Genetics 2 Flashcards
structural variants: hb S vs Hammersmith vs Hyde/M vs Kempsey vs E
beta chain glu6val aa sub –> sickle cell anemia –> hemolysis vs beta chain phe42ser –> hemolysis vs beta chain his92tyr –> nonfxnal metHb reductase –> metHb can’t be Hb –> can’t carry O2 vs Hb has high affinity to O2 –> less O2 in tissue, erythrocytosis, GAIN OF FXN vs abnl RNA splicing –> MILD THAL
causes of alpha thal vs beta thal. which is more severe?
unequal crossing over –> single, triple gene complex vs imbalance in globin synthesis, point mutation > sm deletion. alpha thal more severe
locus control region (LCR). what happens if they’re deleted?
controls beta globin gene expression. complex beta-thal
Hereditary persistence of fetal hemoglobin (HPFH)
prevent perinatal switch from gamma to beta globin synthesis, clinically benign; caused by mutation in gamma gene promoter or beta gene cluster –> ectopic expression of HbF
monogenic traits/single gene dzs vs polygenic traits vs multifactorial inheritance vs chromosomal dzss
controlled by 1 gene vs 2 genes vs 2+ genes + environ vs mono/trisomy, translocations
multifactorial inheritance: qual traits vs quant traits
traits = absent or present vs continuous traits measured in a range
qual traits: relative risk ratio vs familial aggregation
= 1 –> no genetic impact, > 1 –> possible genetic impact vs clustering of certain traits, behaviors, disorders within a family
quant traits: correlation
r > 0 –> pos correlation –> genetics may play a role, = 0 –> no correlation –> genetics don’t play a role
concordance vs discordance vs heritability
when both twins have same dz; greater concordance = b/w MZ than DZ means strong genetic component involved vs when one twin has disease and the other does not vs variance caused by genetic factors of a specific trait in a pop; H2=1 –> strong genetic component, H2=0 –> no genetic component
risk factors of schizo
genetic predisposition and environmental stressor, closer genetic relative –> higher risk; DIGEORGE = INVOLVED IN 2% OF SCHIZO CASES
histone acetylation vs methylation
Histone acetyltransferases (HAT) add histones –> more euchromatin –> inc transcription, Histone deacetylases (HDAC) removes histones –> dec transcription; HDAC inhibitors increase transcription vs * Added to lysine or arginine residues –> different impacts on transcription; Writers add methyl groups (Histone methyltransferase), Erasers remove methyl groups (Histone demethyltransferase), Readers recruit writers and readers
DNA methylation
by DNA methyltransferases; DNMT1 maintains methylation patterns, DNMT3A & B are for de novo methylation
ex of histone tail mods
acetylation, methylation, ubiquitination, phosphorylation, deamination; each mod gives diff conseq –> histone code
histone variants
Proteins that substitute for core canonical histones in nucleosomes of euks –> specific structural and functional features
CCR5 gene
Encodes cytokine receptor found on cell surface of CD4 Th cells; Receptor = cofactor for HIV binding –> entry into T cells; Deletion in gene (ΔCCR5) –> frameshift mutation –> nonfunctional receptor –> immune to HIV; Only for homozygous individuals
4 ca classes: carcinomas vs sarcomas vs hematopoietic vs neuroectodermal
from epith tissue vs from mesen tissue vs from bone marrow, lymphatic system, peripheral blood vs C/PNS
driver vs passenger gene mutations
Directly initiate development and progression of cancer; if in critical driver genes –> initiate oncogenesis vs random mutations that are not recurrent in a particular tissue
chromosomal vs regional/subchromosomal mutation
mutation in intact chrm –> number of chrm changes vs Affect structure or regional organization of a chromosome
how can you get gene mutations?
