Exam 1 Concepts Flashcards
t or f: chronic diseases may consist of acute episodes
True
what disease is epstein barr virus linked to
mononucleosis
in chronic latent infection of EBV, how is it controlled?
it is controlled by the host immune system
what are post transplant lymphoproliferative disorders results of?
reactivation of latent ebv
what are the genetic programs realized by ebv?
Latency 1,2,3
t or f: ebv is found in all burkitt lymphomas and many ebv infected people have lymphomas
false: ebv is found in all burkitt lymphomas but many ebv infected people remain lymphoma free
what are ways to classify human disease according to genetics?
- chromosomal diseases
- single gene disorders
- polygenic (complex or multifactorial)
what are ways to find whether a certain disease has genetic components?
- use classical family study
- use twin studies
- use adoption studies
how does one conduct a classical family study?
- identify the family
- determine the proportion of the relatives affected
- calculate the lifetime risk
what is the relationship when describing the calculation of the lifetime expectation?
somewhat linear
what studies show greater risk to relatives of affected individuals than that of the population incidence?
family, twin, and adoption studies. This is due to genes being shared more with your relatives than a random stranger
what problem does using twin studies solve?
the problem of assigning the shares for genetic and environmental components
what is the rate of concordance in identical twins an important indicator of?
heritability
what is the concordance in genetic and environmental conditions for twins?
genetic conditios concordance is near 100% and environmental conditions it is never 0%
for multifactorial conditions, which has a greater concordance MZ or DZ?
MZ concordance is greater than DZ concordance in multifactorial conditions
what are the difficulties with twin studies?
- rarity of twins
- more concordant pairs of twins being enrolled in studies than discordant
- MZ twins often sharing environment more than DZ
how are difficulties of twin studies solved?
with the study of separated twins
how are adoption studies done?
- evaluating incidence of the disease in the biological relatives and adoptive relatives
- figure out relative importance of the genetic and environmental contributor
concerning human weight, genetic influences have an important role in determining what? what role does the family environment play?
genetics influences fatness in adults and family environment has no apparent effect
what human characteristics are inherited as normally continuously distributed?
weight, height , and skin color
T or F: heritability is the mode of inheritance
False: heritability is not the mode of inheritance, mode of inheritance is a fixed property of a trait but heritability is not
Pure environmental disease also could be viewed as what?
as determined by genes, such as having a pseudo lethal mutation causing trauma seeking behavior
what is the formula for total phenotypic variance?
Ve + Vg=Vp where Ve is the variance within identical genotypes, Vg is variance within identical environments and Vp is the total phenotypic variance
Liability to the condition is described as what?
as polygenic and normally distributed, if liability is above a threshold then they are affected
even in cases of dichotomous characters (diseases) inheritance could be what?
true polygenic
siblings of affected individuals cause the curve to shift in which direction?
to the right and have a higher average liability to the population mean and a greater proportion of them have liability exceeding the threshold so condition tends to run in families
what are the practical conclusions from the liability threshold model?
- as we get closer to the sick relative, greater the risk
- for someone who has more than one affected relative the risk are even greater
- for some characteristics, more severe the disease is in proband the stronger the risk is for the relative
- there is a difference in incidence of the disease between genders
t or f: we do not know what drives liability threshold model at the genetic level
True
t or f: cancers and common human disease have very few candidate genes
False, cancers and common human diseases have many candidate genes
how many gene players do monogenic disease typically have?
typically have more than one gene player
how much are rare and common diseases effected by genes?
rare disease are affected by genes alot, common disease are affected very little
what are the three ways to find CDCV genes?
- linkage analysis
- association studies
- linkage disequilibrium analysis
what are families linkage studies?
simple inheritance, single gene with major effect, and variant rate in the population
what is linkage analysis used for?
used for multi factorial disease
how is a linkage analysis done?
- get at least 200 affected sibling pairs and parents
- analyze with at least 300 polymorphic markers
- use gene hunter or mapmaker software to detect positional linkage
- identified areas are IBD or shared segments
how is linkage analysis done in many non related families?
done by using LOD score
what is the formula for LOD score?
LOD Score= (probability of obtaining the results assuming the two loci are linked)/ ( probability of obtaining the results assuming the two loci are not linked)
what is the odds ratio formula?
OR= (odds for minor allele carrier)/ (odds for non carriers) it can also be done as cross product as well
what are the reasons that an association between polymorphism and a complex disease may exist?
- the polymorphism is causative for the disease
- association is a false positive due to random chance
- polymorphism is associated because of some systematic biased in the biology, study, samples analysis
- polymorphism is in disequilibrium with the true causative allele
what are the methods for proving that the variant is causative for the disease?
- using indirect clues such as SNP in the promoter changing gene expression
- sherlock holmes method
how are genome wide association assays done?
