associated with the _________ loci.
HLA-DP, HLA-DQ, HLA-DR
MHC I molecules are associated with the _______ loci.
HLA-A, HLA-B, HLA-C
Where do Dendritic cells reside primarily?
In tissues that are in contact with the external environment (eg. skin, GI tract, and respiratory tract)
How are dendritic cells unique among antigen-presenting cells?
Dendritic cells are the only APC that can activate a naive T cell.
In APCs they bind _____ inside the cell and migrate with it to the cell surface, where the complex can interact with _____.
Antigen, T-cells
How is it determined which pathway (endogenous/exogenous) is followed?
Location of the pathogen! As intracellular or extracellular.
What is the name of the small protein that signals for degradation in the MHC I pathway?
Ubiquitin
Where is the antigen loaded onto MHC II?
The antigen is loaded onto MHC II in the endolysosome.
Activation of naive T cells (whether CD4 or CD8) is done by _______, making these cells the key to early T-cell differentiation.
Dendritic cells
Activation of memory T cells, is mostly done by _____ and ______.
B cells and macrophages
Cytotoxic T cells are also sometimes activated in response to exogenous pathogens even though Cytotoxic T cells only recognize MHC I. How does this happen?
Cross-presentation
Some dendritic cells have the unique ability to load exogenous pathogens onto MHC I proteins for presentation.
____ is an RER transporter protein that transports viral peptide fragments into the RER for loading onto MHC I.
TAP - Transporters of Antigenic Peptides (see Goodnotes MHCI and MHCII)
Which double strand damage fixation involves Rad 51?
Homologous Recombination