from mutagens (chemical, rad, viral) or error in DNA repair
3 major mechanisms for ssDNA repair: nucleotide excision repair vs base excision repair vs mismatch repair
LOCAL distortions of DNA helix –> nuclear endonucleases recognize and cleave abnl chain on 3’ & 5’ side of distorted region –> short oligonucleotide w/ distortion = released –> gap in DNA –> DNA pol and ligase fill in gap (ex: repair pyrimidine dimers) vs DNA lesions involving base alterations or spontaneous loss –> specific glycosylases cleave base –> apurinic/pyrimidinic site (AP site) –> AP endonucleases recognize missing base and make endonucleolytic cut on 5’ side –> deoxyribose phosphate lyase removes the sugar/phosphate hanging out –> DNA pol and ligase complete repair vs non-dmged mismatched bases after DNA pol proofreading error/slip –> in euks: find nicks in strands and how Mut proteins interact w/ PCNA –> endonuclease cuts into strand –> exonuclease removes mismatched bases –> DNA pol and ligase complete repair
ca genomics vs exome seq vs gene expression microarrays
study of DNA-associated changes that accompany cancer; look for biomarkers representing abnormalities in epi/genome of cell prolif vs look for specific mutations in DNA coding regions vs look for gene expression signatures of a specific tumor
pharmacogenetics vs pharmcogenomics
study individual vs mult genes simult that cause efficacy or toxicity to drugs
xenobx
chemical not naturally produced or expected to be present in org –> body tries to get rid of it
results of drug metab in liver
inactive –> active
inactive –> toxic form
active –> inactive
active = excreted
active = toxic b/c can’t convert and accumulate
pathways for acetominophen
glucuronide or sulfate (95%), glutathione (5%), accumulate –> hepatotox
types of SADRs
lifethreatening, death, congenital, hosp, incapacitiy/disability
cyp2d6 vs cyp3a4/5 account for % cyp in liver?
2%, works on 25% drugs rxed vs 40%
phenocopying. example?
taking an inhibitory drug + CYP2D6 substrate –> alters apparent phenotype of the patient (make nml metab look like poor metab). tamoxifen + paxil –> CYP2D6 can’t convert tamoxifen to endoxifen
PT/INR
prothrombin time/int’l normalized ratio; measure time for blood to clot; phenotypic test; used for warfarin dosing
deletion vs insertion of homozygotes for ACE drugs
more vs less responsive to ACE drugs
ACE inhibitors
prevent conversion of angiotensin I to II –> narrow blood vessels –> release hormones to raise bp
G6P deficiency (G6PD)
inc sensitivity to antimalarial primaquine –> hemolytic anemia
mutation in butrylcholinesterase
dec enzyme activity –> can’t metab succinylcholine –> malignant hyperthermia –> ventilation
6-MP on TMPT activity in RBC
Low TPMT activity in RBCs –> high active agent TGN via HGPRT –> severe tox
High TPMT activity in RBCs –> reduced 6-MP
irinotecan has tandem rpts TATATA
6 rpts = nml
7+ rpts –> low expression –> low removal of active cmpd –> diarrhea, leukopenia
5-fluorouracil = prodrug to FdUMP, FdUTP, FUTP:
FdUMP inhibits thymiddylate synthase by ternary complex –> toxic, FdUTP and FUTP incorporate into D/RNA –> toxic
5-fluorouracil can be inactivated in liver by
dihydropyrimidine dehydrogenase (DPD); but if DPD deficiency –> high 5-FU –> toxic –> fatal
most common DPD variant
G>A transition in exon 14 in Caucasians
how to handle PKU? what are PKU sxs?