- scanning the entire genome with a dense collection of genetic markers
- calculating association at each polymorphic marker along the genome
- identify regions which show significant associations
- study possible disease contributing genes from the linked region in functional assays
what is the evidence that alzheimers is genetic?
- if the a first relative has alzheimers then it is a 30% greater risk
- twin concordance rates are 30-80% MZ and 10-40 DZ
how is alzheimers inherited more than 99% of the time?
as a multifactorial disease
what are the genetic and environmental factors that contribute to alzheimers?
genetic factors are the genes like apo e4 environmental factors are: 1. head injuries 2. high BP 3. high cholesterol 4. heart disease 5. stroke 6. diabetes 7. smoking 8. engaging in active learning
patients with mutations in what genes will develop alzheimers earlier than those with PSEN1 and E3/E2 alleles?
PSEN1 and apo e4 allele
risk for AD after what is much greater in individuals with one or more apo e4 alleles?
severe head injury with loss of consciousness
what is normal plasma glucose?
3.9-8.3 mM
what is high plasma glucose bad?
- activates the protein kinase C beta
- glycation
- oxidative stress
- depletes NAD+ (metabolic pseudohypoxia)
hyperglycaemia induced activation of DAG PKC pathway leads to what?
vascular dysfunction in kidneys
what are some complications with a diabetic kidney?
- leaks proteins
2. high BP whcih always develops of worsens in diabetic neuropathy and can be the first abnormality to develop
what is diabetes 1 abbreviation?
IDDM for insulin dependent diabetes mellitus and is juvenile onset
what is the abbreviation for diabetes type 2?
NIDDM for non insulin dependent diabetes mellitus and is adult onset
diabetes type 1 consists of hypoinsulinemia that requires what?
insulin injections
diabetes type 1 that consists of an autoimmune disease part that does what?
beta cells are destroyed by T cells and several antibodies against beta cells are circulating
what are the diabetes type 1 risk factors from the environment?
- cow milk that leads to antibodies against cow insulin that resembles human insulin
- viral infection of mumps, rubella, and coxsackie
hyperinsulinemia and obesity is associated with which type of diabetes?
type 2
how would one describe the mode of inheritance of IDDM type 2?
very complex
what kind of disease is hirschprung disease?
oligogenic disease
what are the three kids of neural tube defects?
- spina bifida occulta
- meningocele
- myelomeningocele
what are the risks associated with elevated homocysteine levels?
- CAD
- peripheral arterial disease
- dementia
- having a child with neural tube defect
what is the hierarchy of risk when it comes to schizophrenia?
with the highest risk are identical twins > fraternal twins > children > siblings > parents
genes that make women more vulnerable to breast cancer appear to be protected against what?
bipolar disorder and schizophrenia
what is the relationship between schizophrenia, bipolar, and autism?
there is a strong positive correlation because they are caused by a common group of genes
predisposition to migraines has a strong correlation to what?
autism
Hep B and meningococcus overlap with what kinds of diseases?
neurological diseases like migraines, autism, and schizophrenia
your ancestry and your traits can be found typically how?
with the help of a DTC report
why are risk predictions from DTC so different?
because companies use differing sets of markers with moderate to high odds ratios
what are the types of mutations?
- point mutations
- regulatory point mutations
- alternative splicing point mutations
- deletions/insertions
- retrotransposition
- unstable repeat expansion
what happens in a nonsense mutation
a stop codon appears
what are the ways of damage control?
- mRNA with premature stop codons getting degraded
2. truncated proteins that are synthesized getting degraded in the ER
what are people with duffy negative phenotype resistant to?
p. vivax (malaria) invasion
what do human genes contain?
INTRONS
slippage of DNA replication leads to what?
deletions or insertions causing misalignment making a loop in the nascent strand and increase the repeat length. Same happens on template strand causing decrease of repeat length
what are the two possible outcomes for in frame deletions?
- is that protein is too short and doesnt fold and gets degraded
- protein comes out too short but still folds ok
what does unequal crossing over cause?
- disruption of the entire genome
- change gene structure
- produce fusion of genes
what does slippage probably cause?
an increase in the size of the triplet repeat
unstable repeat expansion causes what?
suppression of FMR1 gene and results in fragile X syndrome
what are the ways expanded repeats cause disease?
- repeats in the protein coding sequences make toxic proteins
- repeats in the RNA coding regions causes altered RNA function
- repeats in non coding regions cause reduced transcription or translation
what are the two kinds of functional classes of mutations?
loss and gain of function mutations
what kind of traits do loss of function mutations cause?
recessive
what is haploinsufficiency such as osteogenesis imperfecta aka brittle bone disease an example of?
loss of function causing a dominant trait
what are some dominant loss of function mutations called?
dominant negative or antimorphic mutations
by how much do mutagens increase mistakes?
increase mistakes by 100,000 or 1000 per replicated gene. mutations overload natural repair systems of the human genome
what are the different classes of mutagens?
