Introduction to Genetics and Clinical Genetics Flashcards
Summarize the process of translation with all important enzymes.
1) RNA Pol binds to DNA.
2) Pol melts duplex DNA near transcription start.
3) Pol catalyzes phosphodiester link on 2 initial nucleotides and then advances down template strand 3’ to 5’ while synthesizing RNA 5’ to 3’
4) At transcription stop site polymerase releases DNA and RNA.
TFIID
Binds TATA box. Forms Pre-initiation complex.
TBP
TATA binding protein. Portion of TFIID that actually binds the TATA Box
TFIIB
Binds to PIC complex after TFIID
Core Promoter recognition sites and proteins.
TBP= TATA
TAF1 & TAF2= Inr
TAF6 & TAF9= DPE
Regulatory Promoter Sites
Regulatory= promoter Sites= GC, CCAAT
How does the mediator complex play a role in activation and repression?
Activation= Coactivators and UAS activate mediator which activates TFIID and CFD Repression= repressors inactivate mediator, UAS and activators. Mediator then inactivates TFIID and TBP
CTD
Carboxy Terminal Domain of RNA Pol. Plays 2 roles. Phosphorylation allows binding of RNA Pol to Core Promoter. Phosphorylation also allows the 7-MeG cap to use as a dock before capping RNA
Polyadenylation
The process of adding a PolyA tail via Pol(A) polymerase
PABPN1
Coats PolyA Tail. Stops synthesis at A x 200-300. trinucleotide repeat on this gene= oculopharyngeal muscular distrophy
5’ splice site is
G-GU
3’ splice site is
AG-G
mRNA splicing mechanism
two nucleophilic substitution reactions. catalyzed by the spliceosome= 300 proteins and several snRNPs
Lupus
Autoimmune disease. inflammatory symptoms due to autoimmune activity against snRNPs
zip code binding protein
attaches mRNPs to mRNA and motor proteins to move RNA to different regions of the cell for synthesis
modified scanning hypothesis
40s attaches. scans down 5’ to 3’ looking for AUG in proper context. ACCAUGG. when found 60s is recruited and complex begins translation
PABPI
Protein on Poly A tail which Regulates translation on 5’ end
tRNA role in translation
stacking. aminoacyl joins peptidyl +AA is stacked then converted to peptidyl
How do many antibiotics work?
inhibiting translation
Nonsense Mediated Decay
activates in RNA with premature stop codons. UTF2 binds UTF3 to form functional EJC. Complex bridges to ribosome and activates decay
Nonstop Decay
detects mRNA with no stop codon. Ribosome stalls on PolyA tail. PABPC1 flies off. either ski7 + degrades from 5 end or decapped and degrades 3-5
No Go Decay
degrades mRNA with no start codon. Dom34-Hbs1 binds to stalled ribosome and activates endonucleolytic cleavage and decay.
OPMD
Dysphagia, Dysphonia, Facial weakness, proximal limb weakness, 100% penetrant, autosomal dominant, trinucleotide repeat
Chromosome disorders
abnormalities in number or structure of chromosomes. not very common
single gene disorders
alterations in coding sequence produce effects on function of protein. Usually mendelian based
Mitochondrial disorders
separate genome. can be disrupted in the same way as nuclear DNA but only maternally inherited. passed in cytoplasm of ovum.
Multifactorial disorders
combination of genes + environment
Polygenic
many genes play a role
teratogenic
environment primarily
Mosaicism
more than one genotype
Imprinting
parent of origin different in expression
uniparental disomy
both chromosomes from 1 parent
unstable triplet repeats
develop by expansion of normally present trinucleoside repeats
Inheritance Patterns tools work for which kind of disorders
single gene disorders.
e.g. pedigrees ect,
karyotype
detects alterations in chromosome # and very large mutations
FISH
synthesized DNA is labelled and denatured then paired to control and patient chromosomes.
Comparitive Genomic Hybridization
patient DNA and control DNA dyed and put in wells. cannot detect small deletions or duplication
What do we use for small mutations?
sequencing. individual gene, exome, or whole genome.
What are replication errors and how do we fix them?
base mismatches and base insertion. we fix it with mismatch repair which repairs individual base pairs.
Explain damage from cell environment and how it is repaired.
acid and heat of metabolism. also O2 radicals. removes purines.
Uses BER
How does UV light damage cells and how does the cell fix it?
sunlight= creates DNA base adducts (cyclobutane dimers, 6-4 photoproduct). Direct repair via photolyase. NER.
Explain Ionizing Radiation and how do we fix it
xrays= single/ double strand bond breaks. Double strand breaks are repaired through homologous repair and end rejoining
Chemical exposure how does it happen and how do we repair it.
smoking, fossil fuel, foods. They create polycyclic aromatic hydrocarbons (PAH). heterocyclic amines.
What is interstrand crosslink repair?
It is a mechanism for repairing damage to one DNA strand. In G1 this takes the form of unhooking, translesion synth and then NER.
In S phase there is no need to unhook so it goes straight to NER or homology driven repair.
xeroderma pigmentosum
defect in NER. 1000x increased risk of skin cancer. mutation in one of 8 XP genes used in NER complex.