defect in PAH or BH4 –> Avoid phe, add tyr, add BH4. mental retardation, small head, stunted growth, eczema, sz, fair skin
ex of lifestyle adjustments
Porphyria min sun and alc
Hereditary pancreatitis avoid smoking and alc
Hereditary ca freq ca screen
Hemochromatosis blood letting
ex of diet restrictions
Maple syrup urine dz/branched chain ketoaciduria) –> remove leu, ile, val from diet
Glutaric acidemia –> low lys/high arg
Celiac dz –> avoid gluten
Galactosemia (NOT lac intol) = mutations in 3 enzymes of Leloir pathway –> avoid gal
PKU: Defect in PAH or BH4 –> Avoid phe, add tyr, add BH4
ex of replacement therapy
Congenital adrenal hyperplasia (CAH) give cortisone
Congenital hypothyroid give thyroxine
Homocystinuria give vit B6
Rickets give vit D
Hemophilia give clotting factor 8 for A, 9 for B
oDM insulin
ex of pharmaceutical management
Wilson’s dz penicillamaine, trientine
Factor V Leiden anticoag like warfarin
Crigler-Najjar syndrome Type II and Gilbert syndrome phenobarbital
in vivo vs ex vivo and its main challenge
direct delivery vs pt cells extracted –> cells = modified w/ virus –> viral DNA incorporated into genome –> cells producing good protein reintroduced into pt (one problem: how do you know if reintro cells populate body?)
barriers of in vivo vs ex vivo
How to target correct tissue?
How to avoid immune response?
How to know when change will take effect?
vs
What if DNA did not pick up new genome?
How to maintain sterility throughout process?
What happens if first time doesn’t work?
What if cells can’t grow outside of body?
Also includes in vivo barriers
spinal muscular atrophy
mutation in SMN1 gene + silent mutation in SMN2 gene –> destroy splicing enhancer and create splicing silencer –> skip exon 7 –> malfunctional protein
Hereditary transerythrin-mediated amyloidosis (hATTR)
misfolding of transerythrin in liver –> amyloid plaques –> dysfxn; onpattro has ds siRNA to reduce TTR prod –> no dysfxn
genetic (diagnostic) testing vs genetic screening
analyzing D/RNA, protein, analytes for dz-causing genes vs determine which individuals have higher risk factor for dz; NOT used to make dx but can guide you which diag tests to take; NEED TO BE HIGHLY SENSITIVE AND SPECIFIC
sensitivity vs specificity vs genetic screen
measures affected ppl –> high rate of true pos/low rate of false neg vs measures unaffected ppl –> high rate of true neg, low rate of false pos
CF
mutation in CFTR gene and most delta508; viscous mucus in lungs; auto rec
criteria for heterozygote test
cheap and dependable; no false pos/neg; genetic counseling = avail; accepted and voluntary participation of pop
Tay Sachs dz
mutation in HEXA gene; 1:30 carriers in Ashkenazi Jewish, declined 90%; destroys nerve cells in brain and spinal cord
indications for genetic counseling
previous child w/ birth defect, consanguinity, teratogen exposure, high risk pregnancy, hereditary condition, new dx of genetic dz
VUS/variant of unknown significance
effect of the specific genetic alteration is not known; insufficient genetic data
thalassemia vs structural variants
dec abundance in globin chains –> dec globin protein vs mutation that causes abnl aa seq of globins
hemolytic anemia vs altered O2 transport
d/t hgb tetramer = unstable vs inc/dec O2 affinity or formation of metHb
how is a zygote totipotent?
all its DNA = methylated; becomes pluri when some = unmethylated
genomic imprinting
epigenetic phenomenon causing genes to be expressed in parent of origin manner
allele freq vs genetic equil vs gene pool
% of allele in a pop vs concept that all allele freq = stable from generation to generation vs complete collection of all alleles in a pop
selection
mate for cont advantageous traits –> decline deleterious traits
HW asmptns
random mating in a large pop, no selection or migration, no mutation, allelic freq = constant
carcinogenesis
when nml cells become ca cells: nml –> prolif –> local invasion –> LN invasion –> distant metast
genes causing lynch syndrome/HNCC
mismatch repair genes: MSH 2/6, MLH 1, PMS2 –> microsatellite instability
imatinib
inhibits tyr kinase BCR-ABL1 protein –> tx CML (chrm 9-22 translocation)
nat’l newborn screens
sickle cell anemia, congenital hypothyroid, PKU, galactosemia