- chemical
- physical
- biological
what are examples of of chemical mutagens?
- alkylating agents
- aromatic hydrocarbons
- intercalating agents (fluorescent dyes)
- artificial derivatives of DNA bases
what are physical examples of mutagens?
- ionizing radiation
2. UV radiation
what are biological examples of mutagens?
- viruses
2. transposable elements
what is point mutation in the biochemical view point?
deamination
what do many mutagens intercalate into?
DNA
UV exposure causes what?
thymine dimers, a specific damage
what are the steps to fix a thymine dimer?
- DNA glycosylase removes base
- AP endonuclease makes cut
- excision exonuclease removes stretch of DNA
- Polymerase synthesizes new DNA
- DNA ligase seals nick
what does lots of sun exposure do to our repair systems?
overloads it
what are the outcomes when the repair job introduces a wrong nucleotide leading to a point mutation?
- mutation in germline may be passed to an offspring (worst case scenario)
- mutation in somatic cell might lead to cancer (not good scenario)
- most cases mutations in somatic cells dont produce effect (best case scenario)
de novo mutations in germplasm leads to what?
- spontaneous abortion, 2. baby with genetic syndromes
3. nothing, baby inherits mutations towards evolution
de novo mutations in somatic cells leads to what?
- cell death
- improperly functioning cell
- cancer
- nothing happens, it never gets inherited and its lost in evolution
how often do mutations happen in the egg or sperm
rarely
mutations usually happen where?
in the germline cells which are the precursors of sperm and eggs
mutation rates for base substitutions is much higher in who?
males than in females and increases with paternal age
what is the rate of mutation in humans?
very high spontaneous mutation rate
how many new mutations does a new born have?
50-100 new mutations in their genome
what explains high frequency of conditions that causes reduced fecundity?
high frequency of de novo mutations
what is paternal age a strong contributor to?
to a number of de novo mutations per genome
PAE mutations provide selective advantage for who?
mutated cells through dysregulation of spermatological cell behavior by growth factor receptor RAS signal transduction pathway
what are the three scenarios for spermatological mutations?
- functionally neutral mutations
- typical PAE mutations
- intermediate scenario
what are the steps for identifying a causative de novo mutation?
- sequence the genome
- select only coding mutations
- exclude known variants seen in healthy people
- sequence parents and exclude their private variants
- look at affected gene function and mutational impact
what helped show the mutation rate in humans?
pseudogene resequencing (no selection)
what are the ways that point mutations occur?
- oxidation
- methylation
- hydrolysis
what are transitions?
when a purine is paired to another purine and pyrimidine is paired with another pyrimidine. Most common and due to tautomeric shifts or ionizing mispairs can happen
what are transversions?
when purine pairs with pyrimidine and vice versa. Pairing is energetically favorable but are possible
what other kind of mutation is in the same class as point mutation?
carcinogenic mutation
what kind of mutation is unlikely to awaken apoptosis and is more tolerable for cell reparation?
point mutation
what are the different rate of mutations in human genes?
- random gain
- forced gain
- very high rate
human lymphocytes can survive treatment with 6 thioguanine a poison if only what happens?
if only the HPRT gene is mutated
how are HPRT assays done?
- treating cells with 6 thioguanine
- counting colonies that survived
- if colonies remain then HPRT mutations, if no colonies then no mutation
classical HPRT assays in lymphocytes do not support any hypothesis explaining what?
explaining population variance of the mutational load
T or F: somatic mutation rates are the same as germline mutation rates
False, somatic mutation rates are different from germline mutation rates?
between somatc, germline and mitochondria, who has the highest rates of mutation?
mito mutation rates > somatic cells > germline
how is the extent of DNA damage measured in comet assays?
measured by the size and intensity of the tail produced from a single nucleus following electrophoresis
what happens in airways cell following exposure to whole smoke?
oxidative DNA damage
PAH’s polycyclic aromatic hydrocarbon derivatives do what?
bind and damage DNA
most syndromes caused by mutations in DNA repair genes cause what?
- progeria
- short life span
- cancer
syndromes connected to mutations in reparation related genes are associated with what?
an increase in cancer incidence
what is the modern concept of checkpoints?
several checkpoint genes such as ATR and Chk1 are essential for cell and organism survival
what are checkpoint pathways?
surveyors of occasional damage and integrated components of cell physiology
what do damage checkpoint pathways do?
- controlling cell cycel arrest
- activate DNA repair pathways
- activate different transcriptional programs
- induce apoptosis
- control telomere length
what are examples of repair requiring events being apart of the normal life of our body?
- stalled replication forks need to be removed during regular cell divisions
- DSBs in normal VDJ recombination
- repair in meiosis
- cells under high oxidative stress and long living cells need repair
ATM carriers develop breast cancer in response to what?
radiation since they have higher radiosensitivity and TB screens and mammograms are harmful as well
what kind of gene is ATM?
a true suppressor gene