Ataxia telangiectasia
mutations in ATM gene which is required for homologous recombination. ataxia in infancy. telegiectasia in childhood. bulbar conjunctivae
immunodeficiency.
may progress to malignant
Werner syndrome
premature aging, mutation in WRN gene which unwinds DNA for HR and replication. They get old person diseases.
Bloom syndrome
mutation in BLM gene which codes for helicases like WRN. Also important in decatenation.
Skin sensitivity, narrow face, short, immunodeficiency, retardation, cancer risk.
BRCA1/ BRCA2 dependent inherited breast cancer
involved in homologous recombination repair, also ovarian and fallopian tumors.
Dominant Disorders
Marfans, Achondroplasia, NF1
Recessive Disorders
CF, PKU, most inherited metabolic diseases
What are some confounders to identifying causes in genetic disorders.
expressivity
consanguinity
de novo mutations
mosaicism
germline mosaicism
presence of more than one genetically distinct cell line
penetrance
% of people who carry a pathogenic variant who express the trait
Variable expressivity
traits vary between individuals who carry the gene mutation
Retinoblastoma mutation
Autosomal Dominant. 10% have no symptoms. retinal tumor. reduced penetrance. 2 hit hypothesis (Knudsens)
NF1
neurofibromatosis 1. cafe au lait macules. axillary/inguinal freckling. neurofibromas. lisch nodules (iris). bony lesions and tibial bowing. penetrance 100%, expressively variable, de novo in 50%
Marfans
Michael Phelps disease. FBN1 gene (fibrillin). Major criteria: dialated aortic root and ectopia lentis. Other: skeletal changes, dural ectasia. 25% de novo. some mosaicism.
Achondroplasia
most common form of short limbed dwarfism. complete penetrance. fibroblast growth factor receptor gene (negative regulator)= activation mutation= lower bone growth. fathers germline.
traits of autosomal recessive diseases
complete penetrance, heterozygous= 50% function, usually enough
early onset of symptoms
Sickle cell
Point mutation on HbS. HbS heterozygosity does seem to protect against malaria
CF
most common AR in Caucasians. sweat chloride test. infants= meconium ileus
infancy= fail 2 thrive, pneumonia
adults= azospermia, bronchiectasis.
PKU
inability to to process PHE. microcephaly, severe MR, epilepsy, variable expressivity, can pass maternally through placenta.
topoisomerase
slides down DNA unwinding superhelical turns
irinotecan
topoisomerase inhibitors are used in cancer chemotherapy
Pol A/primase
initiates DNA replication
DNA Polymerase gamma/ episilon
elongation
How does DNA Pol stay on DNA
beta clamp.
clamp= PCNA
brace= RFC
How does P53 affect DNA Pol
P53 to P21 to PCNA inactivation. inactivates DNA Pol
What controls the start of DNA replication
Origin of Replication Complex (ORC) binds to MCM helicase. inactivation happens when ORC binds to Cdc6
telomerase
enzyme that has RNA component. fills in 3’ overhangs on okazaki fragments. telomerase higher in dividing cells
How does DNA repair replication errors?
proofreading= 1/10^7 mismatch= 1/10^10
Lynch Syndrome
Heriditary Non-polyposis Colon cancer. inherited mutations in mismathc repair. MSH2 or 6. May be found by examining microsatellite instability. few polyps. very rare after 40 yrs.
What is Trans Lesion Synthesis
DNA damage that can be tolerated and bypassed during replication. replisome switches DNA Pol to one that “guesses” what base to insert. Cancer cells love it.
spontaneous abortions are caused by
60% defects, 40% normal. our of the 60 nearly half are trisomy.
Trisomy 21
Downs. 1/800 Live births. mainly nonfamilial. simian creases (not called that but i cant remember otherwise), upslant palpebral fissures, heart disease, otitis media, hypothyroidism. mostly nondisjunction. can also occur from robertsonian translocation
How does maternal age affect risk of abnormality
1/1215= Age 15 1/5= Age 50
Trisomy 18
Edwards. short sternum. digit abnormalities. round head. posterior rotation of ears. low hairline. high nasal bridge. semi-lethal= 10% survival rate past year 1.
Trisomy 13
Patau. Holoprosencephaly. heart defects (VSD). cleft lip/ palate. microcephaly. rocker bottom feet.
5p
Cri-du-chat. Cat like cry due to hypotonia and laryngeal abnormalities. growth restriction. microcephaly. moderate to sever intellectual deficit .
22q11.1 deletion
May manifest as Digeorge or Velocardialfacial. facial dysmorphology, slow growth, cleft palate. may have heart problems like tetralogy of fallot or aortic arch interrupt
Turner syndrome
in females. loss of second x. short stature. may have edema or webbing (webneck).
Klinefelter
XXY. can also include multiple x variants although this leads to mental deficits. normally found after Azospermia.
xxx,xyy
not syndromes typically. can have normal chromosomes
Williams (contiguous gene deletion syndrome)
puffy eyes, blue eyes, cocktail personality, aortic stenosis, hypercalcemia
WAGR
aniridia, wilms tumor, late onset kidney dysfunction, undescended testes
46, XY, female
46,XX, male
-SRY mutations where the SRY gene usually found on the Y gene may abnormally crossover and create variants.
